@article {pmid40510202, year = {2025}, author = {Li, L and Lv, L and Wang, Z and Liu, X and Wang, Q and Zhu, H and Jiang, B and Han, Y and Pan, X and Zhou, X and Ren, L and Chang, Z}, title = {From copper homeostasis to cuproptosis: a new perspective on CNS immune regulation and neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1581045}, pmid = {40510202}, issn = {1664-2295}, abstract = {Copper, an essential trace element for the human body, plays a key role in energy metabolism, mitochondrial respiration, redox reactions, and neural signal transmission. The recently proposed concept of "cuproptosis" has further revealed the unique status of copper in cellular regulation: when copper abnormally accumulates within cells, it can directly bind to the lipoylated proteins of the mitochondrial TCA cycle, triggering protein aggregation and metabolic disorders, ultimately leading to cell death. This form of cell death plays an important role in various neurodegenerative diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and stroke. This review summarizes recent research on the mechanisms of cuproptosis, providing new perspectives and a theoretical basis for understanding the pathogenesis of these neurodegenerative diseases.}, }
@article {pmid40509360, year = {2025}, author = {Chang, B and Huang, J and Xie, Q and Ruan, Y and Liu, R}, title = {Identification, Geographical Traceability, and Thermal Oxidation and Photodegradation Studies of Camellia Oil Based on Raman Spectroscopy.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {11}, pages = {}, doi = {10.3390/molecules30112473}, pmid = {40509360}, issn = {1420-3049}, support = {2024KY0802, 2023KY0217,XJ21KT29//the Middle-aged and Young Teachers' Basic Ability Promotion Project of Guangxi，The Guilin University of Aerospace Technology School Fund/ ; No. AD25069073//Guangxi Science and Technology Program Project/ ; }, mesh = {*Spectrum Analysis, Raman/methods ; *Plant Oils/chemistry/analysis ; *Camellia/chemistry ; Oxidation-Reduction ; Photolysis ; Carotenoids/chemistry/analysis ; Temperature ; Least-Squares Analysis ; Discriminant Analysis ; }, abstract = {Camellia oil, rich in monounsaturated fatty acids, squalene, tocopherols, and polyphenols, is highly valued for its nutritional benefits. However, its high market value and regional variations have led to frequent adulteration, highlighting the need for rapid, non-destructive methods for authentication, geographical traceability, and quality assessment. This study employed portable Raman spectroscopy combined with Partial Least Squares Discriminant Analysis (PLS-DA) and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to differentiate camellia oil from other edible oils and evaluate its thermal and photo-oxidative stability. PLS-DA, based on VIP-selected spectral variables, effectively distinguished camellia oil, with Raman bands near 1250 cm[-1] and 1650 cm[-1] contributing significantly. A unique peak at 1525 cm[-1], observed in samples from Gongcheng, Guangxi, was associated with carotenoids and served as a potential marker for geographical traceability. MCR-ALS modeling revealed significant reductions in the 1650 cm[-1] and 1525 cm[-1] peaks when temperatures exceeded 150 °C, indicating degradation of unsaturated fatty acids and carotenoids. Under UV exposure, the 1525 cm[-1] peak declined sharply and nearly disappeared after 24 h, suggesting rapid carotenoid degradation via photooxidation. Extended UV treatment also affected the 1650 cm[-1] peak and led to oxidative product accumulation. Overall, this study demonstrates the feasibility of integrating Raman spectroscopy with chemometric analysis for efficient oil classification, traceability, and stability monitoring, offering a valuable tool for food quality control and market supervision.}, }
@article {pmid40508048, year = {2025}, author = {Tolochko, C and Shiryaeva, O and Alekseeva, T and Dyachuk, V}, title = {Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms and Treatment Strategies (Part 2).}, journal = {International journal of molecular sciences}, volume = {26}, number = {11}, pages = {}, doi = {10.3390/ijms26115240}, pmid = {40508048}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/drug therapy/metabolism/therapy/etiology/pathology ; Humans ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/pharmacology ; Motor Neurons/metabolism/pathology/drug effects ; Glutamic Acid/metabolism ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with damage to motor neurons and leading to severe muscle weakness and, eventually, death. Over the past decade, understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy.}, }
@article {pmid40507679, year = {2025}, author = {Zhou, Y and Ni, Y and Lan, L and Wan, H and Luo, F}, title = {Association Between Allostatic Load and Delirium in ICU Patients: A Retrospective Analysis of the MIMIC-IV Database.}, journal = {Journal of clinical medicine}, volume = {14}, number = {11}, pages = {}, doi = {10.3390/jcm14113916}, pmid = {40507679}, issn = {2077-0383}, support = {82300118//National Natural Science Foundation of China/ ; }, abstract = {Background: Allostatic load reflects the cumulative physiological effects of chronic and repeated stress on the body and is associated with dysregulation of multiple systems. This study aimed to examine the association between the allostatic load score (ALS) and the development of delirium in intensive care unit (ICU) patients. Method: The adult patients from the Medical Information Mart for Intensive Care (MIMIC-IV) database were screened and included in this study. Allostatic load was scored by hemoglobin A1c, high-density lipoprotein, total cholesterol, systolic blood pressure, diastolic blood pressure, body mass index, C-reactive protein, and serum albumin, and varied from 0 to 8. Restricted cubic spline and multivariate logistic regression were used to assess the relationship between ALS and delirium risk in the ICU. The threshold of the ALS was determined by the decision tree approach. A sensitivity analysis was also conducted. Results: A total of 656 patients were included in the study, and the incidence of delirium was 50.6% (n = 332). In a fully adjusted restricted cubic spline model, an increase in ALS was linearly positively correlated with the occurrence of delirium in the ICU (p-overall = 0.039, p-nonlinear = 0.506). The threshold for ALS was determined to be 3. ALS ≥ 3 was associated with increased delirium rates (p < 0.001), longer hospital stays (p < 0.001), and higher in-hospital mortality (p = 0.002). Subgroup analyses revealed no significant interactions (all p values for interactions > 0.05). Conclusions: Higher ALS was linearly associated with increased risk of ICU delirium. An ALS ≥ 3 identified patients with greater delirium incidence, longer hospital stays, and higher mortality.}, }
@article {pmid40506843, year = {2025}, author = {Ashford, BA and Simpson, JE and Dawson, C and Boche, D and Cooper-Knock, J and Heath, PR and Fillingham, D and Appleby-Mallinder, C and Wei, W and Dunning, M and Highley, JR}, title = {Human amyotrophic lateral sclerosis/motor neuron disease: The disease-associated microglial pathway is upregulated while APOE genotype governs risk and survival.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {}, number = {}, pages = {e70019}, doi = {10.1111/bpa.70019}, pmid = {40506843}, issn = {1750-3639}, support = {//Bruker Spatial Biology/ ; //British Neuropathological Society/ ; //Pathological Society of Great Britain and Ireland/ ; }, abstract = {A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post-mortem frozen and formalin-fixed paraffin-embedded specimens from human sporadic ALS/MND and control cases using the nCounter® Neuroinflammation Panel. Archival data were reanalyzed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord and motor cortex and validate changes found during transcriptomic analyses. In the spinal cord, marked inflammation was observed, while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted TREM2, TYROBP, APOE, and CD163, as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity and involvement of TREM2, ApoE (encoded by APOE), and TYROBP were confirmed, suggesting the involvement of the disease-associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the APOE variant and ALS/MND risk, age of onset, and survival. We find confirmed associations between APOE ε3/ε3 and disease and between ε2/ε2 and absence of disease. Further, ε4/ε4 appears to be associated with earlier disease onset and a more aggressive course. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.}, }
@article {pmid40506548, year = {2025}, author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Miller, LM and Hochberg, LR and Brandman, DM and Stavisky, SD}, title = {An instantaneous voice-synthesis neuroprosthesis.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {40506548}, issn = {1476-4687}, abstract = {Brain-computer interfaces (BCIs) have the potential to restore communication for people who have lost the ability to speak owing to a neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech, such as prosody and immediately hearing one's own voice. Here we demonstrate a brain-to-voice neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real time to change intonation and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.}, }
@article {pmid40505784, year = {2025}, author = {Tang, J and Kang, Y and Chen, Q and Zhang, B and Shang, N and Lan, J and Wu, L and Peng, Y}, title = {TIMP1 inhibits Rac1-mediated ROS production to ameliorate blood-spinal cord barrier disruption in amyotrophic lateral sclerosis.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106987}, doi = {10.1016/j.nbd.2025.106987}, pmid = {40505784}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of motor neurons, for which therapeutic strategies and pharmacological interventions remain limited. Disruption of the blood-spinal cord barrier (BSCB) has been identified as a significant factor that may exacerbate motor neuron damage. Tissue inhibitor of metalloproteinase-1 (TIMP1), a molecule known for its dual roles in inhibiting matrix metalloproteinase (MMP) activity and exerting cytokine-like effects via receptor interactions, has been demonstrated to ameliorate endothelial barrier damage in various diseases. Here, we explored the potential of TIMP1 to restore BSCB integrity as a strategy to slow the ALS progression. Specifically, the expression of TIMP1 or its mutant variant AlaTIMP1, which lacks MMP-inhibitory activity, in spinal cord microvascular endothelial cells (SCMECs) prior to disease onset significantly reduces BSCB leakage in mice with ALS, thereby alleviating motor function deficits and delaying disease progression. Additionally, TIMP1 expression restores the expression of junctional complexes in SCMECs, as demonstrated in both in vivo and in vitro ALS models. Mechanistic studies revealed that TIMP1 suppresses ALS injury-induced integrin β1 activation independent of MMP inhibition, blocking downstream Rac1 translocation to the membrane to form a complex with NOX2. The inhibition of NOX2 activity reduces ROS-induced cytoskeletal remodeling, consequently stabilizing overall junctional alignment and preserving the BSCB integrity. Overall, our findings elucidate an MMP-independent mechanism through which TIMP1 regulates BSCB integrity in ALS context, suggesting that TIMP1 could serve as a novel tool for the treatment of ALS, particularly for prophylactic treatment in patients with familial ALS.}, }
@article {pmid40504748, year = {2025}, author = {Andersen, TM and Conde, B and Vollsæter, M}, title = {Seeing in Synchrony: Toward Personalized Noninvasive Ventilation in Amyotrophic Lateral Sclerosis Through Dynamic Upper-Airway Visualization.}, journal = {Respiratory care}, volume = {}, number = {}, pages = {}, doi = {10.1089/respcare.13193}, pmid = {40504748}, issn = {1943-3654}, }
@article {pmid40504265, year = {2025}, author = {Torres-Villaros, H and Streho, M and Hoa, D and Giocanti-Aurégan, A}, title = {STARGUS: a comparative study of a new swept-source biometer and B-mode ultrasound in dense cataracts.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {}, number = {}, pages = {}, pmid = {40504265}, issn = {1435-702X}, support = {IIT #69445453//Alcon/ ; }, abstract = {PURPOSE: This study aimed to compare a new swept-source biometer to the gold standard B-mode ultrasound biometer for measuring the axial length (AL) when standard optical biometers failed due to cataract density.<br><br>METHODS: Patients with advanced cataracts whose AL could not be measured using optical biometers available in our clinics, including the Lenstar LS-900 and IOLMaster 500 and 700, were included. The AL, anterior chamber depth (ACD), and lens thickness (LT) were measured using a new swept-source biometer (SSB) (Argos[&#xae;], Alcon) and B-mode ultrasound. The Enhanced Retinal Visualization (ERV) mode of the new SSB was used when the standard mode did not provide reliable AL measurements.<br><br>RESULTS: AL measurements failed in 183 eyes due to cataract density using available biometers. The new SSB allowed successfully measuring the AL in 89.6% of cases, and the ERV mode was needed in 15.8% of eyes. The ALs measured with the new SSB and B-mode ultrasound were comparable, with an excellent intraclass correlation coefficient (ICC) of 0.99. No significant differences in ACD measurements were observed between new SSB and ultrasound or conventional biometers, with ICC of 0.81 and 0.87, respectively. However, the LT tended to be thinner with the new SSB compared to ultrasound, suggesting a potential source of error, but no significant difference was observed with conventional biometers (ICC of 0.88).<br><br>CONCLUSIONS: The new SSB Argos[&#xae;], in particular when the ERV mode is used, could be a reliable alternative to B-mode ultrasound for measuring AL in eyes with dense cataracts. It is as effective as ultrasound in measuring the AL, and it could help to improve cataract surgery planning and outcomes.}, }
@article {pmid40504117, year = {2025}, author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC}, title = {Visualizing nuclear pore complex plasticity with pan-expansion microscopy.}, journal = {The Journal of cell biology}, volume = {224}, number = {9}, pages = {}, doi = {10.1083/jcb.202409120}, pmid = {40504117}, issn = {1540-8140}, support = {R01 NS122236/NH/NIH HHS/United States ; F31 HL158119/NH/NIH HHS/United States ; R01 GM129308/NH/NIH HHS/United States ; R35 GM15374/NH/NIH HHS/United States ; 2420904//National Science Foundation/ ; }, mesh = {*Nuclear Pore/metabolism/ultrastructure ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; C9orf72 Protein/genetics/metabolism ; Nuclear Envelope/metabolism ; *Microscopy/methods ; Membrane Glycoproteins ; }, abstract = {The exploration of cell-type and environmentally responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-expansion microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation. They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae, depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the nuclear ring to the inner ring of the NPC specifically in induced pluripotent stem cell-derived neurons from a patient with C9orf72 amyotrophic lateral sclerosis. Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.}, }
@article {pmid40503807, year = {2025}, author = {Rudnicki, SA and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and Cudkowicz, ME and De Carvalho, M and Genge, A and Hardiman, O and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and Van Den Berg, LH and Zinman, L and Herder, KE and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Shefner, JM and , }, title = {Hospitalizations as an outcome measure in COURAGE-ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2515907}, pmid = {40503807}, issn = {2167-9223}, abstract = {Objective: To describe the development of a methodology to characterize hospitalizations and their relationship to amyotrophic lateral sclerosis (ALS) and provide results using this process in a phase 3 trial of reldesemtiv in ALS. Methods: ALS clinical trialists assisted in developing a classification system to determine if a hospitalization was related to ALS (HR-ALS), unrelated (HU-ALS), or if the relationship was indeterminate (HI-ALS) and this was applied by the investigators to hospitalizations in COURAGE-ALS. Time to first hospitalization and number of hospitalizations were compared between those assigned reldesemtiv or placebo for up to 48 weeks. Demographic and clinical features were evaluated for prediction of hospitalization risk; this analysis was limited to those participants who completed the first 24-week double-blind placebo-controlled portion of the trial. Results: COURAGE-ALS terminated early due to futility. Time to first hospitalization was similar in the reldesemtiv compared to placebo arms as was the incidence, with 86 of the participants (17.6% of those originally assigned placebo and 18.0% originally on reldesemtiv) experiencing an event. The largest percentage of events was classified as HR-ALS for both placebo (64%, 18/28) and reldesemtiv (76%, 44/58). In a multivariate model, only bulbar or respiratory onset disease was a significant risk factor for hospitalization. Conclusion: While most hospitalizations in COURAGE-ALS were HR-ALS, HU-ALS and HI-ALS also occurred. When using hospitalization as an endpoint in an ALS clinical trial, recording its relationship to ALS provides additional details to characterize disease burden and clinical meaningfulness of the endpoint.}, }
@article {pmid40502782, year = {2025}, author = {White, MA and Crowley, L and Massenzio, F and Li, X and Niblock, M and Coleman, MP and Barmada, SJ and Sreedha, J}, title = {Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependent manner.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6527592/v1}, pmid = {40502782}, issn = {2693-5015}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive and ultimately fatal diseases characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila . Here, we investigated the potential of GSK3 inhibition to ameliorate TDP-43-mediated toxicity in mammalian neurons. Expression of TDP-43 both activated GSK3 and promoted caspase mediated cleavage of TDP-43. Conversely, GSK3 inhibition reduced the abundance of full-length and cleaved TDP-43 in neurons expressing wild-type or disease-associated mutant TDP-43, ultimately ameliorating neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity has therapeutic value.}, }
@article {pmid40502754, year = {2025}, author = {Cheng, F and Lorincz-Comi, N and Song, W and Chen, X and Paz, IR and Hou, Y and Zhou, Y and Xu, J and Martin, W and Barnard, J and Pieper, A and Haines, J and Chung, M}, title = {Combining xQTL and genome-wide association studies from ethnically diverse populations improves druggable gene discovery.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6700169/v1}, pmid = {40502754}, issn = {2693-5015}, abstract = {Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing new treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies (GWAS). Gene-based association tests provide a more powerful alternative to traditional single nucleotide polymorphism (SNP)-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate functional genomic data. To address these challenges, we developed GenT and its various extensions, comprising a framework of gene-based tests utilizing summary-level GWAS data. Using GenT, we identified 16, 15, 35, and 83 druggable genes linked to Alzheimer's disease (AD), amyotrophic lateral sclerosis, major depression, and schizophrenia, respectively. Additionally, our multi-ancestry gene-based test (MuGenT) uncovered 28 druggable genes associated with type 2 diabetes that previous trans-ancestry or ancestry-specific GWAS had missed. By integrating brain expression and protein quantitative trait loci (e/pQTLs) into our analysis, we identified 43 druggable genes (e.g., RIPK2, NTRK1, RIOK1) associated with AD that had supporting xQTL evidence. Notably, experimental assays demonstrated that the NTRK1 protein inhibitor GW441756 significantly reduced tau hyper-phosphorylation (including p-tau181 and p-tau217) in AD patient-derived iPSC neurons, thus providing mechanistic support for our predictions. Overall, our findings underscore the power of gene-based association testing as a strategic tool for informed drug target discovery and validation based on human genetic and genomic data for complex diseases.}, }
@article {pmid40502095, year = {2025}, author = {Poch, D and Mukherjee, C and Mallik, S and Todorow, V and Kuiper, EFE and Dhingra, N and Surovtseva, YV and Schlieker, C}, title = {Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.07.658469}, pmid = {40502095}, issn = {2692-8205}, abstract = {UNLABELLED: Aberrant biomolecular condensates are implicated in multiple incurable neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and DYT1 dystonia. However, the role of condensates in driving disease etiology remains poorly understood. Here, we identify myeloid leukemia factor 2 (MLF2) as a disease-agnostic biomarker for phase transitions, including stress granules and nuclear condensates associated with dystonia. Exploiting fluorophore-derivatized MLF2 constructs, we developed a high-content platform and computational pipeline to screen modulators of NE condensates across chemical and genetic space. We identified RNF26 and ZNF335 as protective factors that prevent the buildup of nuclear condensates sequestering K48-linked polyubiquitinated proteins. Chemical screening identified four FDA-approved drugs that potently modulate condensates by resolving polyubiquitinated cargo and MLF2 accumulation. Our exploratory integrated chemical-genetics approach suggests that modulation of zinc, and potentially autophagy and oxidative stress, is critical for condensate modulation and nuclear proteostasis, offering potential therapeutic strategies for neurological disorders. Application of our platform to a genome-wide CRISPR KO screen identified strong enrichment of candidate genes linked to primary microcephaly and related neurodevelopmental disorders. Two hypomorphic microcephaly-associated alleles of ZNF335 failed to rescue nuclear condensate accumulation in ZNF335 KO cells, suggesting that aberrant condensates and impaired nuclear proteostasis may contribute to the pathogenesis of microcephaly.<br><br>HIGHLIGHTS: MLF2 emerges as a disease-agnostic condensate biomarker co-localizing with TDP-43 and G3BP1FDA-approved drugs target condensates linked to perturbed proteostasis.RNF26 and ZNF335 are identified as modulators of nuclear phase transitions.Microcephaly patient disease alleles fail to counteract aberrant condensates.}, }
@article {pmid40501612, year = {2025}, author = {Bhuiyan, P and Yi, Y and Wei, B and Yan, A and Dong, L and Wei, H}, title = {Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.05.21.655232}, pmid = {40501612}, issn = {2692-8205}, abstract = {Calcium dysregulation, caused by pathological activation of ryanodine receptors, contributes to motor neuron degeneration, motor dysfunction, and muscle weakness in SOD1-G93A transgenic amyotrophic lateral sclerosis (ALS) mice. This study investigates the therapeutic efficacy of intranasally administered dantrolene nanoparticles, a ryanodine receptor antagonist, on motor neuron function, muscle strength, spinal cord degeneration, and survival outcomes. Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) IN-DAN: Intranasal administration of dantrolene in the Ryanodex formulation vehicle (RFV), at a dosage of 5mg/kg, administered daily from ages 90-120 days; 3) IN-VEH: Intranasal administration of RFV alone (as a vehicle control), following the same dosing schedule as the IN-DAN condition. Body weight and general motor function were monitored weekly, with survival recorded daily throughout the treatment period. At the treatment conclusion, neurological function was comprehensively evaluated using a standardized neurological scoring system. Motor coordination and balance were assessed using the balance beam test (beam widths of 12 mm and 6 mm) and the rotarod test. Muscle strength was evaluated by measuring grip force using the Kondziela inverted screen test. After behavioral testing, spinal cord tissues were collected for analysis. The levels of neurofilament light chain (NFL), a skeletal neuron protein, and spinal cord weight were determined to measure spinal cord degeneration. Compared to non-transgenic control mice, SOD1-G93A mice exhibited significantly elevated neurological scores, indicating severely impaired neurological function. This deterioration was robustly and significantly ameliorated by IN-DAN treatment by 90% (P<0.0001). Similarly, ALS mice demonstrated impairments in motor coordination and balance on the beam balance test, with dramatic and significant increases in crossing time and the number of foot slips. These impairments were greatly and significantly mitigated by IN-DAN treatment, by 78% in crossing time (P<0.0001) and 84% in the number of slips (P<0.0001) on the 12 mm-wide beam, but not by the vehicle control. ALS mice demonstrated progressive body weight loss as well, which was similarly reversed by IN-DAN treatment, but not by the vehicle control. Muscle strength, as measured by grip force, was significantly reduced in ALS mice but robustly preserved IN-DAN treatment, which prevented the decrease by 213% (P<0.0001), while the vehicle control had no effect. Spinal cord weight was significantly reduced in ALS mice, a trend reversed by intranasal dantrolene nanoparticle treatment, but not by the vehicle control. Survival analysis revealed that 100% of control mice survived through the 30-day treatment period (up to 120 days of age), while survival in untreated or vehicle-treated ALS mice dropped to 67%. In contrast, ALS mice treated with intranasal dantrolene nanoparticles demonstrated a significantly improved survival rate of 89%. Thus, intranasal dantrolene nanoparticle treatment significantly and robustly improved neurological outcomes in SOD1-G93A ALS mice, inhibiting neurological impairment, motor dysfunction, balance deficits, and muscle weakness. These improvements were associated with a marked inhibition of spinal cord weight loss. Additionally, dantrolene treatment reversed body weight loss and significantly improved survival probability in ALS mice.}, }
@article {pmid40501554, year = {2025}, author = {Trautwig, AN and Shantaraman, A and Chung, M and Dammer, EB and Ping, L and Duong, DM and Petrucelli, L and Ward, ME and Glass, JD and Nelson, PT and Levey, AI and McEachin, ZT and Seyfried, NT}, title = {Molecular Subtyping Based on Hippocampal Cryptic Exon Burden Reveals Proteome-wide Changes Associated with TDP-43 Pathology across the Spectrum of LATE and Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.05.30.656396}, pmid = {40501554}, issn = {2692-8205}, abstract = {TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer's disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: STMN2, UNC13A, ELAVL3, KALRN, ARHGAP32, CAMK2B, PFKP, and SYT7 . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43-depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease.}, }
@article {pmid40501419, year = {2025}, author = {Bischoff, KE and Kojimoto, G and O'Riordan, DL and Leavell, YL and Maiser, S and Grouls, A and Smith, AK and Pantilat, SZ and Kluger, BM and Mehta, AK}, title = {Strengths and Opportunities: Clinicians' Perspectives on Palliative Care for Amyotrophic Lateral Sclerosis (ALS) in the United States.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28458}, pmid = {40501419}, issn = {1097-4598}, support = {/AG/NIA NIH HHS/United States ; //ALS Association/ ; }, abstract = {INTRODUCTION/AIMS: Little is known about the state of palliative care (PC) for people with ALS (pALS) in the U.S. We aimed to examine current practice regarding PC for pALS and how it can be improved.<br><br>METHODS: ALS and PC clinicians completed surveys about: (1) strengths and limitations of PC for pALS provided by ALS and PC teams, (2) reasons for and barriers to referring to specialty PC, and (3) how PC could be improved.<br><br>RESULTS: One hundred forty-one ALS clinicians from 72 institutions and 242 PC clinicians from 96 institutions in 30 states completed surveys. Half of ALS clinicians reported they are able to manage patients' pain (55%) and mood symptoms (52%) "very well." Fewer reported managing care partner needs (43%) and spiritual/existential distress (29%) "very well." Fifty-eight percent of pALS are referred to outpatient PC and 69% to hospice at some point in the illness. Barriers to referring include that PC programs are not sufficiently available to pALS. ALS clinicians generally felt satisfied with PC teams' care, but PC clinicians were less confident managing motor symptoms (51% confident) and helping care partners understand how to provide care (51%) and use equipment (25%). Most clinicians felt the quality of PC provided by ALS (77%) and PC (90%) teams is good/excellent. However, qualitative comments highlighted that both ALS and PC clinicians have knowledge gaps, and collaboration between ALS and PC clinicians should increase.<br><br>DISCUSSION: Clinician education, expansion of PC services, strengthened collaboration, and further research about PC for pALS are needed.}, }
@article {pmid40500504, year = {2025}, author = {Niu, J and Verkhratsky, A and Butt, A and Yi, C}, title = {Oligodendroglia in Ageing and Age-Dependent Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {43}, number = {}, pages = {363-405}, pmid = {40500504}, issn = {2190-5215}, mesh = {Humans ; *Oligodendroglia/pathology/physiology/metabolism ; *Neurodegenerative Diseases/pathology/physiopathology/metabolism ; *Aging/pathology/physiology ; Animals ; }, abstract = {The central nervous system is susceptible to gradual decline with age, affecting all types of glial cells in the process. Compared to other glial cells, the oligodendroglial lineage is highly vulnerable to ageing and undergoes significant characteristic changes that impact upon its structure and impair its physiological functions. Therefore, the ageing and degeneration of oligodendroglia become major risk factors for neurodegenerative diseases. During the age-related disease process, changes in oligodendroglia lead to a decline in their ability to regenerate myelin and respond to the aged microenvironment, which are closely linked to the pathogenesis of neurodegenerative diseases, facilitating the emergence of these diseases in older populations. In this chapter, we introduce the physiological changes of oligodendroglia during ageing and the related mechanisms and then summarise their pathophysiological contributions to age-related cognitive disorders. Finally, we discuss potential therapeutic strategies that target oligodendroglia for future research on neurodegenerative diseases.}, }
@article {pmid40499018, year = {2025}, author = {Yadav, V and Singh, R and Chaturvedi, M and Siddhanta, S and Chaturvedi, R}, title = {Multivariate and Machine Learning-Derived Virtual Staining and Biochemical Quantification of Cancer Cells through Raman Hyperspectral Imaging.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.5c01028}, pmid = {40499018}, issn = {1520-6882}, abstract = {Advances in virtual staining and spatial omics have revolutionized our ability to explore cellular architecture and molecular composition with unprecedented detail. Virtual staining techniques, which rely on computational algorithms to map molecular or structural features, have emerged as powerful tools to visualize cellular components without the need for physical dyes, thereby preserving sample integrity. Similarly, spatial omics enable the mapping of biomolecules across tissue or cell surfaces, providing spatially resolved insights into biological processes. However, traditional dye-based staining methods, while widely used, come with significant limitations. In this context, Raman spectroscopy offers a robust, label-free alternative for probing molecular composition at a high resolution. We present a novel algorithm that reconstructs super-resolved Raman images by extracting spectral patterns from surrounding pixels, enabling detailed, label-free visualization of cellular structures. By employing Raman spectroscopy in conjunction with chemometric tools such as principal component analysis (PCA), multivariate curve resolution-alternating least squares (MCR-ALS), and artificial neural network (ANN), we performed a quantitative analysis of key biomolecular components, including collagen, lipids, glycogen, and nucleic acids, and classify the different cancer cell lines with an accuracy of nearly 99%. This approach not only enabled the identification of distinct molecular fingerprints across the different cancer types but also provided a powerful tool for understanding the biochemical variations that underlie tumor heterogeneity. This innovative combination of virtual staining, spatial omics, and advanced chemometrics highlights the potential for more accurate diagnostics and personalized treatment strategies in oncology.}, }
@article {pmid40498717, year = {2025}, author = {Komolafe, OO and Mustofa, J and Daley, MJ and Walton, D and Tawiah, A}, title = {Current applications and outcomes of AI-driven adaptive learning systems in physical rehabilitation science education: A scoping review protocol.}, journal = {PloS one}, volume = {20}, number = {6}, pages = {e0325649}, doi = {10.1371/journal.pone.0325649}, pmid = {40498717}, issn = {1932-6203}, mesh = {Scoping Review as Topic ; Humans ; *Artificial Intelligence ; *Rehabilitation/education ; *Learning ; }, abstract = {Rationale Integrating artificial intelligence (AI) into education has introduced transformative possibilities, particularly through adaptive learning systems. Rehabilitation science education stands to benefit significantly from the integration of AI-driven adaptive learning systems. However, the application of these technologies remains underexplored. Understanding the current applications and outcomes of AI-driven adaptive learning in broader healthcare education can provide valuable insights into how these approaches can be effectively adapted to enhance multimodal case-based learning in Rehabilitation Science education. Methods The scoping review is based on the Joanne Briggs Institute (JBI) framework. It is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMSA-ScR). A comprehensive search strategy will be used to find relevant papers in Scopus, PubMed, CINAHL, Education Resources Information Center (ERIC), Association for Computing Machinery (ACM), ProQuest Education Journal, Web of Science, ProQuest Dissertations &amp; Theses Global, and IEEE Digital Library. This review will include all types of studies that describe or evaluate our outcomes of interest: AI models used, learning and teaching methods, effective implementation, outcomes, and challenges of ALS's in rehabilitation health science education. Data will be extracted using a pre-piloted data extraction sheet and synthesized narratively to identify themes and patterns. Discussion This scoping review will synthesize the applications of AI models in rehabilitation science education. It will provide evidence for educators, healthcare professionals, and policymakers to incorporate AI into educational curricula effectively. The protocol is registered on Open Science Framework registries at https://osf.io/e46s3.}, }
@article {pmid40498248, year = {2025}, author = {Pahwa, R and Molho, E and Lew, M and Dashtipour, K and Gil, RA and Revilla, FJ and Clinch, T and Qin, P and Isaacson, SH and , }, title = {Long-Term Safety and Efficacy of Repeated Cycles of RimabotulinumtoxinB in the Treatment of Chronic Sialorrhea: Results of the OPTIMYST Trial.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {40498248}, issn = {2193-8253}, abstract = {INTRODUCTION: Botulinum toxin injections into the salivary glands inhibit saliva production by reducing the release of acetylcholine at the parasympathetic nerve terminals within the salivary gland. The phase 3 study reported here assessed the safety, tolerability, and effectiveness of repeated cycles of rimabotulinumtoxinB (RIMA) injections in adults with troublesome sialorrhea.<br><br>METHODS: In this phase 3, open-label multicenter study, 187 adult participants with troublesome sialorrhea due to Parkinson disease (65.8%), amyotrophic lateral sclerosis (13.9%), and other etiologies (20.3%) received up to 4 cycles of RIMA treatment (3500 U every 11-15 weeks).<br><br>RESULTS: Participants (69% male, 31% female; mean age 64.1 years) had sialorrhea for a mean of&#xa0;3.2 years at baseline with a mean Unstimulated Salivary&#xa0;Flow Rate (USFR) of 0.63&#x2009;&#xb1;&#x2009;0.49 g/min. During the first treatment cycle, RIMA significantly reduced the mean&#xb1;standard deviation (SD) USFR from baseline to week 4 by -&#xa0;0.34&#x2009;&#xb1;&#x2009;0.37 g/min (p&#x2009;<&#x2009;0.0001), and efficacy was maintained through week 13 (-&#xa0;0.14&#x2009;&#xb1;&#x2009;0.29 g/min; p&#x2009;<&#x2009;0.0001). Reductions were maintained at subsequent injection cycles 2-4, with mean absolute USFRs at weeks 4 and 13 of each cycle similar to those of cycle 1. Most adverse events (AEs) were mild, and the most commonly reported AEs in each cycle that were considered to be treatment-related were dry mouth (&#x2264;&#x2009;15.5% participants/cycle) and dental caries (&#x2264;&#x2009;6.0% participants/cycle).<br><br>CONCLUSION: This study demonstrates that RIMA 3500 U safely reduces saliva production over repeated treatment cycles through 1&#xa0;year, thereby supporting its utility in the management of troublesome sialorrhea in adults.<br><br>GOV IDENTIFIER: NCT02610868.}, }
@article {pmid40412724, year = {2025}, author = {Xu, Y and Hou, W and Gao, J and Wei, JC and Zhang, L}, title = {Letter to Alameddine et al's "Celiac disease associated with alopecia areata: A multicenter case-control study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.05.1405}, pmid = {40412724}, issn = {1097-6787}, }
@article {pmid40498122, year = {2025}, author = {Doronzio, PN and Lattante, S and Bernardo, D and Patanella, AK and Bisogni, G and Meleo, E and Del Giudice, E and Colavito, D and Porro, LM and Sabatelli, E and Conte, A and Zollino, M and Sabatelli, M and Marangi, G}, title = {Burden of pathogenetic and likely pathogenetic variants in SPG7, SPG11 and AP4 genes in Amyotrophic Lateral Sclerosis. A case-control study.}, journal = {Journal of neurology}, volume = {272}, number = {7}, pages = {455}, pmid = {40498122}, issn = {1432-1459}, support = {Linea D1//Catholic University of Sacred Hearth/ ; Linea D1//Catholic University of Sacred Hearth/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Case-Control Studies ; Aged ; Adult ; *Genetic Predisposition to Disease/genetics ; *Adaptor Protein Complex 4/genetics ; *Proteins/genetics ; Spastic Paraplegia, Hereditary/genetics ; Genetic Variation/genetics ; ATPases Associated with Diverse Cellular Activities ; Metalloendopeptidases ; }, abstract = {BACKGROUND: There is evidence that some Hereditary Spastic Paraplegia (HSP) genes are linked to Amyotrophic Lateral Sclerosis (ALS). In particular, KIF5A and SPG11 genes, which cause two different forms of HSP, are also associated with adult-onset and Juvenile ALS, respectively.<br><br>OBJECTIVES: To study the frequencies of pathogenetic and likely pathogenetic variants in HSP genes in ALS patients and to determine whether they act as predisposing factors.<br><br>METHODS: We analysed 72 HSP-associated genes in 1024 ALS and 44 Primary Lateral Sclerosis patients and applied customized ACMG criteria to identify pathogenic and likely pathogenic variants. Based on the frequency of identified variants, six genes, including SPG7, SPG11 and the four genes encoding the subunits of the AP4 adaptor protein, were selected for analysis in an additional cohort of 481 ALS patients. Overall results on 1549 patients were compared with 1138 controls.<br><br>RESULTS: The frequency of variants in SPG7 gene was 0.45% (7/1549) in patients vs 0.18% (2/1138) in controls (p = 0.19), in SPG11 was 0.77% (12/1549) in cases and 0.26% (3/1138) in controls (p = 0.06), in AP4 genes was 0.64% (10/1549) in patients and 0.26% (3/1138) in controls (p = 0.13). The total number of variants detected across SPG7, SPG11 and AP4 genes was statistically different between patients and controls (1.87% vs 0.7%; p = 0.006).<br><br>CONCLUSIONS: We found a significant enrichment of variants in a set of HSP genes, including SPG7, SPG11 and AP4 genes, in a large cohort of ALS patients, suggesting that they may act as predisposing factors for ALS.}, }
@article {pmid40498024, year = {2025}, author = {Pisoni, L and Donini, L and Gagni, P and Pennuto, M and Ratti, A and Verde, F and Ticozzi, N and Mandrioli, J and Calvo, A and Basso, M}, title = {Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {11}, pages = {}, doi = {10.3390/cells14110848}, pmid = {40498024}, issn = {2073-4409}, support = {MUR PNRR project iNEST - Interconnected Nord-Est Innovation Ecosystem (ECS00000043)//NextGenerationEU/ ; PERMEALS - PNRR-MAD-2022-12375731//Ministero della Salute/ ; CUP E53D23019700001, project "MYSTICALS"//European Union - Next Generation EU, Mission 4, Component 1/ ; RF-2016-02361616//Ministero della Salute/ ; EVTestInALS//AriSLA/ ; Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics//Universit&#xe0; degli Studi di Milano/ ; MUR-PRIN 2022 project EV-PRINT 2022CS9H53//Next Generation EU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/diagnosis ; *Biomarkers/metabolism ; Extracellular Vesicles/metabolism ; Animals ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.}, }
@article {pmid40497426, year = {2025}, author = {Bao, J and Zhou, J and Xie, Z and Zou, M and Napier, R and Li, J}, title = {CYP99A2 from Aegilops tauschii metabolizes pyroxsulam but not mesosulfuron-methyl, causing different natural sensitivity to two herbicides.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8967}, pmid = {40497426}, issn = {1526-4998}, support = {2021YFD1700100//National Key Research and Development Program/ ; }, abstract = {BACKGROUND: Weed tolerance to herbicides poses a major threat to agricultural production. Aegilops tauschii has promising prospects for genetic development; however, the fact that this plant is invasive in China and other countries is often ignored owing to its pronounced adaptability. Among the current acetolactate synthase (ALS) inhibitors, only mesosulfuron-methyl (MM) can control A. tauschii, and pyroxsulam (P) is ineffective. However, a knowledge gap remains regarding differences in sensitivity of A. tauschii to these two ALS inhibitors.<br><br>RESULTS: We hypothesized that differences in sensitivity of A.&#x2009;tauschii to the ALS inhibitors MM and P are mediated by metabolic enzymes. Whole-plant experiments showed that the P450s inhibitor 1-Aminobenzotriazole (ABT) significantly increased the sensitivity of A.&#x2009;tauschii to P compared with MM. In A.&#x2009;tauschii, the P metabolism rate was higher than that of MMl, as detected by liquid chromatography with tandem mass spectrometry. Transcriptome sequencing and quantitative real-time polymerase chain reaction identified seven differentially expressed P450s after P and MM treatments, three of which were upregulated after P treatment and were unaffected by MM. AtCYP99A2 reduced plant sensitivity to P by metabolizing P without affecting MM by overexpressing it in Arabidopsis and inducing in vitro protein expression.<br><br>CONCLUSION: To the best of our knowledge, this is the first report on P450 involvement in A.&#x2009;tauschii sensitivity to two ALS-inhibitor herbicides. This study deepens current understandings of A.&#x2009;tauschii and facilitates subsequent screening of specific metabolic enzyme inhibitors to be used as synergists in combination with herbicides, which will provide new avenues for weed control. &#xa9; 2025 Society of Chemical Industry.}, }
@article {pmid40496636, year = {2025}, author = {Qiao, H and Cheng, X and Tian, H and Zhao, C and Sun, X and Zhao, J}, title = {Lower cervical C6/C7 andersson lesion with upper cervical C1/C2 fracture in ankylosing spondylitis: a case report and literature review.}, journal = {Frontiers in surgery}, volume = {12}, number = {}, pages = {1568553}, pmid = {40496636}, issn = {2296-875X}, abstract = {Cervical andersson lesions (ALs) are rare in patients with ankylosing spondylitis (AS), and even more rare in patients with simultaneous superior cervical atlantoaxial fracture and dislocation. Here, we present a case of C1 Jefferson fracture (C1 bilateral posterior arch fracture), C2 odontoid, lateral mass, vertebral fracture (nonclassic C2 hangman fracture), traumatic posterior atlantoaxial dislocation (AAD) and C6/C7 AL in a long-standing AS cervical spine. The patient with traumatic AS-related cervical fractures underwent a two-stage surgery. The stage I surgery involved a posterior atlantoaxial reduction and fixation surgery combined with C5/C6/T1/T2 posterior pedicle screw fixation plus C6/C7 decompression. One week later, C6/C7 anterior cervical corpectomy decompression and fusion (ACCF) with long anterior plate stabilization combined with iliac crest bone graft transplantation was performed for stage II surgery. The patient recovery observed during follow-up was satisfactory. Nine-month postoperative radiological images revealed fracture union of the upper and lower cervical spine with optimal reduction of the atlantoaxial segment. In conclusion, lower cervical ALs with simultaneous upper cervical C1/C2 fractures in the AS are very rare. Posterior C1-C2 fixation combined with C6-C7 AL corpectomy/fusion and posterior pedicle screw fixation may offer a desirable alternative approach for this complex case of cervical trauma. During treatment, complete decompression, effective reduction, and potent stabilization can comprehensively improve the clinical prognosis.}, }
@article {pmid40496269, year = {2025}, author = {Liu, QZ and Zeng, L and Sun, NZ}, title = {Linguistic exclusion in orthopedic research: Cultural adaptation, multilingual innovations, and pathways to global health equity.}, journal = {World journal of orthopedics}, volume = {16}, number = {5}, pages = {106951}, pmid = {40496269}, issn = {2218-5836}, abstract = {This editorial critically evaluated the recent study by AlMousa et al, which examined the impact of the Arabic version of the American Academy of Orthopedic Surgeons Foot and Ankle Outcomes Questionnaire (AAOS-FAOQ) on postoperative quality of life and recovery in Arabic-speaking patients with traumatic foot and ankle injuries. In the context of systemic linguistic exclusion in orthopedic research-where English-language journals dominated most publications and non-English-speaking populations faced dual barriers of trial underrepresentation and semantic distortions (e.g., mistranslations of terms like "joint instability" in Arabic)-AlMousa et al's work highlighted the transformative potential of culturally adapted methodologies. Their rigorous four-stage adaptation framework validated the Arabic AAOS-FAOQ as a reliable tool, enhancing ecological validity and reducing bias in patient-reported outcomes. However, limitations such as regional specificity (Gulf-centric sampling) and short follow-up periods (4 months) underscored broader challenges in non-English research: Redundant studies, prolonged hospital stays for limited English proficiency patients, and underrepresentation of certain ethnic groups in trials. To dismantle linguistic hegemony, we proposed semantic reconstruction (e.g., integrating culturally specific indicators like "prayer posture"), dialect-aware neural translation, and World Health Organization led terminology standardization. In line with these proposed solutions, AlMousa et al's study exemplified how language-sensitive adaptations could bridge equity gaps, while future efforts would need to balance cultural specificity with cross-study comparability through AI-driven multilingual databases and policy mandates for cultural adaptation roadmaps.}, }
@article {pmid40496257, year = {2025}, author = {Ding, LH and Wu, PF and Sun, NZ}, title = {Investigation of clinical outcomes in conservative management of hook fractures: Commentary on recent findings.}, journal = {World journal of orthopedics}, volume = {16}, number = {5}, pages = {106881}, pmid = {40496257}, issn = {2218-5836}, abstract = {This editorial critically evaluates the landmark study by Tanaka and Yoshii, which demonstrated a 100% union rate with conservative management of hamate hook fractures, challenging the historical preference for surgical intervention. In contrast to Scheufle et al's report of 90%-100% failure rates with early surgical approaches, Tanaka and Yoshii's protocol achieved universal healing despite delayed diagnoses in 25% of cases. Central to this success is the systematic integration of high-resolution computed tomography for early diagnosis and dynamic monitoring of trabecular bone regeneration, significantly reducing missed diagnoses and guiding personalized immobilization timelines. The patient-centered strategy-allowing temporary splint removal during low-risk activities-balanced fracture stability with joint mobility preservation, avoiding post-treatment stiffness. However, limitations such as small sample size (n = 16), selection bias, and insufficient long-term functional data (e.g., grip strength, return-to-sport metrics) underscore the need for comparative trials. Emerging trends, including adjunct therapies like low-intensity pulsed ultrasound and biologics (e.g., teriparatide), are proposed to accelerate healing while minimizing immobilization risks. This work redefines conservative fracture management paradigms, emphasizing innovation without compromising efficacy. Overall, this assessment deepens our understanding of the conservative management of hook fractures and provides evidence-based insights for improved clinical decision-making.}, }
@article {pmid40495844, year = {2025}, author = {Byeon, H}, title = {Unveiling the invisible: How cutting-edge neuroimaging transforms adolescent depression diagnosis.}, journal = {World journal of psychiatry}, volume = {15}, number = {5}, pages = {102953}, pmid = {40495844}, issn = {2220-3206}, abstract = {Yu et al's study has advanced the understanding of the neural mechanisms underlying major depressive disorder (MDD) in adolescents, emphasizing the significant role of the amygdala. While traditional diagnostic methods have limitations in objectivity and accuracy, this research demonstrates a notable advancement through the integration of machine learning techniques with neuroimaging data. Utilizing resting-state functional magnetic resonance imaging (fMRI), the study investigated functional connectivity (FC) in adolescents with MDD, identifying notable reductions in regions such as the left inferior temporal gyrus and right lingual gyrus, alongside increased connectivity in Vermis-10. The application of support vector machines (SVM) to resting-state fMRI (rs-fMRI) data achieved an accuracy of 83.91%, sensitivity of 79.55%, and specificity of 88.37%, with an area under the curve of 0.6765. These results demonstrate how SVM analysis of rs-fMRI data represents a significant improvement in diagnostic precision, with reduced FC in the right lingual gyrus emerging as a particularly critical marker. These findings underscore the critical role of the amygdala in MDD pathophysiology and highlight the potential of rs-fMRI and SVM as tools for identifying reliable neuroimaging biomarkers.}, }
@article {pmid40495464, year = {2025}, author = {Majtan, T and Mijatovic, E and Petrosino, M}, title = {Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria.}, journal = {Molecular and cellular biology}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/10985549.2025.2511338}, pmid = {40495464}, issn = {1098-5549}, abstract = {Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS regulates methionine conversion into metabolites critical for redox balance (cysteine, glutathione) and signaling (H2S). Pathogenic missense mutations in the CBS gene often impair folding, cofactor binding, stability or oligomerization rather than targeting the key catalytic residues of the CBS enzyme. Advances in understanding of CBS folding and assembly as well as CBS interactions with cellular proteostasis network offer potential for therapies using pharmacological chaperones (PCs), i.e., compounds facilitating proper folding, assembly or cellular trafficking. This review discusses progress in identifying PCs for HCU, including chemical chaperones, cofactors, and proteasome inhibitors. We outline future directions, focusing on high-throughput screening and structure-based drug design to develop CBS-specific PCs. These could stabilize mutant CBS, enhance its stability and restore activity, providing new treatments for HCU and possibly other conditions related to dysregulated CBS, such as cancer or Down's syndrome.}, }
@article {pmid40495157, year = {2025}, author = {Gonsalves, GS}, title = {Still we rise: research on bias and discrimination will endure.}, journal = {International journal for equity in health}, volume = {24}, number = {1}, pages = {167}, pmid = {40495157}, issn = {1475-9276}, mesh = {Humans ; Racism ; Boston ; *Prejudice ; United States ; *Social Discrimination ; *Vaping/epidemiology ; Smoking/epidemiology ; Bias ; Sexism ; }, abstract = {This is a commentary on Reisner et al's Analyzing multiple types of discrimination using implicit and explicit measures, comparing target vs. Dominant groups, in a study of smoking/vaping among community health center members in Boston, Massachusetts (2020-2022). This manuscript is a study of the intersection of multiple forms of discrimination-racism, sexism, heterosexism, cissexism, ageism, and sizeism-and measures of implicit and explicit bias in the context of current smoking and vaping behavior among patients from targeted versus dominant groups at community health centers in Boston, Massachusetts (USA) from 2020 to 2022. The authors used logistic regression to assess smoking and vaping behavior with each type of discrimination, and then extended this analysis employing a meta-regression approach to better understand relationships across all types of discrimination under consideration in their study. Recently, the grant from the US National Institutes of Health, which supported this research was terminated in progress for ideological reasons by the current US administration under President Donald J. Trump for simply focusing on discrimination. While this study was among the first to be terminated by the Trump administration, hundreds of grants from the NIH and other US research funders have been cancelled in the first half of 2025. Reisner et al's paper is an important piece of research, but it represents the start of a sophisticated inquiry into discrimination and bias, and future work by this team and in this area of research is necessary and sadly, now impossible to do with federal scientific funding. Work on discrimination and bias has always faced obstacles, but the scope and scale of attacks on science in the US require all scientists to push back against this censorship and political interference in the funding and conduct of research.}, }
@article {pmid40494757, year = {2025}, author = {Luu, S and McGuiness, O and Menadue, C and Piper, AJ and Wong, K and Yee, BJ and Gray, EL}, title = {Inter-Night Variability of Nocturnal Pulse Oximetry in People Living With Motor Neuron Disease: A Retrospective Observational Study.}, journal = {Respirology (Carlton, Vic.)}, volume = {}, number = {}, pages = {}, doi = {10.1111/resp.70072}, pmid = {40494757}, issn = {1440-1843}, abstract = {BACKGROUND AND OBJECTIVE: Nocturnal pulse oximetry (NPO) is a simple and inexpensive assessment tool that has previously been shown to correlate with prognosis and timing of non-invasive ventilation (NIV) initiation in people living with motor neuron disease (plwMND). However, the optimal number of nights for measuring NPO has not been defined for this population, with other respiratory conditions exhibiting both low and high night-to-night variability in NPO parameters. This study aims to determine the inter-night variability in NPO data over three nights in plwMND.<br><br>METHODS: We conducted a retrospective analysis of 132 studies in which plwMND underwent three consecutive nights of NPO. Intraclass correlation coefficients (ICC) were used to assess the reliability of key NPO parameters, including mean percentage of total recording time with oxygen saturation (SpO2) <&#x2009;90% (T90), oxygen desaturation index (ODI), basal SpO2 and nadir SpO2. The proportion of plwMND meeting NIV criteria based on single-night versus multi-night assessments was also compared.<br><br>RESULTS: Excellent reliability was observed for T90 (ICC(1)&#x2009;=&#x2009;0.940) and ODI (ICC(1)&#x2009;=&#x2009;0.901), while basal SpO2 (ICC(1)&#x2009;=&#x2009;0.845) and nadir SpO2 (ICC(1)&#x2009;=&#x2009;0.768) demonstrated good reliability. However, relying on a single-night NPO assessment failed to identify 12% of plwMND who met NIV criteria when evaluated over three nights.<br><br>CONCLUSION: Despite good to excellent inter-night variability of NPO data in plwMND, multi-night NPO monitoring improves the accuracy of identifying plwMND requiring NIV. These findings support the need for multi-night assessments to enhance clinical decision-making in MND management.}, }
@article {pmid40493571, year = {2025}, author = {Nathan Kochen, N and Murray, M and Zafari, S and Vunnam, N and Liao, EE and Chen, L and Braun, AR and Sachs, JN}, title = {Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00266}, pmid = {40493571}, issn = {1948-7193}, abstract = {Pathological aggregates of TDP-43 are implicated in Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. While therapeutic efforts have traditionally focused on mitigating end-stage TDP-43 aggregation, recent evidence highlights an upstream and potentially targetable event: the loss of functional nuclear TDP-43 multimers due to disrupted N-terminal domain (NTD) interactions. To address this, we developed fluorescence lifetime (FLT)-based FRET biosensors to monitor TDP-43 multimerization in living cells that couple a full-length TDP-43 FLT-FRET biosensor screen with an NTD-deletion counter screen, forming the foundation of a novel high-throughput screening (HTS) platform. Screening the 2682 compound FDA-approved Selleck library, we identified the small molecule ketoconazole, which stabilizes functional nuclear TDP-43 multimers in an NTD-dependent manner with low micromolar potency. Ketoconazole rescues TDP-43 mislocalization and aggregation, restores SREBP2 mRNA levels under TDP-43 overexpression, improves neuronal health, and partially restores motor function in a TDP-43 C. elegans model. These findings establish both the biosensors and the HTS platform as innovative tools for TDP-43 drug discovery and support an exciting translational approach for targeting TDP-43 proteinopathies.}, }
@article {pmid40493543, year = {2025}, author = {Lucassen, HJ and Prinsen, EC and Asseln, M and van Vliet, RO and Tuijthof, GJM}, title = {Assistive devices for ALS patients: exploring wishes and values through focus groups.}, journal = {Disability and rehabilitation. Assistive technology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/17483107.2025.2516628}, pmid = {40493543}, issn = {1748-3115}, abstract = {PURPOSE: Amyotrophic Lateral Sclerosis (ALS) is a progressive disease leading to loss of muscle strength and control, and as such limiting patients' independence. Assistive devices can help individuals with ALS; however, their use by ALS patients is limited. To increase use rates, we expect that devices need to be tailored to ALS patients. The aim of this study was to identify wishes, requirements and values of ALS patients regarding assistive devices for the upper extremity through focus groups involving ALS patients, their relatives and medical professionals.<br><br>METHODS AND MATERIALS: Four focus groups were conducted, recorded and transcribed. Two focus groups with ALS patients and their relatives contained a "Day in a Life" and "Empathy map" method, while during two focus groups with medical professionals, "Day in the Life" method and "Provoking statements" were used. Activities mentioned were counted and categorized into "Daily activities" and "Elective activities".<br><br>RESULTS: Qualitative analysis of transcripts yielded three themes: (1) ALS patients' considerations on use and wishes for assistive devices, (2) external factors influencing the use of assistive devices and (3) change in ALS patients' needs over time. In addition to maintaining independence in activities of daily living, the results highlight that retaining the ability to perform elective activities such as hobbies, is important. Moreover, there is a clear need for assistive devices designed for ALS patients with limited upper extremity strength, but who are not confined to a wheelchair.<br><br>CONCLUSION: These findings can guide the development of assistive devices tailored to the needs of ALS patients.}, }
@article {pmid40493233, year = {2025}, author = {Russo, T and Domi, T and Schito, P and Falzone, YM and Pozzi, L and Locatelli, M and Riva, N and Spinelli, EG and Agosta, F and Filippi, M and Quattrini, A}, title = {Osteopontin levels in the serum reflect anatomical disease progression in patients with amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {7}, pages = {452}, pmid = {40493233}, issn = {1432-1459}, support = {Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Universit&#xe0; e della Ricerca/ ; RF-2021-12374238//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology/diagnosis ; *Osteopontin/blood ; Male ; Female ; *Disease Progression ; Middle Aged ; Aged ; Retrospective Studies ; Biomarkers/blood ; Neurofilament Proteins/blood ; Adult ; Longitudinal Studies ; Severity of Illness Index ; Cohort Studies ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) lacks biomarkers for diagnosis, prognostic stratification, and evaluation of response to potential treatments. Previous research supported the role of serum osteopontin (OPN) levels as a potential biomarker in ALS. However, the associations of OPN serum levels with clinical features and their trend over the disease course have not been explored yet.<br><br>METHODS: We measured OPN serum levels in a retrospective cohort of 110 well-characterized patients with ALS, using a commercial ELISA kit, and analyzed their association with demographic and clinical features, as well as with other serum biomarkers. For a subset of patients, longitudinal measurements were available.<br><br>RESULTS: OPN serum levels differed significantly between patients with ALS and a cohort of 45 age and sex-matched healthy controls. However, when considering potential differential diagnoses, elevated OPN serum levels were not specific for ALS. Patients with an advanced disease stage (King's stage 3 or 4) exhibited significantly higher OPN serum levels compared to patients at earlier disease stages, whereas we did not observe any correlation with ALSFRS-R and progression rate. We observed an inverse correlation between OPN serum levels and BMI at diagnosis. Higher OPN serum levels predicted a shorter survival time and a shorter time to King's stage 4. No significant association between serum OPN and serum neurofilament light or glial fibrillary acid protein levels was observed. OPN serum levels were substantially stable over a 9-month observation time.<br><br>CONCLUSION: Our findings indicate that serum OPN is an informative biomarker in ALS, providing valuable prognostic insights, potentially reflecting the extent of disease, and demonstrating potential applications in clinical trials.}, }
@article {pmid40493155, year = {2025}, author = {Kang, A and Qiao, Y and Pan, S and Yan, F and Chen, H and Bai, Y}, title = {From RIPK1 to Necroptosis: Pathogenic Mechanisms in Neurodegenerative Diseases.}, journal = {Neurochemical research}, volume = {50}, number = {3}, pages = {194}, pmid = {40493155}, issn = {1573-6903}, support = {24JRRA346//Natural Science Foundation of Gansu Province/ ; CY2023-QN-B03//"Cuiying Science and Technology Program" of the Second Hospital of Lanzhou University/ ; (23)0207//Foundation for International Medical Exchanges/ ; (23)1263//China Health Promotion Foundation/ ; }, mesh = {Humans ; *Necroptosis/physiology/drug effects ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Signal Transduction/physiology ; }, abstract = {Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis, a newly identified mode of regulated cell death, represents a significant pathogenic mechanism in multiple neurodegenerative disorders. Substantial experimental evidence indicates that RIPK1 regulates necroptotic cell death pathways in both neuronal and glial cell populations through activation of the canonical RIPK3-MLKL signaling cascade, thereby exacerbating neuroinflammatory responses and accelerating neurodegenerative progression. The pathological relevance of this molecular pathway has been extensively validated across multiple major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Pharmacological interventions targeting RIPK1 or its downstream effectors-particularly RIPK3 and MLKL-have demonstrated significant efficacy in mitigating disease-associated pathological manifestations. This highlights the RIPK1 signaling axis as a promising therapeutic target for neuroprotective strategies. Consequently, thorough investigation of RIPK1-mediated necroptosis in neurodegenerative settings holds considerable translational potential. Such inquiry deepens mechanistic understanding of disease pathogenesis while accelerating the advancement of innovative therapeutic approaches with direct clinical relevance.}, }
@article {pmid40492096, year = {2025}, author = {Tzeplaeff, L and Galhoz, A and Meijs, C and Caldi Gomes, L and Kovac, A and Menzel, A and Değirmenci, H and Alaamel, A and Can Kaya, H and Günalp Çelik, A and Dinçer, S and Korucuk, M and Berker Karaüzüm, S and Bayraktar, E and Çiftçi, V and Bilge, U and Koç, F and Demleitner, AF and Buchberger, A and von Heynitz, R and Gmeiner, V and Knellwolf, C and Mouzouri, M and Wuu, J and Başak, AN and Munch Andersen, P and Kohlmayer, F and Ashton, NJ and Kuban, W and Lenz, C and Rogers, ML and Zilka, N and Corcia, P and Lerner, Y and Weber, M and Turcanova Koprusakova, M and Uysal, H and Benatar, M and Menden, MP and Lingor, P}, title = {Identification of a presymptomatic and early disease signature for Amyotrophic Lateral Sclerosis (ALS): protocol of the premodiALS study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.05.27.25328387}, pmid = {40492096}, abstract = {The median time to diagnosis of amyotrophic lateral sclerosis (ALS) is approximately 12 months after the onset of first symptoms. This diagnostic delay is primarily due to the nonspecific nature of early symptoms and the clinical challenges in differentiating ALS from its mimics. Therefore, the discovery of reliable biomarkers for the early and accurate diagnosis of ALS represents a critical medical need. A total of 330 participants will be recruited across six international study sites. The cohort will include (1) pre-symptomatic gene mutation carriers, (2) symptomatic individuals up to 12 months after symptom onset with either ALS, ALS mimics, or a pure motor syndrome with yet unclear assignment, and (3) healthy controls. Participants will engage in a one-year longitudinal study, consisting of an initial evaluation at baseline visit and a follow-up visit 12 months later. Assessments will include an environmental and medical history questionnaire, neurological examinations, olfactory testing, cognitive/behavioral evaluations, and the collection of biological samples (serum, plasma, urine, tear fluid, and cerebrospinal fluid). Proteomic, metabolomic, and lipidomic analyses will be performed using mass spectrometry and targeted immunoassays, with all samples processed under standardized protocols. The resulting multimodal dataset will be systematically integrated in an effort to uncover a clinico-molecular signature characteristic of presymptomatic and early ALS. These findings may have relevance to early ALS diagnosis and future clinical practice.}, }
@article {pmid40492044, year = {2025}, author = {Roshni, J and Mahema, S and Janakiraman, V and Ahmad, SF and Al-Mazroua, HA and Ahmed, SSSJ}, title = {Effect of bovine milk-derived peptide on SNAP-25 of the neurotransmitter system in treating the sialorrhoea in chronic neurological diseases.}, journal = {Food science and biotechnology}, volume = {34}, number = {11}, pages = {2601-2610}, pmid = {40492044}, issn = {2092-6456}, abstract = {Sialorrhea is a prominent symptom of chronic neurological disorders like amyotrophic lateral sclerosis, Parkinson's disease, motor neuron disease, cerebral palsy, and stroke. Synaptosome-Associated Protein-25 (SNAP-25) plays a key role in triggering involuntary saliva secretion. This study aimed to identify SNAP-25-targeting bovine milk-derived peptides to mitigate sialorrhea, using computational and quantum atomistic simulation approach. Among 8559 bovine milk-derived peptides, 8499 were non-toxic, 7749 non-allergenic, 911 with blood-brain barrier crossing potential, and 175 with cell-penetrating capabilities. Using HAPPENN program, 20 non-hemolytic peptides were screened, while PeptideRanker predicted two physiologically active peptides. Protein-peptide docking followed by de novo structural modeling showed that CMPTFQFFK has a stronger inhibitory affinity (- 7.45 kcal/mol) for SNAP-25 than botulinum toxin. Additionally, dynamic simulations, free energy and quantum chemical studies confirmed the stability of CMPTFQFFK's with SNAP-25. Our study recommends CMPTFQFFK as a potential inhibitor of SNAP-25 for sialorrhea treatment, with further in vitro testing needed to confirm efficacy.}, }
@article {pmid40492022, year = {2025}, author = {Ennis, R and Husted, C}, title = {Case Report: Treating Atrial Fibrillation with the Neubie Direct Current Electrical Stimulation.}, journal = {Medical devices (Auckland, N.Z.)}, volume = {18}, number = {}, pages = {291-295}, pmid = {40492022}, issn = {1179-1470}, abstract = {INTRODUCTION: A novel Neuro-Bio-Electric-Stimulation device (Neubie, Neufit, Austin, Texas, USA) using Direct Current (DC) has been used to treat various neurological conditions (ALS, MS, peripheral neuropathy, chronic pain) and functional limitations such as limited range of motion. One method, called the Master Reset Protocol, is thought to stimulate the vagus nerve system, impacting heart rate, digestion and other vital systems.<br><br>PURPOSE: We used the Master Reset Protocol on a subject experiencing paroxysmal Atrial Fibrillation (AFib) to assess whether this treatment might be effective in reversing a cardiac arrhythmia.<br><br>SUBJECT AND METHODS: A single subject is reported in this Case Report. The subject is a 62-year-old healthy, athletic male, 6'2&#x2033; tall, 165 lbs. with a good diet and is not obese nor has other exacerbating underlying conditions related to heart disease. The subject experiences arrhythmia approximately 1-2 times per month lasting generally 3 or more days per the subject. The Master Reset Method was initiated within 12&#xa0;hours of arrhythmia onset, and arrhythmia before and after treatment was confirmed through subject observation and confirmed with pulse readings. A total of ten treatments were conducted over 7 months.<br><br>RESULTS: Reversal of arrhythmia was confirmed during or within 24&#xa0;hours of treatment with DC application for all 10 treatments (100%). Two of the more severe cases of AFib required two treatments on the same day with confirmed reversal of AFib.<br><br>CONCLUSION: Treatment with Direct Current suggests a good correlation with reversal of arrhythmia. Further studies are planned to determine if similar, regular, treatments can be effective in preventing arrhythmia.}, }
@article {pmid40491620, year = {2025}, author = {Sue, S and Yamazaki, S and Sue, K and Kinoshita, T and Yoshida, K}, title = {Combined Effects of Lung Volume Recruitment Training and Mechanical Insufflation-Exsufflation in a Patient With Advanced Amyotrophic Lateral Sclerosis Receiving Long-Term Mechanical Ventilation: A Case Report.}, journal = {Cureus}, volume = {17}, number = {5}, pages = {e83823}, pmid = {40491620}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) degenerates both upper and lower motor neurons. Most patients with ALS require respiratory support due to deterioration of their respiratory muscles. Mechanical insufflation-exsufflation (MI-E) is one option that can help patients with weak cough strength to clear the airway, and it may potentially increase survival time. Another option is lung volume recruitment training (LVRT), a technique commonly used to maintain lung and chest wall flexibility. However, it requires specific equipment, such as one-way valves, to be applied to patients with ALS who undergo invasive mechanical ventilation with tracheostomy. Only limited studies have indicated the effectiveness of LVRT for patients with ALS. Moreover, no study is currently available on the effect of combining LVRT with MI-E. As the disease progresses, treatment options become increasingly limited, making it crucial to explore new therapeutic approaches for patients at the advanced stage. Here, we examined the effects of a combination of LVRT and MI-E in a 74-year-old female patient with ALS who had survived under invasive mechanical ventilation for nine years. We measured tidal volume (TV) and dynamic lung compliance (Cdyn) as respiratory parameters three months before and after the initiation of the combined therapy. Following the intervention, TV improved from 750.15 L/min (standard deviation (SD) ± 34.60) to 859.14 L/min (SD ± 75.63), and Cdyn increased from 24.18 cmH2O (SD ± 2.84) to 26.54 cmH2O (SD ± 2.92). These results suggest that MI-E combined with LVRT may improve lung compliance even in patients with ALS receiving long-term invasive mechanical ventilation.}, }
@article {pmid40491248, year = {2025}, author = {Bernsen, S and Fabian, R and Koc, Y and Schumann, P and Körtvélyessy, P and Castro-Gomez, S and Meyer, T and Weydt, P}, title = {Serum Cardiac Troponin T Levels as a Therapy Response Marker in Tofersen-Treated ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28453}, pmid = {40491248}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Cardiac troponin T (cTnT) levels are elevated in the majority of persons with amyotrophic lateral sclerosis (ALS) and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study, we assess cTnT levels in SOD1-ALS at baseline and during tofersen treatment.<br><br>METHODS: cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1 variants.<br><br>RESULTS: cTnT levels increased in the control ALS cohort over time (p&#x2009;<&#x2009;0.0001) but not in the tofersen group (p&#x2009;=&#x2009;0.36). Creatine kinase (CK) and CK-MB levels did not show significant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p&#x2009;=&#x2009;0.0013). A significantly lower fold change in cTnT levels was observed in the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) relative to the control group (median 1.89; IQR 1.35-2.75) (p&#x2009;=&#x2009;0.0003). Nine (39%) patients treated with tofersen experienced a reduction in cTnT levels.<br><br>DISCUSSION: In this study, we describe a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigation.}, }
@article {pmid40490178, year = {2025}, author = {Akkum, FI and Ozbas, CE and Damar, M and Uversky, VN and Fayetorbay, R and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Impacts of pathogenic mutations on the structures of the CHCHD10 monomer: An AlphaFold3 study linked to the generation of conformational ensembles.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {144970}, doi = {10.1016/j.ijbiomac.2025.144970}, pmid = {40490178}, issn = {1879-0003}, abstract = {CHCHD10, a member of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family, plays a critical role in mitochondrial function. The link between pathological mutations and CHCHD10 is important and increasingly recognized, especially due to mitochondrial dysfunction and its association with neurodegenerative diseases. Several mutations in CHCHD10 have been directly linked to human diseases, such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), mitochondrial myopathies, and Spinal Muscular Atrophy-Jokela type (SMAJ). In this study, we investigate the structural properties of wild-type and mutant CHCHD10 proteins using AlphaFold3 linked to the generation of conformational ensembles. Structural changes may modulate interactions, flexibility, and aggregation tendencies, potentially influencing neurodegenerative disease pathogenesis linked to mitochondrial dysfunction. Notably, disease-associated mutations like R15S, P23L, and S59L alter secondary structure formations such as 310-helices and β-sheets. Despite, we find that the compactness of CHCHD10 is not significantly altered by genetic mutations since radius of gyration values range between 32.69 Å and 35.94 Å. All in all, we find that the compactness is not but the secondary and tertiary structure properties are affected by pathological mutations. We propose that evolution may have optimized CHCHD10 to maintain a suitable radius of gyration that provides sufficient flexibility through its intrinsically disordered region while ensuring efficient interaction with diverse molecules. Thus, alterations in secondary and tertiary structures through mutations might be a mechanism for fine-tuning the protein's functionality while preserving its optimal state. These characteristics might be related to the pathologies of neurodegenerative diseases linked to mitochondrial dysfunction.}, }
@article {pmid40489983, year = {2025}, author = {The Lancet Neurology, }, title = {Honouring the amyotrophic lateral sclerosis research pledge.}, journal = {The Lancet. Neurology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1474-4422(25)00166-8}, pmid = {40489983}, issn = {1474-4465}, }
@article {pmid40489798, year = {2025}, author = {Huang, J and Zhao, L and Xiang, P and Zhang, F and Yang, Y and Chao, L and Liu, W and Li, H and Zhang, X}, title = {Aminated Lignin/Cellulose-Based Hydrogel with High Adhesion for Wearable Sensors.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.langmuir.5c01389}, pmid = {40489798}, issn = {1520-5827}, abstract = {Hydrogels play a significant role in the flexibility, stretchability, and conductivity of wearable sensors. However, it is still a challenge to achieve multifunctional hydrogel sensors with excellent mechanical strength, outstanding self-adhesion, and high stimulus responsiveness for meeting various demands of practical applications. Here, this work presents a one-pot method to prepare a conductive hydrogel with multifunction by introducing aminated lignosulfonate (A-LS) and aminated cellulose nanocrystals (A-CNC) into the hydrogel matrix. Benefiting from the synergistic effect of dynamic reversible noncovalent bond network with the introduction of nanoparticles in the system, the resultant hydrogel showed excellent mechanical properties. In addition, the prepared hydrogels exhibited remarkable adhesion strength (pig skin: 24 kPa) with sustainable adhesion, which still maintained an adhesion strength above 18 kPa after 20 cycles of adhesion/separation. The resultant hydrogel sensor showed a wide operating range (0-200%), high sensitivity (GF = 0.71 at 0-100% strain; GF = 3.15 at 100-200% strain), and fast response time (320 ms). The high-value utilization of renewable forest biomass resources is conducive to the sustainable development of green chemistry.}, }
@article {pmid40489721, year = {2025}, author = {Levison, L and Jepsen, P and Blicher, JU and Andersen, H}, title = {Hospital-Diagnosed Traumatic Head Injury and Associated Risk of Developing ALS: A Nationwide Population-Based Case-Control Study.}, journal = {Neurology}, volume = {105}, number = {1}, pages = {e213809}, doi = {10.1212/WNL.0000000000213809}, pmid = {40489721}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/etiology/diagnosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; Aged ; Risk Factors ; *Craniocerebral Trauma/epidemiology/complications/diagnosis ; Registries ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND AND OBJECTIVES: Previous studies have suggested that traumatic head injury (THI) may be a risk factor of amyotrophic lateral sclerosis (ALS) development, yet the association remains unclear. We aimed to determine whether hospital-diagnosed THI is an important ALS risk factor, and we investigated the magnitude and duration of associated ALS risk.<br><br>METHODS: In this population-based case-control study, we used individual-level data linkage across nationwide health registers from 1980 to 2021 to identify patients with hospital-diagnosed ALS. Each patient was matched 1:10 with individuals from the general population by age, sex, and diagnostic index date. We used conditional logistic regression to examine the relative risk of ALS associated with having previous hospital-diagnosed THI. To avoid the effect of reverse causation, we investigated ALS risk within several time windows and repeated all analyses after restricting THI exposures to more than 3 years before the date of ALS diagnosis.<br><br>RESULTS: THI was observed in 4.7% of 5,943 ALS cases vs 3.7% of 59,426 controls, with a matched odds ratio (OR) of 1.3 (95% CI 1.1-1.4). However, the risk of ALS declined considerably with increasing time since head injury, with a high OR of 4.5 (95% CI 2.8-7.3) observed within the 6 months before ALS diagnosis. If head injury was suffered 6-12 months before ALS diagnosis, the OR was 2.4 (95% CI 1.4-4.0). Restricting the analysis to THI suffered more than 3 years before ALS diagnosis, we found no association with an OR of 1.1 (95% CI 1.0-1.3).<br><br>DISCUSSION: Although a strong association of ALS with THI experienced &#x2264;1 year before ALS diagnosis was evident, our results suggest that this is due to reverse causation. When restricting the analysis to a period deemed relevant for causative events leading to ALS development, no association was observed. Consequently, we do not consider THI an important ALS risk factor. This study was limited by the inability to consider minor THIs not receiving hospital attendance. Future research should explore alternative models to unfold this possible ALS risk factor.}, }
@article {pmid40489271, year = {2025}, author = {Li, B and Han, Y and Zhang, S and Wang, H and Zhao, Z and Zhai, Y}, title = {High-precision Edge Detection Guided by Flow Fields.}, journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TIP.2025.3572763}, pmid = {40489271}, issn = {1941-0042}, abstract = {Edge detection is frequently employed to support downstream visual tasks. However, current edge detection methods still encounter two significant challenges: extracting complex textured targets and capturing valuable information from complex backgrounds. We propose FFED, a flow field-guided edge detection model. FFED integrates the three components of our design. FFED incorporates three designed components: the Feature Broadcast Module (FBM), the Antagonistic Bio-inspired Spatial Attention Module (ABSAM), a novel pixel difference convolution named ALS. The FBM serves as an implementation mode of the flow field, with its input pair selection strategy inspired by video processing.The FBM broadcasts high-level semantic features to high-resolution ones, preserving more meaningful texture details. Inspired by biological studies, we propose the ABSAM. ABSAM extracts valuable information from complex backgrounds by optimizing spatial modeling of data. The ALS exhibits enhanced capability in extracting gradient information and capturing subtle texture details that are easily overlooked. Experimental results demonstrate that FFED achieved competitive detection results on NYUD, BSDS500, and BIPED datasets, as well as good performance on industrial datasets. Additionally, the experiment verified the auxiliary effect of FFED on downstream visual tasks. The code is available at https://github.com/hanyuchen2022/Flow-field-guided-edge-detection-FFED-.}, }
@article {pmid40489211, year = {2025}, author = {Gautam, P and Yadav, R and Vishwakarma, RK and Shekhar, S and Pathak, A and Singh, C}, title = {An Integrative Analysis of Metagenomic and Metabolomic Profiling Reveals Gut Microbiome Dysbiosis and Metabolic Alterations in ALS: Potential Biomarkers and Therapeutic Insights.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00254}, pmid = {40489211}, issn = {1948-7193}, abstract = {ALS is a severe neurodegenerative disorder characterized by motor neuron degeneration, gut dysbiosis, immune dysregulation, and metabolic disturbances. In this study, shotgun metagenomics and [1]H nuclear magnetic resonance (NMR)-based metabolomics were employed to investigate the altered gut microbiome and metabolite profiles in individuals with ALS, household controls (HCs), and nonhousehold controls (NHCs). The principal component analysis (PCA) explained 33% of the variance, and the partial least-squares discriminant analysis (PLS-DA) model demonstrate R[2] and Q[2] values of 0.97 and 0.84, respectively, indicating an adequate model fit. The relative bacterial abundance was 99.34% in the ALS group and 98.94% in the HC group. Among the ten identified genera, Bifidobacterium, Lactobacillus, and Enterococcus were more prevalent in ALS individuals, while Lactiplantibacillus and Klebsiella were more abundant in the HC group. We identified 70 metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), carbohydrates, and aromatic compounds, using NMR. Orthogonal partial least-squares discriminant analysis (O-PLS-DA) explained 15.8% of the variance, with a clear separation between the ALS and HC groups. Univariate receiver operating characteristic (ROC) analysis identified three fecal metabolites with AUC values above 0.70, including butyrate (0.798), propionate (0.727), and citrate (0.719). These metabolites may serve as potential biomarkers for ALS. The statistical model for metabolic pathway analysis revealed interconnected pathways, highlighting the complexity of metabolic dysregulation, as well as potential microbial and metabolic biomarkers in ALS. These results highlight the role of gut microbiome alterations in ALS and suggest potential avenues for therapeutic intervention.}, }
@article {pmid40488810, year = {2025}, author = {Kulkarni, SR and Thokchom, B and Abbigeri, MB and Bhavi, SM and Singh, SR and Metri, N and Yarajarla, RB}, title = {The role of L-DOPA in neurological and neurodegenerative complications: a review.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {40488810}, issn = {1573-4919}, abstract = {L-DOPA remains a cornerstone treatment for Parkinson's disease and is increasingly recognized for its role in various neurological and neurodegenerative disorders. As a direct precursor to dopamine, L-DOPA is synthesized from L-tyrosine through the action of tyrosine hydroxylase and is subsequently converted into dopamine via aromatic L-amino acid decarboxylase. Its ability to cross the blood-brain barrier (BBB) makes it a crucial therapeutic agent for restoring dopaminergic neurotransmission, thereby influencing motor function, cognition, and neuroprotection. Beyond Parkinson's, L-DOPA's therapeutic potential extends to neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, multiple sclerosis, Lewy body dementia, and amyotrophic lateral sclerosis, where dopamine modulation plays a critical role. Furthermore, L-DOPA has demonstrated efficacy in neurological disorders including epilepsy, peripheral neuropathy, cerebrovascular diseases, and traumatic brain injury, suggesting broader neurobiological applications. However, long-term use is associated with challenges such as motor fluctuations, dyskinesias, and loss of therapeutic efficacy due to progressive neurodegeneration and alterations in dopaminergic pathways. Recent advancements in drug delivery systems, combination therapies, and nanotechnology, including plant-derived carbon dots, offer promising strategies to enhance L-DOPA's effectiveness while mitigating its limitations. This comprehensive review explores L-DOPA's synthesis, pharmacokinetics, mechanism of action, and its evolving role in neurological diseases, while highlighting ongoing challenges and future directions for optimizing its clinical application.}, }
@article {pmid40488711, year = {2025}, author = {Tang, IW and Knekt, P and Rantakokko, P and Heliövaara, M and Rissanen, H and Ruokojärvi, P and Mukherjee, R and Weisskopf, MG}, title = {Pre-disease biomarkers of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) risk in Finland.}, journal = {Environmental health perspectives}, volume = {}, number = {}, pages = {}, doi = {10.1289/EHP16539}, pmid = {40488711}, issn = {1552-9924}, abstract = {BACKGROUND: Persistent organic pollutants (POPs) are toxic chemicals that bioaccumulate and were used in pesticides and industrial products/processes. POP-exposed occupations and environmental exposure to POPs have been associated with amyotrophic lateral sclerosis (ALS), but no study has evaluated the association with ALS when measuring POPs in samples collected before ALS onset.<br><br>OBJECTIVES: This study examined the relationship between pre-disease POP exposure and ALS risk.<br><br>METHODS: We conducted a nested case-control study pooling three Finnish cohorts (n=56,862). During a median follow-up of 27 years, 97 incident ALS cases were identified (mean age at ALS=68). Within each cohort, two controls per case were selected by individual matching for age, sex, municipality, and serum freeze-thaw cycles. Thirteen polychlorinated biphenyls (PCB) and nine organochlorine pesticides (OCP) were determined in serum samples collected at baseline and stored at -20C. We considered these POPs both in groups (similar congener, isomer, metabolite groups) and separately. Odds ratios and 95% confidence intervals were estimated using a conditional logistic model in a two-stage approach, further adjusting for smoking, occupation, marital status, BMI, and serum cholesterol level in primary models.<br><br>RESULTS: In the main model hexachlorobenzene (HCB) showed a positive association with ALS occurrence. In contrast, &#x3a3;non-dioxin-like (NDL) PCB and &#x3a3;DDT were significantly inversely associated with ALS incidence. Most other POP groups were non-significantly inversely associated with ALS risk. In co-pollutant models, the only notable changes were that &#x3a3;dioxin-like PCB and &#x3a3;HCH showed large non-significant, elevated, ORs, suggesting some negative co-pollutant confounding. There were some suggestions of stronger findings when limiting to some subgroups.<br><br>DISCUSSION: We found little evidence that POPs were associated with ALS, but we identified a suggestive positive association with HCB and HCH. &#x3a3;NDL PCB and &#x3a3;DDT were inversely associated with ALS. This could suggest protective mechanisms or uncontrolled confounding by neuroprotective factors (e.g. fish oils). https://doi.org/10.1289/EHP16539.}, }
@article {pmid40488544, year = {2025}, author = {Benzo-Iglesias, MJ and Rocamora-Pérez, P and Valverde-Martínez, ML&#xc1; and García-Luengo, AV and Benzo-Iglesias, PM and López-Liria, R}, title = {Efficacy of respiratory muscle training in improving pulmonary function and survival in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Therapeutic advances in respiratory disease}, volume = {19}, number = {}, pages = {17534666251346095}, doi = {10.1177/17534666251346095}, pmid = {40488544}, issn = {1753-4666}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/therapy/diagnosis ; *Respiratory Muscles/physiopathology ; *Breathing Exercises/adverse effects/methods ; Randomized Controlled Trials as Topic ; Quality of Life ; Muscle Strength ; *Lung/physiopathology ; Treatment Outcome ; Recovery of Function ; Male ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, resulting in muscle weakness, loss of function, and ultimately death due to respiratory failure. Due to the lethal prognosis of ALS, respiratory muscle training has been proposed as a potentially beneficial intervention.<br><br>OBJECTIVES: To systematically review the efficacy of respiratory muscle training on lung function and respiratory muscle strength in ALS patients.<br><br>DESIGN: A systematic review and meta-analysis of randomized controlled trials.<br><br>DATA SOURCES AND METHODS: Articles published in PubMed, PEDro, Scopus, and Web of Science databases up to July 2024. The Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement guideline was followed. Included studies had (1) ALS patients, (2) respiratory muscle training, (3) physical exercise, usual care or no intervention were provided as a comparison group, (4) assessments of lung function, respiratory muscle strength, quality of life, survival, fatigue, and functional capacity outcome measures, and (5) a randomized controlled trial design. Methodological quality was analyzed using the PEDro scale, and risk of bias with the Cochrane Collaboration Risk of Bias Tool. Meta-analyses were performed with Review Manager software.<br><br>RESULTS: Five randomized controlled trials with 170 participants were included. The results showed that respiratory muscle training improved muscle strength, particularly maximum expiratory and inspiratory pressures. One study suggested inspiratory muscle training as a survival predictor in ALS patients. No significant effects were observed in forced vital capacity or quality of life. No adverse effects were reported.<br><br>CONCLUSION: Respiratory muscle training improves ventilatory function, particularly respiratory muscle strength, in people with ALS. While evidence is limited, it shows promise as an adjuvant therapy to enhance quality of life and survival. It has been registered in the PROSPERO (CRD42024568235).}, }
@article {pmid40488385, year = {2025}, author = {Hermann, A and Prudlo, J and Kasper, E and Synofzik, M and Peters, O and Priller, J and Dinter, E and Wiltfang, J and Zerr, I and Flöel, A and Bürger, K and Höglinger, GU and Levin, J and Düzel, E and Teipel, S and Beichert, L and Brosseron, F and Wagner, M and Frommann, I and Ramirez, A and Yakupov, R and Schmid, M and Lingor, P and Haass, C and ,  and Spottke, A and Günther, R and Weydt, P and Neumann, M and Schneider, A}, title = {"The DESCRIBE-ALS-FTD study: a prospective multicenter observational study of the ALS-FTD spectrum".}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2509617}, pmid = {40488385}, issn = {2167-9223}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit significant clinical, genetic and neuropathological abnormalities, and are regarded as belonging to a common disease spectrum, referred to as the ALS-FTD spectrum disorders. Our understanding of the underlying mechanisms of these diseases has advanced significantly, including molecular neuropathology, genetics and molecular pathophysiology. The heterogeneity of these diseases poses significant challenges to translational research and drug development, particularly in sporadic cases. Consequently, there is an urgent need to improve patient stratification for the successful execution of future clinical trials. Methods/Results: We here describe the study design of the DESCRIBE-ALS/FTD study which aims to address this research gap by undertaking a systematic sampling of patients from the ALS FTD spectrum, encompassing all possible disease variants. The main objective of the study is to systematically document detailed cross-sectional phenotyping and the temporal progression of motor and neuropsychological abnormalities that occur in both ALS and FTD. Additionally, it seeks to systematically correlate these abnormalities with genetics and potentially predictive biomarkers including longitudinal biomaterial sampling, brain imaging and brain banking. Furthermore, first-degree relatives of patients with disease-causing gene variants undergo the same assessments to also sample presymptomatic risk gene carriers. Conclusion: With this prospective registry study we aim to generate datasets which will help researchers identifying different disease traits in people with sporadic and genetic ALS and FTD and to develop biomarkers to identify preclinical and prodromal disease stages.}, }
@article {pmid40488178, year = {2025}, author = {Benetton, C and Preuilh, A and Khamaysa, M and Chaumon, M and Lackmy-Vallée, A and Er, A and Pélégrini-Issac, M and Querin, G and Rouaux, C and Pradat, PF and Marchand-Pauvert, V}, title = {Encephalography cross-frequency coupling and brain alteration in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf192}, pmid = {40488178}, issn = {2632-1297}, abstract = {The diagnosis of amyotrophic lateral sclerosis requires identifying degeneration in both brain and bulbospinal motor neurons. However, detecting cortical dysfunction remains challenging, as peripheral symptoms often overshadow upper motor neuron signs. Although transcranial magnetic stimulation and MRI are valuable tools, transcranial magnetic stimulation is challenged as disease progresses but also at early stage in some patients, and brain MRI shows in most cohorts no significant change at the time of diagnosis. This emphasizes the need for neuromarkers facilitating detection of cortical dysfunction and longitudinal monitoring. EEG offers promising avenues. Accordingly, we recently identified altered theta-gamma phase-amplitude coupling in amyotrophic lateral sclerosis. The present study aimed to further explore phase-amplitude coupling in patients, focusing not only on theta and gamma bands but also on alpha and beta bands, and the link with handedness and brain structure. Resting-state EEG was recorded in 26 patients with amyotrophic lateral sclerosis and 26 age- and sex-matched controls, alongside anatomical and diffusion MRI. PAC was calculated between slow and gamma oscillations at five sensorimotor electrodes bilaterally. Grey and white matter integrity was evaluated through cortical thickness measurements and diffusion metrics along the corticospinal tract. Results revealed significantly decreased theta-gamma PAC in the dominant hemisphere of patients, without changes in band powers or other frequency couplings. MRI confirmed well-known handedness-related brain structural asymmetry in both groups, although it was less pronounced in patients. Specifically, diffusion metrics were altered in the most caudal segment (brainstem level) of the pyramidal tract within the dominant hemisphere in patients. These findings align with lateralized theta-gamma PAC alterations and the greater vulnerability of the dominant hemisphere to amyotrophic lateral sclerosis. No correlation was found between electrophysiological and diffusion metrics, likely because they are related to different mechanisms: PAC alteration being presumably linked to excitation/inhibition imbalance preceding upper motor neuron degeneration. Moreover, theta-gamma PAC was found to be particularly altered in patients with altered cognitive scores, consistent with previous findings in patients with mild cognitive impairment. Lastly, receiver operating characteristic analyses demonstrated that PAC outperformed diffusion MRI in diagnostic accuracy, underscoring its potential as a very sensitive marker of cortical dysfunction in amyotrophic lateral sclerosis. Although these results need validation in a larger cohort at different stages of the disease and across different forms (sporadic and familial), they confirm that PAC can detect cortical dysfunctions in amyotrophic lateral sclerosis.}, }
@article {pmid40487949, year = {2025}, author = {Kumar, S}, title = {Nomogram-based strategy to predict relapse-free survival in patients with gastrointestinal stromal tumor using inflammatory indicators.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {5}, pages = {103127}, pmid = {40487949}, issn = {1948-5204}, abstract = {Zhao et al's investigation on the assessment of inflammatory markers prognostic value for relapse-free survival in patients with gastrointestinal stromal tumor (GIST) using a nomogram-based approach is a scientific approach. This study explored the potential of an inflammatory marker-based nomograph model, highlighting the relapse-free survival-associated risk factors prognostic potential in patients with GIST. The author assessed 124 samples from patients with GIST to find an association between inflammatory markers and tumor size in a retrospective study using multivariate regression analysis. Further, a nomogram model was developed to identify the independent risk factors for the prognosis. GIST clinical treatment can use preoperative monocyte/lymphocyte ratio and platelet/lymphocyte ratio for relapse-free survival prognosis as independent factors.}, }
@article {pmid40486953, year = {2025}, author = {Lehrer, S and Rheinstein, PH}, title = {Insulin and Metformin are Associated With Reduced Risk of Amyotrophic Lateral Sclerosis.}, journal = {Chronic diseases and translational medicine}, volume = {11}, number = {2}, pages = {148-155}, pmid = {40486953}, issn = {2589-0514}, abstract = {BACKGROUND: Type 2 diabetes (T2D), but not type 1, protected against amyotrophic lateral sclerosis (ALS). In T2D serum insulin is normal or elevated in the early stages. Type 1 diabetes, characterized by a total lack of insulin, is associated with an increased risk of ALS. The antidiabetic metformin also protects against ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open channel via which toxic substances from astrocytes reach motor neurons to cause ALS.<br><br>METHODS: In the current study we analyzed FDA MedWatch data to determine whether insulin or metformin could reduce the risk of ALS. We performed in silico molecular docking studies and molecular dynamics simulation with Cx43 to determine if insulin or metformin dock within the Cx43 channel and can block it effectively, again reducing risk of ALS.<br><br>RESULTS: In MedWatch, Insulin use is associated with a significantly reduced risk of ALS (Proportional Reporting Ratio 0.401). Metformin use is associated with a significantly reduced risk of ALS (PRR 0.567). The Human insulin heterodimer docked within center of the Cx43 channel, effectively blocking it. Molecular dynamics simulation showed that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Metformin docks within the Cx43 channel, but the relatively small size of the metformin molecule may not allow it to obstruct the passage of toxic substances from astrocytes to motor neurons.<br><br>CONCLUSION: MedWatch data indicate that both insulin and metformin reduce risk of ALS. The results of our in silico docking study and molecular dynamics simulation corroborate our previous findings with Cx31. Insulin docks within the open hemichannel of hexameric Cx43, potentially blocking it. Molecular dynamics simulation showed that the block is stable and may be responsible for the protective effect of T2D and insulin on ALS.}, }
@article {pmid40485888, year = {2025}, author = {Liu, Y and Ren, Y and Song, P}, title = {Traditional Chinese medicine for intractable and rare diseases: Research progress and future strategies.}, journal = {Intractable &amp; rare diseases research}, volume = {14}, number = {2}, pages = {109-121}, pmid = {40485888}, issn = {2186-3644}, abstract = {Rare diseases have become a global public health challenge due to their low prevalence, difficult diagnosis, and limited treatment options. Intractable diseases are more common but often involve complex mechanisms, treatment with limited efficacy, and high medical costs, placing a heavy burden on patients and healthcare systems. In recent years, traditional Chinese medicine (TCM) has demonstrated unique advantages in the treatment of intractable and rare diseases and has gradually become an important complementary treatment. The current work is a systematic review of the progress of clinical and experimental research on TCM in typical rare diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), mitochondrial encephalomyopathy, aplastic anemia (AA), and Wilson's disease (WD). It focuses on the multi-target therapeutic mechanisms of key Chinese herbal compound formulas, including immune regulation, antioxidative stress, and neuroprotection. The core TCM theories of "syndrome differentiation", "different treatments for the same disease" and the "same treatment for different diseases" are also discussed in the context of personalized medicine. In recent years, China has continuously promoted the development of TCM through a series of national plans and supportive policies, such as the 14th Five-Year Plan for TCM development, funding for key special projects, expedited approval pathways, and expanded coverage by medical insurance. These efforts have provided strong support for the clinical translation of TCM and technological innovation in the field of intractable and rare diseases. Notwithstanding the encouraging advances, the field of Chinese medicine continues to grapple with numerous challenges. In the future, the enhancement of mechanistic studies and quality multicenter clinical trials needs to be promoted while further enhancing policy support and international collaboration to substantiate the scientific basis and clinical value of TCM in the prevention and treatment of intractable and rare diseases.}, }
@article {pmid40485533, year = {2025}, author = {Alves, I and Gromicho, M and Pronto-Laborinho, AC and Lopes, D and Oliveira Santos, M and De Carvalho, M}, title = {Federated sport activity in amyotrophic lateral sclerosis: a case-control study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2511124}, pmid = {40485533}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) develops in a multistep process combining environmental variables and genes. Among the identified risk factors, the role of regular vigorous physical activity is still debatable. Objective: This case-control study investigated the relationship between ALS and different degrees of sports engagement, with federated status as a proxy for strenuous activity. Methods: 586 ALS patients and 558 controls were consecutively assessed by using a standard questionnaire. Due to low female participation in regular or intensive sports activity, the study focused on men (327 with ALS and 314 controls). Results: Overall, football (soccer) had the most practitioners (n = 137, 35.8%), accounting for 62.1% of ALS and 32.3% of control federated athletes. Male football players have a 3.07-fold increased ALS risk (95% CI: 1.82-5.19) compared to other men (p < 0.0001) and 3.43-fold increase (95% CI: 1.77-6.68) compared to those federated in other sports (p = 0.0003). After controlling for age and trauma, football players still had 2.91-fold (95% CI: 1.70-5.01) increased risk compared to non-federated and non-participants in contact sports intensively. No significant ALS risk difference existed for other sports practiced with identical intensity and contact levels. Clinical characteristics of ALS federated football players were similar to other ALS patients. Conclusion: Our results suggest ALS susceptibility is not linked to general physical activity, but specifically to competitive football, regardless of a history of head and neck trauma. Given football's popularity, even a small risk increase could impact many. Further research is required to understand the mechanisms linking football to ALS, and why this association is not observed in other sports.}, }
@article {pmid40485494, year = {2025}, author = {Genge, A and Pattee, GL and Sobue, G and Aoki, M and Yoshino, H and Couratier, P and Lunetta, C and Petri, S and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Apple, S and Wamil, A and Kalin, A and Jackson, CE}, title = {Safety Extension Study of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis for up to an Additional 96 Weeks of Treatment.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28451}, pmid = {40485494}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America Inc/ ; }, abstract = {INTRODUCTION/AIMS: Edaravone intravenous (IV) and oral suspension have been shown to have similar pharmacokinetics, safety, and slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Study MT-1186-A01 indicated that edaravone oral suspension was well-tolerated over 48 weeks, with no new safety concerns identified relative to existing safety data of IV edaravone, including Study MCI186-19. The aim of this study was to assess the long-term safety and tolerability of edaravone oral suspension in patients with ALS.<br><br>METHODS: Study MT-1186-A03 (NCT04577404) was a phase 3, open-label, multi-center, extension study that evaluated the long-term safety of edaravone oral suspension over an additional 96&#x2009;weeks in patients with ALS who have completed the initial 48&#x2009;weeks of Study MT-1186-A01, for a total of up to 144&#x2009;weeks of treatment. Patients received a 105-mg dose of edaravone administered in treatment cycles identical to the approved edaravone on/off dosing schedule. Patients had definite, probable, probable-laboratory-supported, or possible ALS.<br><br>RESULTS: In Study MT-1186-A03, edaravone oral suspension was well tolerated with no new safety concerns. The most common treatment-emergent adverse events (TEAEs) were fall, muscular weakness, dyspnea, constipation, and dysphagia. These TEAEs were consistent with the safety profile for edaravone from previous clinical trials.<br><br>DISCUSSION: These results help establish the long-term safety and tolerability profile of edaravone oral suspension.}, }
@article {pmid40484835, year = {2025}, author = {Zhao, JR and Pang, XY and Bai, JM and Zhang, JH and Wang, HF and Li, M and Chen, ZH and Cheng, HM and Ling, L and Huang, XS}, title = {[Progression patterns of lower motor neuron involvement in the lower medulla oblongata and cervical spinal cord of amyotrophic lateral sclerosis patients].}, journal = {Zhonghua yi xue za zhi}, volume = {105}, number = {21}, pages = {1721-1727}, doi = {10.3760/cma.j.cn112137-20241229-02957}, pmid = {40484835}, issn = {0376-2491}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; *Medulla Oblongata/pathology ; Male ; Female ; *Cervical Cord/pathology ; Electromyography ; *Motor Neurons/pathology ; Middle Aged ; Disease Progression ; Adult ; Aged ; *Spinal Cord/pathology ; }, abstract = {Objective: To investigate the lower motor neuron (LMN) involvement patterns in the lower medulla oblongata and cervical spinal cord in amyotrophic lateral sclerosis (ALS) patients. Methods: The needle electromyography (EMG) data of 200 patients with non-thoracic onset sporadic ALS, hospitalized in the Neurology Department of the First Medical Center of the Chinese PLA General Hospital from September 2022 to December 2023, were retropectively analyzed. All participants met the EI Escorial-Revised diagnostic criteria. According to the onset site, the patients were divided into the lower medulla oblongata onset group(34 cases), the spinal cord onset group(166 cases) [including the lower cervical spinal cord onset group (92 cases) and the lumbosacral spinal cord onset group (74 cases)]. Electromyography (EMG) abnormalities in the muscles innervated by the lower medulla oblongata and cervical cord were counted, and the characteristics of LMN involvement were analyzed. The binomial distribution test was used to determine whether the progression of LMN involvement to the second central nervous system segment was random. Results: Among 200 ALS patients, there were 111 males (55.5%) and 89 females (44.5%), with an age onset of 28-86 (56±11) years. 20 (10.0%) cases with normal sternocleidomastoid (SCM)-EMG or trapezius (TRA)-EMG results, and 7 (3.5%) cases with normal SCM-EMG and TRA-EMG results were observed in patients with LMN involvement in both the lower medulla oblongata and lower cervical spinal cord. The abnormal rates of EMG at the onset of lower cervical spinal cord were tongue muscle (GEN)-EMG (88.2%, 30/34), TRA-EMG (70.6%, 24/34) and SCM-EMG (67.6%, 23/34), respectively. The abnormal rates of EMG at the onset of lower cervical spinal cord were TRA-EMG (72.8%, 67/92), SCM-EMG (38.0%, 35/92) and GEN-EMG (32.6%, 30/92), respectively. The binomial distribution test showed that the progression of LMN involvement to the second segment of the central nervous system was not random (all P<0.05). In low bulbar onset patients, the abnormal rate of LMN involvement was higher in the lower cervical spinal cord segment [100.0% (34/34)], and lower in the lumbosacral spinal cord segment[91.2% (31/34)]. In the lower cervical spinal cord onset group, the abnormal rate of LMN involvement was lower in the the low medulla obliterum[32.6% (30/92)] and high in the lumbosacral spinal cord [96.7% (89/92)].In the lumbosacral spinal cord onset group, the abnormal rate of LMN involvement was low in the low medulla oblata [27.0% (20/74)] and high in the lower cervical spinal cord [94.6% (70/74)]. Conclusions: The progression of LMN involvement in the lower medulla oblongata and cervical spinal cord is primarily continuous, while a discontinuous progression pattern was also observed. The lower medulla oblongata of ALS patients with spinal onset is relatively less involved in disease progression.}, }
@article {pmid40482989, year = {2025}, author = {Qin, J and He, Y and Yu, W and Zhang, Z and Chen, X and Hu, Y and Jiang, H}, title = {Knockdown of OPTN modulates miRNA-125b-5p expression via NF-κB pathways in amyotrophic lateral sclerosis.}, journal = {Archives of biochemistry and biophysics}, volume = {}, number = {}, pages = {110499}, doi = {10.1016/j.abb.2025.110499}, pmid = {40482989}, issn = {1096-0384}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterized by severe dysfunction in upper and lower motor neurons. Previous studies have reported that the optineurin gene (OPTN) downregulation is one of the causative genetic factors for ALS, leading to the dysfunction of optineurin (OPTN), a multifunctional protein implicated in several cellular processes. Herein, we found that conditional knockout of the OPTN gene in mouse microglia leads to activation of microglia. In subsequent studies, we also found that OPTN knockdown in BV2 cells leads to the activation of BV2 cells and promotes the apoptosis of co-cultured NSC34 cells via exosomes derived from BV2 cells in vitro. In contrast, OPTN knockdown in NSC34 cells did not cause apoptosis of the NSC34 cells themselves. It was suggested that microglia activation is involved in ALS initiation and development, but the nature of microglial-neuronal interactions remained elusive, requiring further exploration. Exosomes have been proven to be essential mediators. Notably, increased miRNA-125b-5p expression was uncovered in BV2 cells with the OPTN gene silenced, their derived exosomes, as well as the cocultured NSC34 cells. Interestingly, we proved that increased miRNA-125b-5p enhanced the apoptosis of NSC34 cells. We further noted that the overexpression of miRNA-125b-5p in BV2 cells can be regulated by an NF-κB activator (LPS) or inhibitor (withaferin A). Altogether, this study showed that silencing the OPTN gene may overexpress miRNA-125b-5p levels via the classical NF-κB pathway in BV2 cells. Up-regulated miRNA-125b-5p might be transmitted from exosomes to NSC34 cells, resulting in NSC34 cells apoptosis. Microglial-neuronal interactions mediated by exosomes were the crucial mechanism of OPTN gene downregulation leading to ALS, and this conclusion had been verified in cell models.}, }
@article {pmid40482900, year = {2025}, author = {La Cognata, V and Guarnaccia, M and Morello, G and Gentile, G and Cavallaro, S}, title = {Predicting amyotrophic lateral sclerosis in the pre-symptomatic phase: Insights from SOD1G93A mouse gene expression profiles.}, journal = {Experimental neurology}, volume = {392}, number = {}, pages = {115329}, doi = {10.1016/j.expneurol.2025.115329}, pmid = {40482900}, issn = {1090-2430}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fast-paced fatal disease that requires immediate intervention to slow down the course of pathology and improve patients' quality of life. However, in most cases, ALS is diagnosed too late. For this reason, an accurate diagnostic test is urgently needed to identify ALS patients early, enabling a timely introduction of novel therapeutics and effective monitoring of disease progression. To address this significant unmet medical need, we explored a transcriptome-based signature to predict ALS during the preclinical phase. Using publicly available gene expression profiles from central nervous system (lumbar isolated motor neurons and spinal cord homogenates) of transgenic SOD1G93A mice with different genetic background and their respective control littermates, covering pre-symptomatic to late stages of the disease, we identified 463 differentially expressed genes (DEGs), primarily involved in immune response and metabolic processes. Based on this ALS gene-associated signature, we tested three machine learning binary classifiers (Support Vector Machine, Neural Network and Linear Discriminant Analysis), which demonstrated highly significant predictive power in discriminating mutant SOD1G93A from controls mice, even at pre-symptomatic stages. This was evident in both the discovery cohort and in two additional peripheral cross-tissue validation datasets from preclinical SOD1G93A sciatic nerve and muscles. Our study provides the first proof of concept for early ALS detection using a machine learning-based transcriptomic classifier. This could lead to earlier diagnosis, potentially enabling effective monitoring of disease progression and earlier interventions.}, }
@article {pmid40482733, year = {2025}, author = {Ting, CH and Tai, ST and Chang, HY and Huang, PY and Jeng, LF and Lai, HJ and Kuo, YC and Kao, CH and Wang, IF and Tsai, LK}, title = {Baicalein benefits amyotrophic lateral sclerosis via reduction of Intraneuronal misfolded protein.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {}, number = {}, pages = {130831}, doi = {10.1016/j.bbagen.2025.130831}, pmid = {40482733}, issn = {1872-8006}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by muscle weakness and atrophy, with limited treatment options. The accumulation of misfolded proteins, such as misfolded superoxide dismutase 1 (mSOD1), contributes significantly to neuronal degeneration in ALS. Therapies targeting misfolded proteins represent a promising strategy. Baicalein, a flavonoid compound with neuroprotective properties, has shown efficacy in clearing misfolded proteins and improving behaviors in rodent models of Alzheimer's and Parkinson's diseases. However, its effects in ALS remain largely unexplored. This study demonstrated that baicalein treatment reduced total and misfolded SOD1 protein levels in both soluble and insoluble fractions of a motor neuron cell line overexpressing mutant SOD1. Baicalein also reduced intracellular SOD1 aggregates in cultured motor neurons transfected with SOD1/G93A, preserving neurite length. In an ALS mouse model expressing the SOD1/G93A transgene, baicalein treatment decreased mSOD1 aggregation, increased spinal motor neuron density, and reduced neuromuscular junction denervation. Furthermore, baicalein partially improved motor behaviors, as assessed by the rotarod test. These findings highlight baicalein's potential as a therapeutic agent for ALS, targeting intraneuronal misfolded proteins to ameliorate pathological changes and preserve motor function.}, }
@article {pmid40482730, year = {2025}, author = {Mori, H and Sato, T and Tsuboguchi, S and Takahashi, M and Nakamura, Y and Hoshina, K and Kato, T and Fujii, M and Onodera, O and Ueno, M}, title = {TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106988}, doi = {10.1016/j.nbd.2025.106988}, pmid = {40482730}, issn = {1095-953X}, abstract = {TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43[C173/175S] and TDP-43[G298S] as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43[C173/175S] induced insoluble inclusions more robustly than TDP-43[G298S] did. In contrast, TDP-43[G298S] induced cell death more severely than TDP-43[C173/175S]. TDP-43[G298S] was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43[C173/175S]. Instead, TDP-43[C173/175S] was frequently trapped in the axon initial segments. Finally, TDP-43[G298S] was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43[C173/175S] to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.}, }
@article {pmid40482593, year = {2025}, author = {Tankisi, H and Jacobsen, AB and Fanella, G and Cengiz, B and Kılınç, H and Matamala, JM and Moreno-Roco, J and Abrahao, A and Zinman, L and Koltzenburg, M and Howells, J and Samusyte, G and Awiszus, F and Bostock, H}, title = {Short-interval intracortical inhibition and facilitation in amyotrophic lateral sclerosis related to disease phenotype.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {176}, number = {}, pages = {2110770}, doi = {10.1016/j.clinph.2025.2110770}, pmid = {40482593}, issn = {1872-8952}, abstract = {OBJECTIVE: To investigate the relationship between short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF) and amyotrophic lateral sclerosis (ALS) phenotype, using threshold-tracking transcranial magnetic stimulation (TMS).<br><br>METHODS: A new paired-pulse TMS protocol was applied to 49 patients with ALS and 49 age-matched healthy controls. Motor evoked potentials (MEPs) were recorded from first dorsal interosseus muscle, while paired pulses were delivered at interstimulus intervals (ISI) of 1.0, 2.5 or 3.0&#xa0;ms, with stimuli related to the resting motor threshold for a 200&#xa0;&#xb5;V MEP. For each ISI, 6 SICI and 3 SICF pulse pairs with different conditioning stimuli were randomised and interleaved with test-alone stimuli.<br><br>RESULTS: ALS phenotypes were characterised as Pyramidal (n&#xa0;=&#xa0;12, with prominent upper motor neuron signs), Classic (n&#xa0;=&#xa0;20, with limb onset), or Bulbar (n&#xa0;=&#xa0;17). Compared with healthy controls, Bulbar patients had significantly less inhibition at all ISIs, while SICI in Pyramidal patients was normal, and in Classic patients intermediate. The only SICF abnormalities independent of the changes in SICI were less facilitation in Pyramidal patients at ISIs 1 and 3&#xa0;ms.<br><br>CONCLUSION: Changes in SICI and SICF depend on ALS phenotype.<br><br>SIGNIFICANCE: ALS phenotypes should be matched between treatment and placebo arms of clinical trials.}, }
@article {pmid40482451, year = {2025}, author = {Attiq, A and Afzal, S and Raman, H and Ahmad, W}, title = {Neuroinflammation to neurodegeneration: Boulevard of broken nerves.}, journal = {International immunopharmacology}, volume = {161}, number = {}, pages = {115015}, doi = {10.1016/j.intimp.2025.115015}, pmid = {40482451}, issn = {1878-1705}, abstract = {Neuroinflammation is caused by various factors, such as the activation of glial cells, the excessive release of chemokines and cytokines, and the accumulation of blood cells in the brain parenchyma. The inflammatory processes occur in acute and chronic phases, with traumatic brain injuries triggering the release of neurotoxins from CNS-specific glial cells. Furthermore, activation of microglia, astrocytes, and mast cells worsens the situation by producing pro-inflammatory cytokines, chemokines and glia maturation factors. Chronic activation of astroglia and microglial cells promotes loss of neurons, memory, and impaired learning capacity, leading to neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. These implications have led to a rational search for inflammatory druggable targets. Based on various preclinical and clinical studies, NSAIDs (aspirin, ibuprofen, diclofenac, and mefenamic acid), SSRIs (fluoxetine and sertraline), antipsychotics (risperidone), corticosteroids (dexamethasone), antidiabetics (metformin and rosiglitazone), and statins (simvastatin and atorvastatin) have exhibited promising results. These drugs have anti-inflammatory and neuromodulation activities that enhance neuroplasticity and effectively manage neurodegenerative symptoms. In addition, non-pharmacological interventions such as art creation and physical exercise have been linked with improving neural development and stimulating the production of anti-inflammatory cytokines, which can attenuate disease progression and promote synaptic plasticity. Hence, it is imperative to understand the complex interplay between glial cells, inflammatory signalling and neural pathways. We reviewed the interconnected pathways between neuroinflammation and neurodegeneration. Moreover, recommendations for pharmacological and non-pharmacological interventions to address these issues are discussed herein.}, }
@article {pmid40481583, year = {2025}, author = {Johnson, B and Gibson, G and Baskerville, D and Castellano, G and de Courcy, J and Iqbal, H and Piercy, J and Williams, A and Pinedo-Villanueva, R and Rylands, A}, title = {Health-related quality of life and productivity burden for non-professional caregivers of adults with rare diseases: a real-world study.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {282}, pmid = {40481583}, issn = {1750-1172}, mesh = {Humans ; *Quality of Life ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; *Rare Diseases ; Adult ; Efficiency ; Aged ; Surveys and Questionnaires ; Cost of Illness ; }, abstract = {BACKGROUND: Rare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases.<br><br>METHODS: We analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017-March 2021 via Adelphi Disease Specific Programmes&#x2122; in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington's disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity.<br><br>RESULTS: Data were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients' mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients' mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers' mean age was 55.8 (13.8) years, 66% were female. Caregivers' EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers' HRQoL and productivity. Caregivers' HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients' EQ-5D utility and caregivers' age. Outcomes relating to caregivers' employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients' EQ-5D utility, caregivers' age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD.<br><br>CONCLUSIONS: The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.}, }
@article {pmid40480719, year = {2025}, author = {Fuentes, CA and Montoya, D and Öztop, M and Rojas-Rioseco, M and Bravo, M and González, F and Castillo, RDP}, title = {Interval resonance analysis (InRA): A versatile tool for automated untargeted [1]H NMR fingerprinting - A case study in sugar beet field authentication.}, journal = {Analytica chimica acta}, volume = {1363}, number = {}, pages = {344175}, doi = {10.1016/j.aca.2025.344175}, pmid = {40480719}, issn = {1873-4324}, mesh = {*Beta vulgaris/chemistry ; *Proton Magnetic Resonance Spectroscopy/methods ; Least-Squares Analysis ; Software ; Automation ; Multivariate Analysis ; Algorithms ; }, abstract = {BACKGROUND: The extraction of relevant information from proton nuclear magnetic resonance ([1]H NMR) spectra through preprocessing and multivariate analysis requires integrating multiple software tools and extensive manual intervention, compromising efficiency and reproducibility when the technique is used. Consequently, the development of automated, versatile, and reliable methodologies has become imperative to streamline workflows, improve analytical performance, and broaden the applicability of multivariate methods for the analysis of diverse sample types and experimental conditions.<br><br>RESULTS: This work presents the development and application of Interval Resonance Analysis (InRA), an alternative software tool focused on [1]H NMR multivariate analysis. InRA includes a novel algorithm for resonance signal detection (intervals), specifically designed to operate with flexibility across diverse [1]H NMR spectra. All intervals are integrated using multivariate curve resolution with alternating least squares (MCR-ALS) and analyzed by exploratory analysis. The performance of InRA was tested by evaluating the [1]H NMR spectra of hydrophilic sugar beet root extracts cultivated in three different fields and their discrimination by partial least squares - discriminant analysis (PLS-DA). The workflow provided by InRA yielded consistent results regarding the distribution of samples according to their field, enabling the identification of subtle sources of variation and achieving classification accuracies &#x2265; 88.9&#xa0;%.<br><br>SIGNIFICANCE: The proposed methodology represents an advancement in the multivariate analysis of [1]H NMR spectra for untargeted studies and enhances analytical efficiency by reducing manual intervention and reliance on analyst experience. InRA is versatile and can be applied to various sample types and analytical objectives, as it is not restricted by specific experimental conditions.}, }
@article {pmid40480675, year = {2025}, author = {Reitzle, L and Rohmann, JL and Kurth, T and Audebert, HJ and Piccininni, M}, title = {External validation of risk prediction models for post-stroke mortality in Berlin.}, journal = {BMJ open}, volume = {15}, number = {6}, pages = {e089320}, doi = {10.1136/bmjopen-2024-089320}, pmid = {40480675}, issn = {2044-6055}, mesh = {Humans ; Male ; Female ; Aged ; Berlin/epidemiology ; Registries ; Risk Assessment/methods ; *Stroke/mortality ; Hospital Mortality ; Aged, 80 and over ; Middle Aged ; Risk Factors ; }, abstract = {OBJECTIVES: Prediction models for post-stroke mortality can support medical decision-making. Although numerous models have been developed, external validation studies determining the models' transportability beyond the original settings are lacking. We aimed to assess the performance of two prediction models for post-stroke mortality in Berlin, Germany.<br><br>DESIGN: We used data from the Berlin-SPecific Acute Treatment in Ischaemic or hAemorrhagic stroke with Long-term follow-up (B-SPATIAL) registry.<br><br>SETTING: Multicentre stroke registry in Berlin, Germany.<br><br>PARTICIPANTS: Adult patients admitted within 6 hours after symptom onset and with a 10th revision of the International Classification of Diseases discharge diagnosis of ischaemic stroke, haemorrhagic stroke or transient ischaemic attack at one of 15 hospitals with stroke units between 1 January 2016 and 31 January 2021.<br><br>PRIMARY OUTCOME MEASURES: We evaluated calibration (calibration-in-the-large, intercept, slope and plot) and discrimination performance (c-statistic) of Bray et al's 30-day mortality and Smith et al's in-hospital mortality prediction models. Information on mortality was supplemented by Berlin city registration office records.<br><br>RESULTS: For the validation of Bray et al's model, we included 7879 patients (mean age 75; 55.0% men). We observed 763 (9.7%) deaths within 30 days of stroke compared with 680 (8.6%) predicted. The model's c-statistic was 0.865 (95% CI: 0.851 to 0.879). For Smith et al's model, we performed the validation among 1931 patients (mean age 75; 56.2% men), observing 105 (5.4%) in-hospital deaths compared with the 92 (4.8%) predicted. The c-statistic was 0.891 (95% CI: 0.864 to 0.918). The calibration plots of both models revealed an underestimation of the mortality risk for high-risk patients.<br><br>CONCLUSIONS: Among Berlin stroke patients, both models showed good calibration performance for low and medium-risk patients and high discrimination while underestimating risk among high-risk patients. The acceptable performance of Bray et al's model in Berlin illustrates how a small number of routinely collected variables can be sufficient for valid prediction of post-stroke mortality.}, }
@article {pmid40482112, year = {2024}, author = {LaForge, JR}, title = {A Poem About ALS.}, journal = {The American journal of nursing}, volume = {124}, number = {5}, pages = {10}, doi = {10.1097/01.NAJ.0001016304.08449.3a}, pmid = {40482112}, issn = {1538-7488}, }
@article {pmid40480424, year = {2025}, author = {Lin, CY and Wu, HC and Fu, RH and Weng, EF and Hsieh, WC and Su, TP and Wu, HE and Wang, SM}, title = {Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106992}, doi = {10.1016/j.nbd.2025.106992}, pmid = {40480424}, issn = {1095-953X}, abstract = {Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC34 cells and in an AAV-mediated poly-PR42 mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS.}, }
@article {pmid40480222, year = {2025}, author = {Oldani, EG and Reynolds Caicedo, KM and Spaeth Herda, ME and Sachs, AH and Chapman, EG and Kumar, S and Linseman, DA and Horowitz, S}, title = {The effect of G-quadruplexes on TDP43 condensation, distribution, and toxicity.}, journal = {Structure (London, England : 1993)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.str.2025.05.006}, pmid = {40480222}, issn = {1878-4186}, abstract = {Many proteins implicated in neurodegenerative diseases (e.g., trans-active response DNA binding protein 43 kDa [TDP43]) interact with nucleic acids, including RNA G-quadruplexes (G4s). We here investigate whether RNA G4s play a role in TDP43 condensation in biophysical and cellular models. We find that G4s modulate TDP43 aggregation in vitro and condensation in multiple cell types, including yeast, HEK293T, and motor-neuron-like NSC-34 cells. In yeast cells, treatment with G4s causes increased TDP43 accumulation in cells before cellular death. In HEK293T cells expressing TDP43, incubation with G4-binding small molecules causes an increase in G4 stability that also stabilizes TDP43 and reduces TDP43 condensation induced by proteasomal or oxidative stress. Finally, in NSC-34 cells overexpressing exogenous TDP43, we show that G4s co-localize with TDP43 condensates under stress conditions, and treatment with G4-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest exploring treating protein misfolding diseases by targeting specific RNA structures such as G4s.}, }
@article {pmid40478288, year = {2025}, author = {Wilbert, D and Voigt, M and Jaeger, M}, title = {A process analyzer assembly for real-time automated near-infrared, Raman, and proton nuclear magnetic resonance spectroscopic monitoring enhanced by heterocovariance spectroscopy and chemometry applied to a Schiff base formation.}, journal = {Analytical and bioanalytical chemistry}, volume = {}, number = {}, pages = {}, pmid = {40478288}, issn = {1618-2650}, abstract = {Process analytical technology (PAT) plays a key role in enhancing the efficiency and resulting quality of chemical processes. Hitherto, suitable methods enable real-time analysis and provide meaningful and robust data and models. Spectroscopic techniques, e.g., vibrational or absorption, offer in situ insight into reaction progress but may require advanced data analysis to interpret the complex spectra. In this study, inline and online monitoring by spectroscopic techniques was applied to a Schiff base formation as an illustrative example and enhanced by data analysis. Two-dimensional heterocorrelation spectroscopy was used to identify and select relevant spectral regions. The results allowed data reduction and data fusion for model building and process description. First, qualitative process representation was achieved through principal component analysis (PCA). Quantitative prediction models were then developed using multivariate curve resolution-alternating least squares (MCR-ALS) with evolving factor analysis (EFA), partial least squares (PLS), and supporting vector regression (SVR) analysis. The low- and mid-level data fusion based on the spectroscopic data and the multivariate models enabled the development of accurate predictive models, with the best prediction achieved by PLS models from low-level data fusion. The results demonstrate the strength of the combination of spectroscopy, multivariate data analysis, and-in the field of PAT rarely exploited-heterocovariance transformation and data fusion to obtain process understanding and reaction models. The methodology may provide further contributions to automatable process control in industrial applications.}, }
@article {pmid40476320, year = {2025}, author = {Bombaci, A and De Marco, G and Casale, F and Salamone, P and Marchese, G and Fuda, G and Calvo, A and Chiò, A}, title = {Peripherin: A Novel Early Diagnostic and Prognostic Plasmatic Biomarker in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {6}, pages = {e70241}, doi = {10.1111/ene.70241}, pmid = {40476320}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Male ; Female ; Middle Aged ; *Peripherins/blood ; Biomarkers/blood ; Aged ; Prognosis ; Disease Progression ; Adult ; Early Diagnosis ; }, abstract = {BACKGROUND: Motor neuron diseases (MND) are heterogeneous and complex neurodegenerative disorders. Biomarkers could facilitate early diagnosis, prognosis determination, and patient stratification. Among the most studied biomarkers are neurofilaments, with peripherin (PRPH), a specific type predominantly expressed in the peripheral nervous system, gaining attention. To date, no studies have evaluated PRPH in human plasma.<br><br>METHODS: Sandwich-ELISA was used to quantify plasma peripherin from 120 MND (100 ALS, 4 PMA, 15 PLS), 73 MND-mimics, and 38 healthy-controls (HCs). Plasma was collected at diagnosis or some months earlier. 41 ALS were evaluated longitudinally. ALSFRSr, MRC, spirometry, genetic tests, disease progression rate (PR), blood examinations, and neuropsychological tests were performed. Statistical analyses included Kruskal-Wallis, Mann-Whitney, Cox regression, and Kaplan-Meier curves.<br><br>RESULTS: Plasma PRPH levels differed significantly among groups (p&#x2009;<&#x2009;0.0001), showing higher values in MND participants than MND mimics and HCs. Moreover, PRPH levels were elevated in PLS compared with HSP patients (p&#x2009;=&#x2009;0.0001). Differences persisted after adjusting for age and sex. ROC curve demonstrated that PRPH discriminated MND from MND mimics (AUC&#x2009;=&#x2009;0.85). Elevated PRPH correlated positively with ALSFRSr and lower motor neuron index, whereas inversely with disease progression rate. Higher PRPH levels at the beginning of the disease were associated with longer survival.<br><br>DISCUSSION: Plasma PRPH is raised in MND, particularly ALS, from the earliest stages, distinguishing MND from mimics and correlating with clinical parameters and survival. This suggests PRPH may reflect an endogenous response of lower motor neuron to injury. Further multicenter studies are required to refine the diagnostic and prognostic utility of PRPH in MND.}, }
@article {pmid40476303, year = {2025}, author = {Mustafa, MA and Bansal, P and Pallavi, MS and Panigrahi, R and Nathiya, D and Kumar, S and Al-Hasnaawei, S and Chauhan, AS and Singla, S}, title = {Exploring the Role of NLRP3 in Neurodegeneration: Cutting-Edge Therapeutic Strategies and Inhibitors.}, journal = {Developmental neurobiology}, volume = {85}, number = {3}, pages = {e22982}, doi = {10.1002/dneu.22982}, pmid = {40476303}, issn = {1932-846X}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists &amp; inhibitors ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Inflammasomes/metabolism ; *Neuroprotective Agents/pharmacology ; }, abstract = {Inflammasomes, particularly the NLRP3 inflammasome, play a pivotal role in mediating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD). Recent findings indicate that the activation of the NLRP3 inflammasome in microglia and astrocytes triggers the release of pro-inflammatory cytokines, including IL-1β and IL-18, which contribute to chronic inflammation and neuronal damage. This process accelerates neurodegeneration and exacerbates disease progression. Misfolded protein aggregates, mitochondrial dysfunction, and oxidative stress are key factors in the pathological activation of the NLRP3 inflammasome in these diseases. Recent studies have highlighted that targeting the NLRP3 inflammasome, either through direct inhibitors like MCC950 or natural compounds such as oridonin and β-hydroxybutyrate, shows promise in mitigating neuroinflammation and protecting neuronal integrity. These inhibitors have demonstrated neuroprotective effects in animal models of AD, PD, and MS, presenting a new therapeutic approach for halting disease progression. However, the complexity of NLRP3 regulation requires further investigation to balance its inflammatory and protective roles. This review examines the recent advancements in NLRP3 inflammasome research and discusses potential strategies for modulating inflammasome activity to slow or prevent the progression of neurodegenerative diseases.}, }
@article {pmid40475252, year = {2025}, author = {Seyedi Asl, FS and Malverdi, N and Ataei Kachouei, FS and Zarei, F and Ghiabi, S and Baziyar, P and Nabi-Afjadi, M}, title = {Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1569777}, pmid = {40475252}, issn = {2296-2646}, abstract = {Protein misfolding and aggregation in superoxide dismutase 1 (SOD1) are linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). SOD1 mutations have a significant role in the pathophysiology and fast behavior of protopathic proteins in ALS illness. The E100K mutation may be useful in uncovering the pathogenic mechanism of SOD1 associated with ALS. According to several studies, giving small molecule inhibitors made from polyphenolic flavonoid compounds may be a viable treatment strategy for neurological conditions. Using molecular docking and MD simulations, we have identified a potential flavonoid drug that may successfully inhibit SOD1's amyloidogenic activity. Puerarin, Fisetin, and Peonidin provided intriguing pharmacological hints during the initial screening of flavonoids. The Fisetin-E100K complex had a larger residual energy contribution and substantial binding than other flavonoid compounds. The findings showed that, unlike other materials, Fisetin increased the structural stability, hydrophobicity, and flexibility of the mutant while reducing the amount of β-sheets. Furthermore, to distinguish aggregation in the mutant (unbound/bound) states, we displayed modifications in the free energy landscape (FEL). As a result, Fisetin was identified as having therapeutic potential against the E100K, which might make it a viable pharmacological option for the creation of inhibitors that lower the chance of ALS death.}, }
@article {pmid40474686, year = {2025}, author = {Rothstein, J and Genge, A and De Silva, S and Zinman, L and Chum, M and Chio, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Sasson, N and Hirai, M and Takahashi, F and Salah, A and Wamil, A and Apple, S}, title = {Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT-1186-A02).}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28448}, pmid = {40474686}, issn = {1097-4598}, support = {//Mitsubishi Tanabe Pharma America Inc./ ; }, abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is approved in the US for the treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed IV edaravone slows the rate of physical functional decline. This study evaluated whether investigational daily dosing displayed superior efficacy vs. approved on/off dosing of edaravone oral suspension, and assessed safety and tolerability, over 48 weeks in patients with ALS.<br><br>METHODS: Study MT-1186-A02 (NCT04569084) was a multicenter, phase 3b, double-blind, parallel group, superiority study that randomized patients to edaravone oral suspension (105-mg dose) administered Once Daily or the same edaravone oral suspension dose administered according to the approved On/Off regimen including placebo to mimic daily drug dosing. Patients had definite or probable ALS, baseline forced vital capacity &#x2265;&#x2009;70%, and baseline disease duration &#x2264;&#x2009;2&#x2009;years. The primary endpoint was a combined assessment of function and survival (CAFS) at week 48, which included change in ALS Functional Rating Scale-Revised (ALSFRS-R) and time to death.<br><br>RESULTS: CAFS at week 48 indicated Once Daily dosing did not show a statistically significant difference vs. approved on/off dosing (p&#x2009;=&#x2009;0.777). Both dosing regimens provided comparable change from baseline ALSFRS-R total score to week 48 (least squares mean difference: 0.27 [95% CI -1.43 to 1.97]). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.<br><br>DISCUSSION: Daily edaravone oral suspension did not show superiority and had equivalent safety and tolerability vs. the approved On/Off regimen, reinforcing the appropriateness of the approved dosing regimen.}, }
@article {pmid40473629, year = {2025}, author = {Li, Y and Fang, J and Ding, Y and Zhang, X and Liu, Y and Qiu, W and Xu, H and Kang, Y and Chen, J and Gao, Y and Zhao, YG and Yang, P and Wang, B and Tian, W and Chen, Y and Bi, W and Zhang, P}, title = {β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5227}, pmid = {40473629}, issn = {2041-1723}, support = {20240484503//Beijing Nova Program/ ; 7244365//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; 32471202//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32270856//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Stress Granules/metabolism ; RNA Recognition Motif Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Carrier Proteins/metabolism/genetics ; Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism/genetics ; RNA Helicases/metabolism/genetics ; Animals ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mutation ; Mice ; HEK293 Cells ; Phase Separation ; DNA Helicases ; }, abstract = {β-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked neurodegenerative disorder caused by mutations in the WDR45 gene, yet its molecular mechanisms remain poorly understood. Here, we identify a role for WDR45 in stress granule (SG) disassembly, mediated through its phase separation with Caprin-1. We demonstrate that WDR45 forms gel-like condensates via its WD5 domain, which competitively displaces G3BP1 from Caprin-1 to promote SG disassembly. BPAN-associated WDR45 mutations impair condensate formation and Caprin-1 interaction, leading to delayed SG disassembly, which correlates with earlier disease onset. WDR45 depletion also exacerbates amyotrophic lateral sclerosis-associated pathological SGs, highlighting its broader relevance to neurodegenerative diseases. Using iPSC-derived midbrain neurons from a BPAN patient, we demonstrate delayed SG recovery, directly linking WDR45 dysfunction to neurodegeneration. These findings establish WDR45 as a critical regulator of SG dynamics, uncover a potential molecular basis of BPAN pathogenesis, and identify therapeutic targets for neurodegenerative diseases associated with SG dysregulation.}, }
@article {pmid40473505, year = {2025}, author = {Song, W and Huang, Q and Jiang, Z}, title = {Clinical efficacy of athletic taping-assisted physiotherapy for plantar fasciitis: A systematic evaluation and meta-analysis.}, journal = {Foot and ankle surgery : official journal of the European Society of Foot and Ankle Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.fas.2025.05.013}, pmid = {40473505}, issn = {1460-9584}, abstract = {BACKGROUND: Plantar fasciitis is a common sports injury with long-term chronic pain in the heel as the main symptom, and athletic taping has achieved certain therapeutic effects to improve it, but the clinical efficacy of the problem is still controversial, which was evaluated by Meta-analysis to evaluate the clinical efficacy of the athletic taping technique on patients with plantar fasciitis.<br><br>METHODS: The Cochrane Library, Embase, PubMed, Web of Science, CNKI, Wanfang, and Vip databases were searched by computer for randomized controlled trial on the clinical efficacy of exercise taping in patients with PF from the time of construction to 1 September 2024, and the PRISMA 2020 checklist was strictly followed. Quality was assessed using the cochrane 2.0 randomized controlled trials scale by two independent reviewers. Endings were meta-analysis using RevMan 5.4.1 analysis software to analyse the data.<br><br>RESULTS: Eleven randomized controlled trial with a total of 395 patients were included. On VAS scores, KT effectively reduced VAS pain scores (MD=-0.79,95&#x202f;% CI -1.10,-0.48, P&#x202f;<&#x202f;0.00001); on AOFAS scores, KT improved AOFAS function scores (MD=6.58, 95&#x202f;% CI 5.03,8.13, P&#x202f;<&#x202f;0.00001) and the results remained consistent across intervention durations; on plantar fascia thickness measurements, KT significantly reduced plantar fascia thickness (MD=-0.33, 95&#x202f;% CI -0.56,-0.10, P&#x202f;=&#x202f;0.005); on BBS scores, KT significantly improved BBS scores [MD=&#x202f;4.75, 95&#x202f;% CI (3.17, 6.32), P&#x202f;<&#x202f;0.00001]; on FFI-FPS scores, KT effectively improved FFI-FPS scores [MD =&#x202f;-2.59, 95&#x202f;% CI (-3.50, -1.69), P&#x202f;<&#x202f;0.00001]; on FFI-FDS scores, there was a significant improvement on FFI-FDS scores; on FFI-ALS scores, KT had a significant improvement on the FFI-ALS score had a significant effect [MD=&#x202f;-11.03, 95&#x202f;% CI (-14.79, -7.27), P&#x202f;<&#x202f;0.00001]; and on VAS scores after follow-up, the pain relief effect was sustained (MD=-1.03, 95&#x202f;% CI -1.21, -0.85, P&#x202f;<&#x202f;0.00001).<br><br>CONCLUSION: Based on the available evidence, preliminary analyses suggest that KT combined with conventional rehabilitation may have some advantages in improving pain, ankle-hindfoot function, and plantar fascia thickness in patients with plantar fasciitis, and some of the efficacy is short-term sustained. However, due to the heterogeneity and sample size of the included studies, the above conclusions need to be further validated by more high-quality studies.}, }
@article {pmid40473122, year = {2025}, author = {Mueller, KA and Suneby, EG and Ferola, MH and Moreno, AJ and Kidd, JD and Thompson, K and Vieira, FG and Valdez, G and Hatzipetros, T}, title = {Comprehensive characterization and validation of the Prp-hPFN1[G118V] mouse model: Guidelines for preclinical therapeutic testing for ALS.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106975}, doi = {10.1016/j.nbd.2025.106975}, pmid = {40473122}, issn = {1095-953X}, abstract = {The hPFN1[G118V] mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral, electrophysiological, and neuropathological assessments to define the chronology of pathological events and assess inherent subject variability. The early stage of the disease in this model was characterized by elevated plasma neurofilament light chain levels, an effect that persisted and progressed throughout the course of the disease, followed by spinal cord neuroinflammation, suggesting that axonal pathology is the initiating event. The middle stage of the disease involved progressive neuromuscular decline, including reductions in compound muscle action potential (CMAP) and grip strength, accompanied by neuromuscular junction degeneration. The end-stage of the disease was characterized by the onset of visible changes such as weight loss, gait abnormalities and hindlimb paresis that quickly progressed to paralysis. At end-stage we also observed spinal motor neuron loss and TDP-43 pathology. The average humane endpoint was 213 days for females and 237 days for males. Our findings demonstrate that hPFN1[G118V] mice recapitulate key ALS features with moderate disease progression and a reproducible disease course, making them a valuable model for therapeutic testing. Recommendations are provided to optimize study design for preclinical testing, emphasizing survival duration as the primary endpoint, with CMAP and plasma NFL as key secondary readouts.}, }
@article {pmid40470490, year = {2025}, author = {Ren, S and Che, X and Hu, S and Feng, X and Zhang, J and Shi, P}, title = {The effect of exercise intervention on amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1499407}, pmid = {40470490}, issn = {1664-2295}, abstract = {OBJECTIVE: Quantitative evaluation of the effect of exercise intervention in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: The CNKI, WOS, PubMed, and Scopus databases were searched by computer, and randomized controlled trials (RCTs) of exercise intervention in ALS were screened out according to the inclusion and exclusion criteria of the PICOS principle. Stata 12.0 software was used for statistical analysis.<br><br>RESULTS: A total of 12 RCTs including 430 participants were included. Meta-analysis results show that exercise intervention can significantly improve the overall function, walking test (WT) distance and maximum expiratory pressure (MEP) of ALS patients (p <&#x202f;0.05). However, exercise interventions did not show significant effects on fatigue, maximum inspiratory pressure (MIP), forced vital capacity (FVC), and peak expiratory flow (PEF) in ALS patients (p >&#x202f;0.05). Subgroup analysis showed that resistance exercise is the most effective intervention for improving the function of ALS patients, while aerobic exercise is the most effective intervention for improving FVC in ALS patients.<br><br>CONCLUSION: Exercise intervention in ALS has a positive effect, but due to the small number of included studies and possible heterogeneity, risk of bias and sensitivity issues, further research is needed.}, }
@article {pmid40469844, year = {2025}, author = {Shen, D and Yang, X and He, D and Zhang, K and Liu, S and Sun, X and Li, J and Cai, Z and Liu, M and Zhang, X and Liu, Q and Cui, L}, title = {Genetic analysis of ERBB4 gene in Chinese patients with amyotrophic lateral sclerosis: a single-center study and systematic review of published literature.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1584541}, pmid = {40469844}, issn = {1663-4365}, abstract = {BACKGROUND: Rare ERBB4 variants have been implicated in amyotrophic lateral sclerosis (ALS), but their prevalence and clinical significance remain poorly understood, particularly across different ethnic populations.<br><br>METHODS: We performed genetic screening of ERBB4 in 1627 Chinese ALS patients using whole-exome sequencing. A systematic review and meta-analysis of the published literature were conducted to evaluate the global frequency of ERBB4 variants and their clinical correlations.<br><br>RESULTS: We identified 14 missense variants and 6 splice region variants in 23 unrelated patients, with four variants classified as damaging (p.R782P, p.M799T, p.R847C, and p.S997R). The splice variant c.1490-3C&#x202f;>&#x202f;T, associated with a 50% reduction in ERBB4 mRNA expression, was maternally inherited by a male ALS patient, while its presence in his asymptomatic mother suggests the involvement of potential genetic modifiers. ERBB4 variant carriers demonstrated earlier disease onset compared to non-carriers (46.9&#x202f;&#xb1;&#x202f;10.3 vs. 52.6&#x202f;&#xb1;&#x202f;11.2&#x202f;years; p&#x202f;=&#x202f;0.015), though survival duration remained comparable. Meta-analysis revealed a pooled ERBB4 variant frequency of 0.83% (95% CI, 0.56-1.10%) in ALS patients globally, with notable ethnic differences (1.36% in Chinese, 0.66% in European, and 1.44% in American populations).<br><br>CONCLUSION: Our findings establish the prevalence of ERBB4 variants in ALS across different populations and suggest their potential role as disease modifiers, particularly affecting the age of onset. The ethnic variation in mutation frequency highlights the importance of population-specific genetic screening strategies in ALS.}, }
@article {pmid40468914, year = {2025}, author = {Cao, Y and Yuan, B and Jiang, X and Xie, C and Wu, D and Zhang, Z}, title = {Quantification of Skeletal Muscle at the First Lumbar Level for Prognosis in Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {16}, number = {3}, pages = {e13827}, doi = {10.1002/jcsm.13827}, pmid = {40468914}, issn = {2190-6009}, support = {81830040//National Natural Science Key Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/pathology/diagnostic imaging/diagnosis ; Female ; Male ; Middle Aged ; Prognosis ; *Muscle, Skeletal/diagnostic imaging/pathology ; Aged ; *Lumbar Vertebrae/diagnostic imaging ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: Skeletal muscle parameters at the first lumbar vertebra (L1) level on computed tomography (CT) are common indicators for muscle mass. However, their relationship with the severity and prognosis of amyotrophic lateral sclerosis (ALS) patients remains unclear.<br><br>METHODS: This cohort study included ALS patients who underwent chest CT scans between January 2018 and January 2022 and healthy controls (HCs) matched for gender and age. Overall survival (OS) was determined from the date of chest CT to death, tracheal intubation or 1 January 2024. Using ImageJ software, skeletal muscle area and density (L1 SMA/SMD), skeletal muscle index (L1 SMI), paraspinal muscle area and density (L1 PMA/PMD) and subcutaneous fat area and density (L1 SFA/SFD) at L1 were quantified. The relationships between the quantified muscle parameters and both King's clinical stages and the Revised ALS Functional Rating Scale (ALSFRS-R) were analysed. The Cox proportional hazard model was used to evaluate the hazard ratio (HR) of skeletal muscle parameters as risk factors for outcome events, and to construct a nomogram.<br><br>RESULTS: Muscle parameters in ALS patients (n&#x2009;=&#x2009;102; 36.27% female; mean age, 60.85&#x2009;&#xb1;&#x2009;10.58&#x2009;years) were significantly lower compared with HCs (p&#x2009;<&#x2009;0.001). L1 SMD (p&#x2009;=&#x2009;0.047) and L1 PMD (p&#x2009;=&#x2009;0.003) both differed significantly across the King's clinical stages. ALSFRS-R scores correlated with L1 SMA (r&#x2009;=&#x2009;0.35, p&#x2009;<&#x2009;0.001), L1 SMI (r&#x2009;=&#x2009;0.34, p&#x2009;<&#x2009;0.001), L1 PMA (r&#x2009;=&#x2009;0.27, p&#x2009;=&#x2009;0.007) and L1 PMD (r&#x2009;=&#x2009;0.27, p&#x2009;=&#x2009;0.007). Multivariate Cox regression analysis revealed that L1 SMA (HR&#x2009;=&#x2009;0.96, 95% confidence interval [CI]&#x2009;=&#x2009;0.94-0.98, p&#x2009;=&#x2009;0.001), L1 SMD (HR&#x2009;=&#x2009;0.92, 95% CI&#x2009;=&#x2009;0.88-0.96, p&#x2009;<&#x2009;0.001) and L1 PMA (HR&#x2009;=&#x2009;1.06, 95% CI&#x2009;=&#x2009;1.01-1.11, p&#x2009;=&#x2009;0.022) significantly influenced ALS survival, with area under the curves (AUCs) of 0.687 and 0.851 for 1- and 3-year OS prediction. The consistency index (C-index) for the nomogram was 0.72 (95% CI&#x2009;=&#x2009;0.641-0.793).<br><br>CONCLUSIONS: Skeletal muscle parameters at L1 level on CT are significantly associated with clinical severity and prognosis in ALS.<br><br>TRIAL REGISTRATION: Chinese Clinical Trial Registration Center: ChiCTR230078702.}, }
@article {pmid40468389, year = {2025}, author = {Rummens, J and Da Cruz, S}, title = {RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {64}, pmid = {40468389}, issn = {1750-1326}, support = {G064721N//Fonds Wetenschappelijk Onderzoek/ ; 1S15218N//Fonds Wetenschappelijk Onderzoek/ ; 962700//Muscular Dystrophy Association/ ; SAO-FRA 20230035//Alzheimer's Research Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Animals ; DNA-Binding Proteins/metabolism ; RNA-Binding Protein FUS/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with overlapping clinical, genetic and pathological features. A large body of evidence highlights the critical role of RNA-binding proteins (RBPs) - in particular TAR DNA-binding protein 43 (TDP-43) and Fused in sarcoma (FUS) - in the pathogenesis of these diseases. These RBPs normally regulate various key aspects of RNA metabolism in the nervous system (by assembling into transient biomolecular condensates), but undergo cytoplasmic mislocalization and pathological aggregation in ALS and FTD. Furthermore, emerging evidence suggests that RBP-containing aggregates may propagate through the nervous system in a prion-like manner, driving the progression of these neurodegenerative diseases. In this review, we summarize the genetic and neuropathological findings that establish RBP dysfunction as a central theme in ALS and FTD, and discuss the role of disease-associated RBPs in health and disease. Furthermore, we review emerging evidence regarding the prion-like properties of RBP pathology, and explore the downstream mechanisms that drive neurodegeneration. By unraveling the complex role of RBPs in ALS and FTD, we ultimately aim to provide insights into potential avenues for therapeutic intervention in these incurable disorders.}, }
@article {pmid40466410, year = {2025}, author = {Guillen-Sola, A and Bertran-Recasens, B and Martinez-Llorens, J and Balaña, A and Villatoro, M and Rubio, MA}, title = {[Use of tongue pressure to determine the indication for instrumental swallowing assessment in patients with spinal ALS].}, journal = {Rehabilitacion}, volume = {59}, number = {3}, pages = {100917}, doi = {10.1016/j.rh.2025.100917}, pmid = {40466410}, issn = {1578-3278}, abstract = {OBJECTIVE: Systematic swallowing assessment in amyotrophic lateral sclerosis (ALS) is essential, as approximately 85% of patients will develop dysphagia, and 8% of these cases may remain clinically silent. Although instrumental diagnostic tools exist, they are not always accessible. Recent studies suggest that lingual pressure measurements may be valuable for early detection of bulbar dysfunction. This study aims to establish lingual pressure cutoff points for early screening of such dysfunction.<br><br>DESIGN: Transversal study based on prospectively collected data from patients with spinal-onset ALS at the Motor Neuron Unit, Hospital del Mar (Barcelona).<br><br>MATERIALS AND METHODS: A total of 58 patients were included. Anterior (PA) and posterior (PP) lingual pressures were measured using the IOPI system and analyzed alongside the ALSFRS-R scale. Statistical analysis included descriptive statistics, Spearman correlation, and ROC curve analysis (SPSS v25).<br><br>RESULTS: A moderate correlation was found between lingual strength and ALSFRS-R scores (PA: r=.634, P<.001; PP: r=.539, P<.001). Identified cutoff values: PA: 39.5kPa (AUC=.766; 95%CI: .700-.831; P<.001), sensitivity 64.6%, specificity 76.4%. PP: 37.0kPa (AUC=.726; 95%CI: .653-.799; P<.001), sensitivity 55.1%, specificity 72.2%.<br><br>CONCLUSION: In spinal-onset ALS, a moderate correlation exists between global functionality and lingual pressures. Cutoff points of PA=39.5kPa and PP=37.0kPa are proposed for early screening of bulbar dysfunction.}, }
@article {pmid40465292, year = {2025}, author = {Chourpiliadis, C and Lovik, A and Ingre, C and Press, R and Samuelsson, K and Valdimarsdottir, U and Fang, F}, title = {Use of Common Psychiatric Medications and Risk and Prognosis of Amyotrophic Lateral Sclerosis.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2514437}, doi = {10.1001/jamanetworkopen.2025.14437}, pmid = {40465292}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Case-Control Studies ; Middle Aged ; Sweden/epidemiology ; Aged ; Prognosis ; *Antidepressive Agents/adverse effects/therapeutic use ; *Hypnotics and Sedatives/adverse effects/therapeutic use ; *Mental Disorders/drug therapy ; *Anti-Anxiety Agents/adverse effects/therapeutic use ; Risk Factors ; Registries ; Disease Progression ; *Psychotropic Drugs/adverse effects/therapeutic use ; }, abstract = {IMPORTANCE: Although several studies have shown an increased risk of subsequent amyotrophic lateral sclerosis (ALS) diagnosis for individuals with a history of psychiatric disorders, the evidence of an association between use of common psychiatric medications and ALS is scarce and inconclusive.<br><br>OBJECTIVE: To examine whether there is an association of prescribed use of common psychiatric medications, namely anxiolytics, hypnotics and sedatives, and antidepressants, with the risk and disease progression of ALS.<br><br>This nationwide register-based case-control study was conducted in Sweden among all patients diagnosed with ALS from January 1, 2015, to July 1, 2023, according to the Swedish Motor Neuron Disease Quality Registry, who were age- and sex-matched with as many as 5 individuals with no ALS as well as their full siblings and spouses. Patients with ALS were followed up for a median (IQR) of 1.33 (0.64-2.37) years after diagnosis.<br><br>EXPOSURES: At least 2 prescriptions of the studied psychiatric medications before ALS diagnosis.<br><br>MAIN OUTCOMES AND MEASURES: The risk of ALS diagnosis associated with prediagnostic prescribed use of common psychiatric medications was estimated using conditional logistic regression models, comparing patients with ALS with population or relative control participants. Patients with ALS were followed up from diagnosis to assess the association of prediagnostic prescribed use of common psychiatric medications with disease progression. The association of mortality (or use of invasive ventilation) with the use of common psychiatric medications was estimated with a joint longitudinal-survival model accounting for the longitudinal changes of ALS Functional Rating Scale-Revised (ALSFRS-R) in the time-to-event analysis.<br><br>RESULTS: Among the 1057 case participants and 5281 population control participants, the mean (SD) age at diagnosis of the case participants (ie, date of selection of the control participants) was 67.5 (11.5) years, and 3363 (53.1%) were male. In the population comparison, prescribed use of common psychiatric medications across all studied time windows before ALS diagnosis was associated with a higher risk of ALS (eg, among individuals prescribed hypnotics and sedatives 0-1 year before diagnosis: odds ratio [OR], 6.10; 95% CI, 3.77-9.88; prescribed anxiolytics 1-5 years before diagnosis: OR, 1.60; 95% CI, 1.15-2.23; prescribed antidepressants >5 years before diagnosis: OR, 1.21; 95% CI, 1.02-1.44). Excluding the year before diagnosis from the analysis, prescribed use of anxiolytics (OR, 1.34; 95% CI, 1.12-1.60), hypnotics and sedatives (OR, 1.21; 95% CI, 1.02-1.43), or antidepressants (OR, 1.26; 95% CI, 1.06-1.49) was associated with an increased risk of ALS. Similar results were noted in the comparison with relative control participants, partially alleviating the concern on familial confounding, with the exception of hypnotics and sedatives. Shorter survival was demonstrated among patients with ALS who had prediagnostic use of anxiolytics (hazard ratio [HR], 1.52; 95% CI, 1.12-2.05) or antidepressants (HR, 1.72; 95% CI, 1.30-2.29), compared with patients with ALS without such experience.<br><br>CONCLUSIONS AND RELEVANCE: In this case-control study, prescribed use of anxiolytics, hypnotics and sedatives, or antidepressants was associated with a higher subsequent risk of ALS. Prediagnostic use of such medications was also associated with a poor prognosis after ALS diagnosis.}, }
@article {pmid40464816, year = {2025}, author = {Savran, Z and Baltaci, SB and Aladag, T and Mogulkoc, R and Baltaci, AK}, title = {Vitamin D and Neurodegenerative Diseases Such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS): A Review of Current Literature.}, journal = {Current nutrition reports}, volume = {14}, number = {1}, pages = {77}, pmid = {40464816}, issn = {2161-3311}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Vitamin D/metabolism ; Multiple Sclerosis ; Alzheimer Disease ; Parkinson Disease ; Receptors, Calcitriol/metabolism ; Amyotrophic Lateral Sclerosis ; Oxidative Stress/drug effects ; Animals ; Cholecalciferol ; }, abstract = {PURPOSE OF REVIEW: This review explores the role of Vitamin D3 and its derivatives as inhibitors of pathological metabolic modifications in neurodegenerative diseases. The manuscript investigates how Vitamin D3 impacts neuronal calcium regulation, antioxidative pathways, immunomodulation, and neuroprotection during detoxification, beyond its known functions in intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization.<br><br>RECENT FINDINGS: Recent studies have highlighted the synthesis of the active metabolite 1,25(OH)2D3 (vitamin D) in glial cells via the hydroxylation process of CY-P24A1, an enzyme in the cytochrome P450 system in the brain. The effects of vitamin D occur through the vitamin D receptor (VDR), a nuclear steroid receptor, which has been identified in various brain regions, including the cerebellum, thalamus, hypothalamus, basal ganglia, hippocampus, olfactory system, temporal, and orbital regions. Neurodegeneration is primarily associated with oxidative stress, protein aggregation, neuroinflammation, mitochondrial dysfunction, apoptosis, and autophagy changes, all of which Vitamin D and VDR are believed to influence. Vitamin D and VDR are recognized as both environmental and genetic factors in the etiopathogenesis of neurodegenerative diseases such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS). A deficiency in Vitamin D is postulated to have detrimental effects on the brain and other diseases throughout various stages of life. This review consolidates findings from clinical and experimental studies, as well as past publications, focusing on the implications of Vitamin D deficiency in these neurodegenerative conditions. Current articles published in PubMed were extensively considered for this review.}, }
@article {pmid40464500, year = {2025}, author = {Dedoni, S and Avdoshina, V and Olianas, MC and Onali, P}, title = {Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {5}, pages = {28245}, doi = {10.31083/FBL28245}, pmid = {40464500}, issn = {2768-6698}, mesh = {Humans ; *Lysophospholipids/metabolism ; *Nervous System Diseases/physiopathology/metabolism/drug therapy ; Animals ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; }, abstract = {Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.}, }
@article {pmid40464332, year = {2025}, author = {Naim, A and Farooqui, AM and Badruddeen,  and Khan, MI and Akhtar, J and Ahmad, A and Islam, A}, title = {The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment.}, journal = {The European journal of neuroscience}, volume = {61}, number = {11}, pages = {e70156}, doi = {10.1111/ejn.70156}, pmid = {40464332}, issn = {1460-9568}, mesh = {Humans ; *Neurodegenerative Diseases/enzymology/drug therapy/metabolism ; Animals ; *Protein Kinases/metabolism ; Protein Kinase Inhibitors/therapeutic use ; }, abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.}, }
@article {pmid40463912, year = {2025}, author = {Liu, T and Sun, W and Guo, S and Yuan, Z and Zhu, M and Lu, J and Chen, T and Qu, Y and Feng, C and Yang, T}, title = {Role of mitochondrial quality control in neurodegenerative disease progression.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1588645}, pmid = {40463912}, issn = {1662-5102}, abstract = {Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.}, }
@article {pmid40463522, year = {2025}, author = {Cohen, Y and Sinai, I and Magen, I and Danino, MY and Wuu, J and Malaspina, A and Benatar, M and Hornstein, E}, title = {IsomiR Utility in ALS Prognostication.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.05.12.25325848}, pmid = {40463522}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored. Intriguingly, loss of TAR DNA-binding protein 43 (TDP-43) nuclear function is a hallmark of disease and is known to impair isomiR expression. Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing. We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients and was in two orthogonal approaches. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181. These results establish isomiRs as a novel class of blood-based biomarkers in ALS with potential to refine prognostication in clinical trials for neurodegenerative diseases.}, }
@article {pmid40462869, year = {2025}, author = {Acan, D and Cakar, BB and Karahan, E}, title = {Low anterior chamber volume as a risk factor in non-arteritic anterior ischemic optic neuropathy.}, journal = {Frontiers in ophthalmology}, volume = {5}, number = {}, pages = {1554279}, pmid = {40462869}, issn = {2674-0826}, abstract = {PURPOSE: This study aimed to compare the anterior chamber depth (ACD), anterior chamber volume (ACV), and iridocorneal angle (ICA) of the eyes of patients with non-arteritic anterior ischemic optic neuropathy (NAION) and normal eyes.<br><br>METHODS: In this cross-sectional study, 28 patients with NAION who were admitted to our institution were examined. Central corneal thickness (CCT), ACV, ACD, and ICA of all eyes were measured using corneal topography (Sirius, CSO, Italy). Axial lengths (ALs) were measured using an IOL-Master 500 (Carl Zeiss, Meditec). The eyes of these patients were compared with the eyes of 29 healthy individuals of similar age and gender.<br><br>RESULTS: The mean ALs of the eyes with NAION and those in the control group were not statistically different, measuring 22.95 &#xb1; 0.68 mm and 23.13 &#xb1; 0.80mm, respectively (p=0.651). While the average ACV was 137.93 &#xb1; 41.01 mm[3] in the control group, it was significantly lower at 117.86 &#xb1; 22.23 mm[3] in the patients with NAION (p=0.038). The mean ACD, ICA, and CCT values in the control and study groups were not statistically different, with 2.82 &#xb1; 0.57 mm and 2.64 &#xb1; 0.31 mm, 41.62 &#xb1; 6.99&#xb0; and 40.14 &#xb1; 7.04&#xb0;, and 542.48 &#xb1; 19.39&#xb5;m and 544.68 &#xb1; 31.26 &#xb5;m, respectively (p1 = 0.236, p2 = 0.693, and p3 = 0.959). No statistical differences were found between the eyes with NAION and their fellow eyes in terms of AL, CCT, ACD, ACV, and ICA (p>0.05).<br><br>CONCLUSION: Differences in anterior segment morphology were observed in eyes with NAION compared to healthy eyes. Decreased ACV may be a risk factor for NAION.}, }
@article {pmid40462740, year = {2025}, author = {DeCastro, J and Mehta-Doshi, A and Liu, C and Ray, A and Aran, K}, title = {Red Blood Cell-Derived Exosomes as Mediators of Age-Related Neurodegeneration.}, journal = {Rejuvenation research}, volume = {}, number = {}, pages = {}, doi = {10.1089/rej.2025.0013}, pmid = {40462740}, issn = {1557-8577}, abstract = {Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid biomarkers, are invasive, costly, and lack early diagnostic reliability. Recent studies highlight the potential of extracellular vesicles, particularly exosomes, derived from erythrocytes or red blood cells (RBCs), as emerging indicators of aging and age-associated diseases. Exosomes carry noncoding RNA, lipid, and protein molecules, and modulate cellular pathways at distant sites, providing neuroprotective and anti-inflammatory effects. In this study, we isolated RBC-derived exosomes of young and old mice. MicroRNA sequencing analysis revealed differential expression of several miRNA species between young and old mice. We report an upregulation of miR-125a-5p and a downregulation of miR-302a-5p in old mice that are potentially linked to neurodegenerative pathways. This study underscores the potential of RBC-derived exosomes as noninvasive biomarkers for NDDs.}, }
@article {pmid40462656, year = {2025}, author = {Gong, Z and Cao, R and Zhu, H}, title = {Exploring the Causal Association Between 91 Circulating Inflammatory Proteins and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization and Bioinformatics Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {6}, pages = {e70586}, doi = {10.1002/brb3.70586}, pmid = {40462656}, issn = {2162-3279}, support = {2025JJ70054//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; Mendelian Randomization Analysis/methods ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/blood ; Computational Biology ; CD40 Antigens/genetics ; Polymorphism, Single Nucleotide ; Amyotrophic Lateral Sclerosis/genetics ; Quantitative Trait Loci ; Parkinson Disease/genetics ; Multiple Sclerosis/genetics ; Alzheimer Disease/genetics ; Inflammation/genetics ; }, abstract = {BACKGROUND: Circulating inflammatory proteins play a significant role in the pathogenesis of neurodegenerative diseases (NDDs). However, the precise causal relationship and the underlying mechanisms of their interaction remain elusive.<br><br>METHODS: Genome-wide association study (GWAS) data for 91 circulating inflammatory proteins were obtained from the GWAS Catalog. Additionally, GWAS data for Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and ischemic stroke (IS) were acquired from the IEU Open GWAS Project. Four Mendelian randomization (MR) methods were employed to analyze causal effects, accompanied by sensitivity and pleiotropy analyses. Expression quantitative trait loci (eQTL) analyses for CD40 and MS-associated SNPs were performed. Transcriptomic data from the peripheral blood of MS patients were used to identify differentially expressed genes (DEGs) in relapsing-remitting MS (RRMS). RRMS patients were divided into two subgroups (C1 and C2) based on CD40 expression levels for comparative analysis. A single gene set enrichment analysis (GSEA) was conducted to investigate potential molecular mechanisms through which CD40 influences MS.<br><br>RESULTS: MR analyses indicated that CD40 ligand receptor (CD40) is associated with a reduced risk of MS (OR, 0.78; 95% CI, 0.72-0.84; PFDR&#xa0;=&#xa0;8.75E-07). No statistically significant bidirectional causal relationships were found between other inflammatory proteins and PD, AD, ALS, or IS, and the findings were robust. Functional enrichment analysis revealed that these eQTLs primarily relate to transcriptional regulation, herpes simplex virus 1 (HSV-1) infection, and bile and fatty acid metabolism. In MS peripheral blood microarray data, CD40 is significantly downregulated in RRMS. Intergroup comparisons revealed elevated levels of resting memory CD4[+] T cells, activated NK cells, and neutrophils in C1, alongside increased autophagy, apoptosis, multiple immune responses, and upregulation of transforming growth factor-&#x3b2; (TGF-&#x3b2;) signaling pathways. Conversely, C2 exhibited higher levels of Tregs, resting NK cells, and activated dendritic cells, as well as upregulation in processes such as cholesterol homeostasis, glucose metabolism, and CD4/CD8 downregulation. Single-GSEA results suggest that CD40 promotes nucleotide metabolism, mitochondrial calcium ion transport, unfolded protein response (UPR), and adaptive immune regulation, while inhibiting androgen response and TGF-&#x3b2; signaling pathways, thereby influencing the progression of RRMS.<br><br>CONCLUSION: CD40 may exert neuroprotective effects in MS patients via diverse cellular and molecular pathways, potentially representing a novel target for MS intervention.}, }
@article {pmid40462477, year = {2025}, author = {Shaka, Z and Mojtabavi, H and Taebi, M and Mahmoodi-Bakhtiari, B and Sarraf, P}, title = {Examining cognitive decline over time in Iranian ALS patients: Adapting successive versions B and C of the Edinburgh cognitive and behavioral screen to Persian.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2025.2509615}, pmid = {40462477}, issn = {2167-9223}, abstract = {OBJECTIVE: To adapt successive versions B and C of the Edinburgh Cognitive and Behavioral Screen (ECAS) into Persian and evaluate cognitive and behavioral changes over time in Iranian ALS patients.<br><br>METHODS: This study included 38 ALS patients in the ECAS-B group and 29 in the ECAS-C group, diagnosed between May 2021 and February 2023 at the Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran, Iran. Additionally, 59 age- and education-matched healthy controls were enrolled (30 for ECAS-B and 29 for ECAS-C). The Montreal Cognitive Assessment (MoCA) was used to validate the ECAS versions.<br><br>RESULTS: The Persian versions of ECAS-B and ECAS-C demonstrated strong internal consistency (Cronbach's alpha: 0.88 for ECAS-B and 0.89 for ECAS-C) and a positive correlation with MoCA and ALS-FRS-r scores. The area under the ROC curve was 0.851 for ECAS-B and 0.861 for ECAS-C. ECAS-C scores were significantly lower than ECAS-B scores, suggesting a faster cognitive decline over time. Optimal cutoff values of 72 for ECAS-B and 78 for ECAS-C were identified for detecting cognitive impairment. Cognitive impairment was observed in 10 patients (26.31%) in the ECAS-B group and 15 patients (51.72%) in the ECAS-C group.<br><br>CONCLUSIONS: The Persian versions of ECAS-B and ECAS-C demonstrate good validity and reliability for detecting cognitive impairment and tracking cognitive decline in ALS patients.}, }
@article {pmid40462117, year = {2025}, author = {Akif, A and Nguyen, TTM and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Fluids and barriers of the CNS}, volume = {22}, number = {1}, pages = {55}, pmid = {40462117}, issn = {2045-8118}, support = {R21NS133895-01//National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS105787//National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists &amp; inhibitors/metabolism/drug effects ; Mice ; *Dementia, Vascular/drug therapy/metabolism ; *Signal Transduction/drug effects ; *Sulfonylurea Compounds/pharmacology ; *Cognitive Dysfunction/drug therapy/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Carotid Stenosis/complications ; Brain/drug effects/metabolism ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.<br><br>METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD&#x2009;+&#x2009;Vehicle, and VaD&#x2009;+&#x2009;AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1&#x3b2;), Tumor Necrosis Factor-alpha (TNF-&#x3b1;) and Interleukin-4 (IL-4) in the blood were measured using ELISA.<br><br>RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-&#x3b1; and IL-1&#x3b2; levels, while increasing the anti-inflammatory IL-4 level in the blood.<br><br>CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.<br><br>CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid40461666, year = {2025}, author = {Orologio, I and Russo, A and Trojsi, F and Todisco, V and Cirillo, M and Tessitore, A and Silvestro, M}, title = {A case of rapidly progressive juvenile amyotrophic lateral sclerosis associated with a pathogenetic heterozygous de novo variant in the FUS gene.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40461666}, issn = {1590-3478}, }
@article {pmid40460399, year = {2025}, author = {Pommée, T and Bouvier, L and Barnett-Tapia, C and Maffei, MF and Gutz, SE and Tilton-Bolowsky, VE and Martino, R and Berry, JD and Abrahao, A and Zinman, L and Green, JR and Yunusova, Y}, title = {Construct Validity of the Amyotrophic Lateral Sclerosis Bulbar Dysfunction Index-Remote.}, journal = {American journal of speech-language pathology}, volume = {}, number = {}, pages = {1-23}, doi = {10.1044/2025_AJSLP-24-00489}, pmid = {40460399}, issn = {1558-9110}, abstract = {PURPOSE: The Amyotrophic Lateral Sclerosis Bulbar Dysfunction Index-Remote (ALSBDI-R) is a clinician-administered tool designed to assess bulbar dysfunction remotely in patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate the construct validity of the ALSBDI-R by examining its correlation with established clinical measures and its ability to discriminate among different bulbar disease severities.<br><br>METHOD: A total of 92 patients with ALS were recruited from two multidisciplinary clinics. Participants were assessed using the ALSBDI-R, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), the Center for Neurologic Study Bulbar Function Scale (CNS-BFS), the Sentence Intelligibility Test, and the Eating Assessment Tool (EAT-10). Construct validity was established through Spearman correlations and comparison of ALSBDI-R scores across bulbar severity groups (asymptomatic, mild, moderate, severe).<br><br>RESULTS: Strong correlations were found between ALSBDI-R total scores and bulbar-specific measures such as ALSFRS-R bulbar subscore (r = -.85), CNS-BFS (r = .85), and EAT-10 (r = .77). The ALSBDI-R effectively discriminated between severity groups, supporting its construct validity. Severity bins were created based on median ALSBDI-R total scores for each group.<br><br>CONCLUSIONS: The ALSBDI-R is a valid tool for remotely assessing bulbar dysfunction in patients with ALS. Despite several limitations, its ability to capture varying degrees of severity makes it valuable for clinical use and research, offering a standardized approach to monitor disease progression remotely.}, }
@article {pmid40460337, year = {2025}, author = {van Unnik, JWJ and Ing, L and Oliveira Santos, M and McDermott, CJ and de Carvalho, M and van Eijk, RPA}, title = {Remote Monitoring of Amyotrophic Lateral Sclerosis Using Digital Health Technologies: Shifting Toward Digitalized Care and Research?.}, journal = {Neurology}, volume = {105}, number = {1}, pages = {e213738}, doi = {10.1212/WNL.0000000000213738}, pmid = {40460337}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/diagnosis ; *Telemedicine ; Wearable Electronic Devices ; Videoconferencing ; Digital Technology ; *Biomedical Technology ; Monitoring, Physiologic/methods ; Digital Health ; }, abstract = {Current care and research pathways for amyotrophic lateral sclerosis (ALS) primarily rely on regularly scheduled visits to specialized centers. These visits provide intermittent clinical information to health care professionals and require patients to travel to the clinic. Digital health technologies enable continuous data collection directly from the patient's home, bringing new opportunities for personalized, timely care and a refined assessment of disease severity in clinical trials. In this review, we summarize the state of the art in digital health technologies for remote monitoring of patients with ALS, ranging from televisits through videoconferencing to sensor-based wearable devices. We explore how these technologies can benefit clinical care and advance treatment development. Despite significant progress, real-world adoption of these technologies remains limited. An overview is provided of the key barriers hindering their widespread implementation and the opportunities to advance the field. Significantly, there is an urgent need for harmonization across stakeholders through consensus guidelines and consortia. These efforts are essential to accelerate progress and harness the full potential of digital health technologies to better meet the needs of patients.}, }
@article {pmid40459673, year = {2025}, author = {Dengri, C and Mayberry, W and Koriesh, A and Nouh, A}, title = {Neurology of Androgens and Androgenic Supplements.}, journal = {Current neurology and neuroscience reports}, volume = {25}, number = {1}, pages = {39}, pmid = {40459673}, issn = {1534-6293}, mesh = {Humans ; *Androgens/metabolism/therapeutic use ; *Nervous System Diseases/drug therapy/metabolism ; *Dietary Supplements ; Receptors, Androgen/metabolism ; Animals ; Testosterone/therapeutic use ; }, abstract = {PURPOSE OF REVIEW: This article explores the intricate relationship between androgens, androgen receptors, and the central nervous system. We examine the role of physiologically derived androgens and androgenic supplements in neurodevelopment and neuroplasticity and delve into the involvement of androgen pathways in the pathogenesis of various neurological disorders.<br><br>RECENT FINDINGS: This review highlights the increasing recognition of testosterone and androgen signaling in various neurological conditions, with evidence of both protective and harmful effects depending on dosage and context. Although limited to experimental use, testosterone replacement therapy (TRT) may serve potential benefits in the management of multiple sclerosis, epilepsy, headache, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and Parkinson disease. On the other hand, androgen-blocking treatments may help alter disease progression in spinal and bulbar muscular atrophy. Testosterone supplementation can have potential adverse events when used at a supratherapeutic level, and prenatal testosterone exposure is believed to contribute to the pathogenesis of neurodevelopmental disease. Additionally, androgen-blocking agents could increase the risk of neurodegenerative conditions, such as Parkinson disease and Alzheimer disease. Despite the above findings, there is no established indication of TRT or androgen-blocking medication in neurological disorders. The body of evidence highlighting the involvement of androgens and androgen receptors (ARs) in pathogenesis of neurological diseases is growing. This includes ongoing research exploring the potential therapeutic targets involving the androgen signaling pathway for management of neurological disorders. Future placebo-controlled clinical trials are essential to determine the efficacy and safety of TRT or androgen-blocking therapies in managing neurological disease.}, }
@article {pmid40459635, year = {2025}, author = {Abraham, I and Martin, P and Vaghela, S and Klein, T and Chow, E and Rush, M and Morlock, R and Huang, H}, title = {Budget impact analysis of revumenib for the treatment of relapsed or refractory acute leukemias with a KMT2A translocation in the United States.}, journal = {Journal of managed care &amp; specialty pharmacy}, volume = {}, number = {}, pages = {1-14}, doi = {10.18553/jmcp.2025.25027}, pmid = {40459635}, issn = {2376-1032}, abstract = {BACKGROUND: Acute leukemias (ALs), including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), are heterogeneous diseases characterized by different phenotypic, genetic, and molecular alterations that can guide treatment decisions. ALs harboring lysine methyltransferase 2A gene translocation (KMT2t), previously known as mixed-lineage leukemia, are associated with high rates of relapsed or refractory (R/R) disease. Revumenib, a first-in-class oral menin inhibitor, has shown improved clinical outcomes in patients with R/R KMT2At ALs.<br><br>OBJECTIVE: To estimate, using a budget impact model (BIM), the financial impact of introducing revumenib for the treatment of adult patients with R/R KMT2At ALs on the formulary of a hypothetical US 1-million-member commercial health plan.<br><br>METHODS: The BIM compared scenarios with or without revumenib and the resulting impact on commercial US third-party payers over a 3-year time horizon. Although no other therapies specifically targeted for R/R KMT2At ALs were approved during BIM development, 11 additional pharmacotherapies for R/R ALs (5 for AML and 6 for ALL, not including revumenib) were included as treatment options in the model. Clinical data included adverse event (AE) rates, duration of treatment, time to subsequent treatment, and survival outcomes. Cost inputs (USD 2024) included in the model comprised drug acquisition and administration, grade 3 or greater AEs, treatment-related supportive care and monitoring, subsequent treatment, and end-of-life costs. The differential cost per member per month (PMPM) was estimated. One-way sensitivity analyses varying the costs of drug acquisition and toxicity by &#xb1;20% and scenario analyses varying uptake of revumenib and epidemiology inputs, as well as excluding costs related to supportive care and posttreatment discontinuation, were performed.<br><br>RESULTS: An estimated 1.7 adult patients (AML, 1.1; ALL, 0.6) were treatment eligible annually. Estimated 3-year total plan costs without and with revumenib were $2,146,564 and $2,126,919, respectively, for savings of -$19,646. Including revumenib was estimated to yield a differential PMPM cost of -$0.0005 over 3&#xa0;years. The total number of grade 3 or greater AEs was lower over 3&#xa0;years (10.82 vs 10.99, respectively) in the plan with revumenib vs without. Sensitivity and scenario analyses validated the robustness of the model.<br><br>CONCLUSIONS: The BIM demonstrated that including revumenib in a formulary for adult patients with R/R KMT2At ALs was approximately cost neutral, offering patients access to a targeted treatment with potential for improved clinical outcomes.}, }
@article {pmid40458045, year = {2025}, author = {Weng, R and Li, X and Yue, H and Xu, Y and Wei, Z and Xu, S and Li, B and Zhang, Z}, title = {A missense mutation in close proximity of ALS-linked PFN1 mutations causes only early-onset Paget's disease of bone.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgaf314}, pmid = {40458045}, issn = {1945-7197}, abstract = {CONTEXT: Paget's disease of bone (PDB) is a metabolic disorder characterized by abnormal osteoclast activation. Recently, mutations in the PFN1 gene, which encodes Profilin 1, an actin-binding protein controlling actin dynamics and cell movement, have been linked to early-onset PDB. Interestingly, mutations in PFN1 (C71G, T109M, M114T, E117G, G118V, etc.) are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons.<br><br>OBJECTIVE: To provide insights into the underlying molecular mechanism of early-onset PDB.<br><br>METHODS: We observed the clinical responses to denosumab in early-onset PDB patients. Additionally, a mouse model carrying the c.335T>C mutation in the Pfn1 gene was generated.<br><br>RESULTS: We reported a second Chinese family affected by early-onset PDB with malignant giant cell tumor (GCTs), in which we indentified the same heterozygous missense mutation (c.335T>C/p. L112P) in PFN1 that we have reported previously in another family. Despite its proximity to ALS-linked PFN1 mutations, the PFN1 L112P mutation did not induce ALS in affected individuals. These early-onset PDB patients exhibited a significantly poorer response to denosumab compared to typical PDB patients. The heterozygous mice displayed PDB-like phenotypes, including skeletal deformities and focal osteoclastic lesions with giant osteoclasts, and did not show ALS-like phenotypes. We further show that mutation of Pfn1 leads to enhanced actin ring-like structures at the bone surfaces without affecting NF-&#x3ba;B activation in osteoclast cultures.<br><br>CONCLUSION: The observation of recurrent mutations highlights the causative role of PFN1 (L112P) in early-onset PDB/GCT within the Chinese population and provides insights into the physio-pathological functions of Profilin 1.}, }
@article {pmid40457777, year = {2025}, author = {Martin, EM and Cichon, C and Choudhury, R and Day, SR and Fatemi, Y and Luther, VP and Stillwell, T and Sung, A}, title = {Society for Healthcare Epidemiology of America (SHEA) infectious diseases fellow infection prevention and control and healthcare epidemiology curriculum.}, journal = {Infection control and hospital epidemiology}, volume = {}, number = {}, pages = {1-10}, doi = {10.1017/ice.2025.85}, pmid = {40457777}, issn = {1559-6834}, abstract = {With the rapid expansion of the Infection Prevention Control/Healthcare Epidemiology (IPC/HE) fields over recent decades, the pivotal roles of IPC/HE in hospital regulation, quality improvement, patient safety, and healthcare finances have become increasingly apparent. Consequently, the demand for effective IPC/HE leaders has surged.[1,2] Training in IPC/HE is essential for all infectious diseases (ID) fellows (both adult and pediatric), including those planning a career in hospital epidemiology as well as those planning to focus on general ID, transplant, HIV, etc. ID fellows, however, have historically felt ill-prepared in IPC/HE. Joiner et al's survey highlighted this gap, revealing that only half of respondents felt adequately trained in infection control, despite half of them participating in infection control in their practice.[3] IPC/HE fellow education is not currently standardized, and most IPC/HE training is led by individual mentors and healthcare facilities.}, }
@article {pmid40457619, year = {2025}, author = {Alaydin, HC and Kocak, OK and Arslan, I and Kılınc, H and Boran, HE and Tankisi, H and Cengiz, B}, title = {Assessing MScanFit MUNE in Amyotrophic Lateral Sclerosis: Influence of Nerve Conduction Distance and Temporal Dispersion.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28446}, pmid = {40457619}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: MScanFit is a promising method for motor unit number estimation (MUNE) based on compound muscle action potential (CMAP) scanning. Considering that CMAP morphology may be altered by temporal dispersion associated with nerve conduction distance, it is important to evaluate the potential impact of these changes on MScanFit measurements. Therefore, we aimed to investigate the effect of nerve conduction distance on MScanFit MUNE in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: MScanFit MUNE was recorded from the abductor digiti minimi (ADM) muscle by stimulating the ulnar nerve at the wrist and elbow in twenty-three ALS patients. Consistency of MScanFit MUNE and size parameters, CMAP amplitude, and CMAP duration were evaluated using intraclass correlation coefficients (ICC).<br><br>RESULTS: Significant differences were noted in CMAP amplitudes (6.35&#x2009;&#xb1;&#x2009;2.5&#x2009;mV vs. 5.7&#x2009;&#xb1;&#x2009;2.4&#x2009;mV; p&#x2009;=&#x2009;0.003) and CMAP durations (5.8&#x2009;&#xb1;&#x2009;0.7&#x2009;ms vs. 6.2&#x2009;&#xb1;&#x2009;0.8&#x2009;ms; p&#x2009;<&#x2009;0.001), reflecting temporal dispersion effects. MUNE values showed high consistency between wrist and elbow stimulations (61&#x2009;&#xb1;&#x2009;32.4 vs. 61.1&#x2009;&#xb1;&#x2009;30.7; p&#x2009;=&#x2009;0.99), with an ICC of 0.86. Similar repeatability was also observed for MScanFit size parameters.<br><br>DISCUSSION: The reliability of MScanFit MUNE in determining motor unit values in ALS patients remains consistent regardless of the stimulation distance. Our findings highlight the effectiveness of MScanFit MUNE in evaluating motor unit loss of ALS patients and demonstrate its resilience to temporal dispersion effects. Proximal stimulation serves as a viable alternative, enhancing the utility of MScanFit in clinical settings.}, }
@article {pmid40457327, year = {2025}, author = {Gilchrist, L and Mutz, J and Hysi, P and Legido-Quigley, C and Kõks, S and Lewis, CM and Proitsi, P}, title = {Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders.}, journal = {BMC medicine}, volume = {23}, number = {1}, pages = {326}, pmid = {40457327}, issn = {1741-7015}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; Mendelian Randomization Analysis ; *Metabolome ; *Mental Disorders/genetics/metabolism ; Bayes Theorem ; Risk Factors ; }, abstract = {BACKGROUND: Evidence indicates phenotypic and biological overlap between psychiatric and neurodegenerative disorders. Further identification of underlying mutual and unique biological mechanisms may yield novel multi-disorder and disorder-specific therapeutic targets. The metabolome represents an important domain for target identification as metabolites play critical roles in modulating a diverse range of biological processes.<br><br>METHODS: We used Mendelian randomisation (MR) to test the causal effects of&#x2009;~&#x2009;1000 plasma metabolites and&#x2009;~&#x2009;300 metabolite ratios on anxiety, bipolar disorder, depression, schizophrenia, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Follow-up analyses were conducted using statistical colocalisation, multivariable Bayesian model averaging MR (MR-BMA) and polygenic risk score analysis in the UK Biobank.<br><br>RESULTS: MR analyses identified 85 causal effects involving 77 unique metabolites passing FDR correction and robust sensitivity analyses (IVW-MR OR range 0.73-1.48; pFDR&#x2009;<&#x2009;0.05). No evidence of reverse causality was identified. Multivariable MR-BMA analyses implicated sphingolipid metabolism in psychiatric disorder risk and carnitine derivatives in risk for amyotrophic lateral sclerosis and multiple sclerosis. Although polygenic risk scores for prioritised metabolites showed limited prediction in the UK Biobank, those nominally significant were directionally consistent with MR estimates. Downstream colocalisation in regions containing influential variants identified greater than suggestive evidence (PP.H4&#x2009;&#x2265;&#x2009;0.6) for a shared causal variant for 29 metabolite/psychiatric disorder trait-pairs on chromosome 11 at the FADS gene cluster. Most of these metabolites were lipids containing linoleic or arachidonic acid. Additional colocalisation was identified between the ratio of histidine-to-glutamine, glutamine, Alzheimer's disease and SPRYD4 gene expression on chromosome 12.<br><br>CONCLUSIONS: Although no single metabolite had a causal effect on both&#xa0;a psychiatric and a neurodegenerative disease, results suggest a broad effect of lipids across brain disorders, with a particular role for lipids containing linoleic or arachidonic acid in psychiatric disorders. The metabolites identified here may help inform future targeted interventions.}, }
@article {pmid40456951, year = {2025}, author = {Douglas, AGL}, title = {Penetrance and pleiotropy in ATXN2-related amyotrophic lateral sclerosis.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {40456951}, issn = {1476-5438}, support = {HMR04192 HM40.01//DH | National Institute for Health Research (NIHR)/ ; }, }
@article {pmid40456907, year = {2025}, author = {Rhine, K and Li, R and Kopalle, HM and Rothamel, K and Ge, X and Epstein, E and Mizrahi, O and Madrigal, AA and Her, HL and Gomberg, TA and Hermann, A and Schwartz, JL and Daniels, AJ and Manor, U and Ravits, J and Signer, RAJ and Bennett, EJ and Yeo, GW}, title = {Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {40456907}, issn = {1546-1726}, support = {R01-HG004659//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35-GM148339//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R35-GM148339//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01-NS103172//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 23-PDF-639//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; DGE-2038238//National Science Foundation (NSF)/ ; T32-CA067754//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01-CA267031//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30-CA014195//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01-CA267031//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; IL-2023-C2-L4//Target ALS (Target ALS Foundation)/ ; P30-AG068635//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, abstract = {Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.}, }
@article {pmid40454831, year = {2025}, author = {Santos Silva, C and Pavey, N and Calma, AD and Kiernan, MC and Menon, P and van den Bos, M and Vucic, S}, title = {Utility of Cortical Inhibitory and Facilitatory Neuronal Circuits in Amyotrophic Lateral Sclerosis Diagnosis.}, journal = {European journal of neurology}, volume = {32}, number = {6}, pages = {e70203}, doi = {10.1111/ene.70203}, pmid = {40454831}, issn = {1468-1331}, support = {//Motor Neurone Disease Research Institute of Australia/ ; 1024915//National Health and Medical Research Council of Australia/ ; 1055778//National Health and Medical Research Council of Australia/ ; 233//National Health and Medical Research Council of Australia/ ; 510//National Health and Medical Research Council of Australia/ ; GIA 1726//National Health and Medical Research Council of Australia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Transcranial Magnetic Stimulation/methods ; Cross-Sectional Studies ; Aged ; *Neural Inhibition/physiology ; *Evoked Potentials, Motor/physiology ; Adult ; *Motor Cortex/physiopathology ; }, abstract = {BACKGROUND: Cortical hyperexcitability is an early feature of amyotrophic lateral sclerosis (ALS), linked to dysfunction in inhibitory and facilitatory cortical circuits, measurable using paired-pulse transcranial magnetic stimulation (TMS). Short-interval intracortical inhibition (SICI) is a robust biomarker of inhibitory function and an ALS diagnostic marker. Short interval intracortical facilitation (SICF) serves as a biomarker of facilitatory function, while the index of excitation assesses the contribution of these circuits to hyperexcitability. This study aimed to evaluate the diagnostic effectiveness of SICF and the index of excitation in distinguishing ALS from non-ALS mimic disorders.<br><br>METHODS: This cross-sectional study assessed cortical excitability in participants with suspected ALS from two Sydney centres, classified using the Gold Coast criteria. Threshold tracking TMS measured SICI, SICF, and the index of excitation. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, with sensitivity, specificity, and optimal cut-off values determined.<br><br>RESULTS: Of 154 participants, 95 were diagnosed with ALS and 48 with non-ALS mimics. SICI demonstrated a marginally higher diagnostic accuracy (AUC 0.84, 95% CI:0.77-0.89) compared to SICF (AUC 0.77, 95% CI:0.68-0.84, p&#x2009;=&#x2009;0.028). The index of excitation showed comparable accuracy to SICI (AUC 0.82, 95% CI: 0.75-0.88, p&#x2009;=&#x2009;0.328). The optimal SICF cut-off (&#x2264;&#x2009;-13.6%) provided 70.5% sensitivity and 70.8% specificity, while the index of excitation cut-off (&#x2265;&#x2009;64.5%) yielded 71.6% sensitivity and 70.8% specificity.<br><br>CONCLUSIONS: The present study established modest diagnostic potential of increased SICF and index of excitation in differential ALS from mimic disorders, thereby enhancing understanding of the role of inhibitory and facilitatory cortical circuits in ALS diagnosis.}, }
@article {pmid40454774, year = {2025}, author = {Madrer, N and Perera, ND and Uccelli, NA and Abbondanza, A and Andersen, JV and Carsana, EV and Demmings, MD and Fernandez, RF and de Fragas, MG and Gbadamosi, I and Kulshrestha, D and Lima-Filho, RAS and Marian, OC and Markussen, KH and McGovern, AJ and Neal, ES and Sarkar, S and Šimončičová, E and Soto-Verdugo, J and Yandiev, S and Fernández-Moncada, I}, title = {Neural Metabolic Networks: Key Elements of Healthy Brain Function.}, journal = {Journal of neurochemistry}, volume = {169}, number = {6}, pages = {e70084}, doi = {10.1111/jnc.70084}, pmid = {40454774}, issn = {1471-4159}, mesh = {Humans ; *Brain/metabolism ; Animals ; *Nerve Net/metabolism ; *Energy Metabolism/physiology ; *Metabolic Networks and Pathways/physiology ; *Neurons/metabolism ; }, abstract = {Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.}, }
@article {pmid40454605, year = {2025}, author = {Zheng, X and Zhang, K and Zhao, X and Zhou, J and Shen, H and Kong, J and Guo, Y}, title = {Achieving High-Yield Conversion of Janus Transition Metal Dichalcogenides on Diverse Substrates.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.5c02687}, pmid = {40454605}, issn = {1936-086X}, abstract = {Janus transition metal dichalcogenides (TMDCs) with intrinsic broken mirror symmetry and vertical dipole moment provide an additional degree of freedom to manipulate material symmetry down to atomic-layer thickness. However, despite advances in synthesis strategies, fundamental understanding of this atomic substitution process remains limited, which has impeded their implementation in advanced devices. Here, by using a room-temperature atomic-layer substitution (RT-ALS) strategy, we systematically investigate the critical factors facilitating the high-yield conversion of Janus TMDCs on diverse substrates. Combining Raman spectroscopy probes, X-ray photoelectron spectroscopy (XPS) measurements, and density functional theory (DFT) calculations, we demonstrate that substrates with enhanced electron doping or larger surface polarity substantially benefit the conversion of Janus TMDCs reaching a near-unity yield. Intriguingly, the strong affinity between Janus TMDCs and substrates (e.g., Au) brings about abnormal Raman spectroscopic phenomena. These findings highlight the significance of substrates in achieving the reliable synthesis of Janus two-dimensional materials with improved homogeneity on various substrates. In addition, this takes us one step closer to utilizing Janus TMDCs as a versatile platform in next-generation optoelectronic devices, sensors, and quantum technologies.}, }
@article {pmid40454469, year = {2025}, author = {Arnold, FJ and Cui, Y and Michels, S and Colwin, MR and Stockford, CM and Ye, W and Maheswari Jawahar, V and Jansen-West, K and Philippe, J and Gulia, R and Gou, Y and Tam, OH and Menon, S and Situ, WG and Cazarez, SL and Zandi, A and Ehsani, KC and Howard, S and Dickson, DW and Gale Hammell, M and Prudencio, M and Petrucelli, L and Li, W and La Spada, AR}, title = {TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {11}, pages = {}, doi = {10.1172/JCI182088}, pmid = {40454469}, issn = {1558-8238}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Polyadenylation ; tau Proteins/metabolism/genetics ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3' UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.}, }
@article {pmid40453434, year = {2025}, author = {Voosala, S and Sandhya, M and Mathuranath, PS and Mahale, RR}, title = {Autoimmune Encephalitis Pattern on PET-MRI in a Patient with Amyotrophic Lateral Sclerosis.}, journal = {Indian journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India}, volume = {40}, number = {1}, pages = {22-25}, pmid = {40453434}, issn = {0972-3919}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive primary motor neuron disorder whose etiology is a subject of debate even today. Interplay between multiple genetic and environmental factors and co-existent/antecedent infection, inflammation, and malignancy have all been hypothesized as potentially causative for this disease. Owing to its hybrid diagnostic capability, fluorodeoxyglucose positron emission tomography-magnetic resonance imaging is highly valuable in detecting varied autoimmune encephalitis patterns, one of which we report in a patient with ALS providing insight into autoimmunity as a potential etiology in the pathogenesis of this disease.}, }
@article {pmid40453369, year = {2025}, author = {Slagt, C and Van Kuijk, SMJ and Bruhn, J and Van Geffen, GJ and Mommers, L}, title = {First Results of Our Local Practice Guide Used During the Late Phase of Resuscitation in Patients with Refractory VF in Out of Hospital Cardiac Arrest.}, journal = {Open access emergency medicine : OAEM}, volume = {17}, number = {}, pages = {203-213}, pmid = {40453369}, issn = {1179-1500}, abstract = {OBJECTIVE: Treatment of refractory ventricular fibrillation (rVF) is a clinical challenge. If rVF is still present after standard advanced life support (ALS) guideline care, including amiodaron administration, other therapeutic options might be necessary. Based on the available evidence and expertise, our Helicopter Emergency Medical Service (HEMS) team developed a local practice guide for the prolonged resuscitation of patients in rVF and implemented this as standard HEMS care in March 2022.<br><br>METHODS: This database study contains all patients treated with our local practice guide during out of hospital cardiac arrest (OHCA) with rVF beyond the fifth regular ALS shock-block. This local practice HEMS treatment algorithm consisted of, among others, cessation of epinephrine and alternating administration of esmolol and norepinephrine combined with enoximone. Data were derived from the HEMS database and the treating hospitals. Primary outcome was the return of spontaneous circulation. Secondary outcome was defined as survival to hospital discharge and cerebral performance. This outcome was compared to the literature to analyze for inferiority of treatment.<br><br>RESULTS: In a 21-month period, HEMS was 761 times deployed for OHCA. Nineteen patients were treated with the local practice guide, nine patients (47%) were admitted to hospital with return of spontaneous circulation. Median resuscitation time was 22min. Hospital survival with good neurology was achieved in 42% vs 17% as expected. Exact Clopper-Pearson and logistic regression analysis revealed non-inferiority of the local practice guide. Withholding epinephrine was achieved in 84% of patients. A total of 79% and 90% of patients received esmolol and norepinephrine/enoximone mixture, respectively. Alternative defibrillation positions were indicated in 18 patients but applied in only 6 (33%).<br><br>CONCLUSION: In patients with persisting VF despite prolonged advanced life support care, a multifaceted bundle of care approach shows promising results and warrants further research. Alternative drug administrations were found to be substantially easier to achieve compared to alternative defibrillation positions.}, }
@article {pmid40452868, year = {2025}, author = {Labarre, A and Guitard, E and Tossing, G and Parker, JA}, title = {har-1/CHCHD10 mutations induce neurodegeneration and mitochondrial fragmentation in Caenorhabditis elegans.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40452868}, issn = {2578-9430}, abstract = {CHCHD10 encodes a mitochondrial protein that plays a role in cristae morphology and oxidative phosphorylation, with mutations associated with neurodegenerative diseases, including the spectrum of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The Caenorhabditis elegans ortholog of CHCHD10 is har-1 , which can be used to model CHCHD10-related neurodegenerative diseases. We focused on two har-1 mutant strains: one featuring a 260 bp deletion (gk3124) and the other with a G73E point mutation (ad2155). Both har-1 mutants displayed progressive paralysis, degeneration of GABAergic motor neurons, and mitochondrial fragmentation. These strains may be valuable tools for investigating pathogenic mechanisms and therapeutic strategies for neurodegenerative diseases.}, }
@article {pmid40452867, year = {2025}, author = {Labarre, A and Guitard, E and Tossing, G and Parker, JA}, title = {Suppression of har-1/CHCHD10 phenotypes for ALS-FTD therapy discovery.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40452867}, issn = {2578-9430}, abstract = {Mutations in CHCHD10 are linked to a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The Caenorhabditis elegans orthologue of CHCHD10 is har-1 , and we investigated whether har-1 mutants could be used for therapeutic discovery in ALS-FTD. Our results show that the small molecule pioglitazone and the probiotic Lacticaseibacillus rhamnosus HA-114 can alleviate har-1 mutant phenotypes. These findings suggest that har-1 mutants are suitable for modifier screens and could be adapted for high-throughput drug screening and microbiome studies to aid in discovering therapies for ALS-FTD.}, }
@article {pmid40451302, year = {2025}, author = {Thang, CJ and Garate, D and Sánchez-Feliciano, A and Barbieri, JS}, title = {Response to Cho et. al's "GLP-1 Receptor Agonist Use Is Associated with Increased Rates of Acne Vulgaris Diagnosis In Non-Diabetic Obese Women but Not Men: A Retrospective Cohort Study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.102}, pmid = {40451302}, issn = {1097-6787}, }
@article {pmid40450587, year = {2025}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Punjani, R and Larson, T and Berry, J and Mohidul, S and Xue, S and Horton, DK}, title = {Incidence of ALS in all 50 states in the United States, data from the National ALS Registry, 2012-2019.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2506448}, pmid = {40450587}, issn = {2167-9223}, abstract = {OBJECTIVE: To summarize amyotrophic lateral sclerosis (ALS) incidence in all 50 states and the District of Columbia from 2012 to 2019. In 2010, the Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated National ALS Registry (Registry) to determine the incidence and prevalence of ALS within the United States, characterize demographics, and identify potential risk factors. This is the first analysis of state-level ALS incidence estimates for all 50 states and the District of Columbia.<br><br>METHODS: ALS is not a notifiable disease in the United States. As such, the Registry identifies cases using existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration), and a secure web portal that identifies cases not included in the national databases. Confirmed and likely cases are deduplicated and counted as incident cases for the first year they are identified using a validated algorithm. Incident counts, incident rates, and rate ratios were then calculated.<br><br>RESULTS: State-level age-adjusted overall incidence rates for 2012 to 2019 ranged from 0.65 per 100,000 persons (Alaska) to 2.25 per 100,000 persons (Vermont), with an overall incidence of 1.44 per 100,000 persons in the United States. New England and the upper Midwest regions had higher incidence rates than national rates.<br><br>CONCLUSIONS: These findings summarize the incidence of ALS for all 50 states from 2012 to 2019. This is a continuing effort to identify ALS cases nationally. The establishment of the Registry allows for epidemiological analyses of ALS data and the assessment of potential risk factors.}, }
@article {pmid40450581, year = {2025}, author = {Tokuda, E and Leykam, L and Zetterström, P and Brännström, T and Andersen, PM and Marklund, SL}, title = {Diverse effects of coexpression of human SOD1 variants on motor neuron disease.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf088}, pmid = {40450581}, issn = {1460-2083}, support = {56103-7002829//V&#xe4;sterbotten County Council/ ; 223-2808-12//Torsten and Ragnar S&#xf6;derberg Foundation, Ume&#xe5; University Insamlingsstiftelsen/ ; 223-1881-13//Torsten and Ragnar S&#xf6;derberg Foundation, Ume&#xe5; University Insamlingsstiftelsen/ ; 2.1.12-1605-14//Torsten and Ragnar S&#xf6;derberg Foundation, Ume&#xe5; University Insamlingsstiftelsen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; 2014.0305//Knut and Alice Wallenberg Foundation/ ; 2020.0232//Knut and Alice Wallenberg Foundation/ ; 2012-3167//Swedish Research Council/ ; 2017-03100//Swedish Research Council/ ; 2012-0262//Swedish Brain Foundation/ ; 2012-0305//Swedish Brain Foundation/ ; 2013-0279//Swedish Brain Foundation/ ; 2016-0303//Swedish Brain Foundation/ ; 2018-0310//Swedish Brain Foundation/ ; 2020-0353//Swedish Brain Foundation/ ; 2022-0309//Swedish Brain Foundation/ ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.}, }
@article {pmid40449058, year = {2025}, author = {Zhang, Q and Ding, Y and Zhang, Y and Li, Q and Shi, S and Liu, Y and Chen, S and Wu, Q and Xu, X and Wu, F and Cheng, X and Niu, Q}, title = {Early cortical alterations and neuropsychological mechanisms in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {47}, number = {}, pages = {103809}, doi = {10.1016/j.nicl.2025.103809}, pmid = {40449058}, issn = {2213-1582}, abstract = {OBJECTIVE: This study investigates the characteristics of cortical structural and functional alterations in amyotrophic lateral sclerosis (ALS) patients and their modulation of emotional and cognitive functions, as well as to discuss their diagnostic value in early-stage ALS.<br><br>METHODS: Fifty-nine ALS patients (28 in ALS 1 and 31 in ALS 2, categorized using King's College Staging) and 31 healthy controls were evaluated using multiparametric MRI, motor and neuropsychological assessments, and serum neurofilament light chain (NfL) levels. Mediation analyses were performed to examine how cortical alterations influence the relationship between emotional and cognitive functions. Support vector machine (SVM) classification models were constructed to assess the diagnostic utility of differential cortical parameters.<br><br>RESULTS: ALS 1 patients exhibited increased cortical thickness (CT) and functional activity in the cingulate and frontotemporal regions, correlating with neuropsychological performance and NfL levels. Mediation analysis revealed that perigenual and frontotemporal functional activity significantly modulated the relationship between depressive symptoms and cognitive function. SVM classification showed that the combined altered regions with Amplitude of Low Frequency Fluctuations (ALFF) model achieved slightly better performance (AUC&#xa0;=&#xa0;0.853, 95&#xa0;%CI: 0.687-1.000, p&#xa0;<&#xa0;0.001) compared to CT (AUC&#xa0;=&#xa0;0.779, 95&#xa0;%CI: 0.587-0.972, p&#xa0;<&#xa0;0.001), although both models showed limited efficacy in differentiating between ALS 1 and ALS 2 groups.<br><br>CONCLUSIONS: Cortical structural and functional alterations in ALS mediate the impact of depression on cognitive function, offering insights into the neuropsychological mechanisms of the disease and potential biomarkers for early-stage diagnosis.}, }
@article {pmid40446958, year = {2025}, author = {Yuan, L and Yang, Y and Guo, Y and Deng, H}, title = {Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review.}, journal = {Journal of genetics and genomics = Yi chuan xue bao}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jgg.2025.05.008}, pmid = {40446958}, issn = {1673-8527}, abstract = {Amyotrophic lateral sclerosis (ALS), one of the most prevalent neurodegenerative disorders, is pathologically characterized by the progressive degeneration of both upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 2-4 years post-diagnosis. ALS is categorized into familial ALS (FALS) and sporadic ALS, with FALS accounting for approximately 10% of ALS cases. As a genetically heterogeneous disease, ALS exhibits diverse inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked transmission, and genetic factors play pivotal roles in disease pathogenesis. To date, at least 34 disease-causing loci and 32 genes for ALS have been identified. The investigations of mutant protein products and the establishment of animal models have unraveled potential pathogenic pathways, offering insights into the mechanisms of neurodegeneration in ALS. This review focuses on ALS clinical characteristics, neuropathological features, causative loci/genes, genetic susceptibility factors, animal models, and pathogenic mechanisms, with particular attention to recent advances in genetic findings and pathogenic pathways of ALS. Elucidation of the genetic basis of ALS could provide the scientific foundation for personalized treatments to address this recalcitrant disease.}, }
@article {pmid40446399, year = {2025}, author = {Holdom, CJ and Pilkar, R and Guo, CC and Eijk, RPAV and Sethi, N and Henderson, RD and Ngo, ST and Steyn, FJ}, title = {Identification of passive wrist-worn accelerometry outcomes for improved disease monitoring and trial design in motor neuron disease.}, journal = {EBioMedicine}, volume = {117}, number = {}, pages = {105779}, doi = {10.1016/j.ebiom.2025.105779}, pmid = {40446399}, issn = {2352-3964}, abstract = {BACKGROUND: Motor neuron disease (MND) leads to progressive functional decline, making reliable measures of disease progression critical for patient care and clinical trials. Current clinical outcome measures lack the ability to continuously and objectively track functional decline in daily life of patients with MND. This study assessed and validated wrist-worn accelerometry outcome measures for continuous monitoring in MND, with the potential to refine clinical trial outcomes.<br><br>METHODS: This longitudinal study included 95 patients with MND who wore an ActiGraph GT9X Link device on their non-dominant wrist for 8 days, with follow-up every 3-4 months. Accelerometer data were processed using ActiLife and GGIR. Joint models were used to simultaneously investigate the longitudinal change in ALS Functional Rating Scale-Revised (ALSFRS-R) scores and accelerometer-derived outcomes alongside their relationship with overall survival. Sample size estimates for clinical trials were generated using both accelerometer- and ALSFRS-R-based outcomes, and principal component analysis (PCA) explored outcome relationships.<br><br>FINDINGS: Accelerometer outcomes showed a slower rate of decline (-0.03 to -0.07 SD/month) compared to ALSFRS-R (-0.10 SD/month) and had stronger correlations with ALSFRS-R motor subdomains (partial r: 0.60-0.73). PCA revealed that longitudinal measures of accelerometry were distinct from the ALSFRS-R, highlighting the complementary nature of these measures. Peak 6-min activity predicted smaller clinical trial sample sizes for studies over 12 months. Accelerometer-derived outcomes were not significantly associated with survival.<br><br>INTERPRETATION: Wrist-worn accelerometry offers a practical solution for continuous monitoring in MND, complementing ALSFRS-R. Measures of peak performance, and specifically peak 6-min activity shows promise, potentially reducing sample sizes and improving disease tracking over longer duration studies. Further refinement and validation are needed to adopt actigraphy measures as clinical assessment outcomes.<br><br>FUNDING: This study was supported by Wesley Medical Research (2016-32), the Honda Foundation, Motor Neurone Disease Research Australia, and FightMND. CJH received a Higher Degree Research Scholarship from UQ. STN received support from the Scott Sullivan Fellowship (MND and Me Foundation/RBWH Foundation), a FightMND Mid-Career Fellowship, and the AIBN.}, }
@article {pmid40445869, year = {2025}, author = {Moisseyev, R and Kostyukova, VS and Pozharskiy, AS and Mendybayeva, A and Gritsenko, D}, title = {First Report of Grapevine Yellow Speckle Viroids and Hop Stunt Viroid in Vitis vinifera in Kazakhstan.}, journal = {Plant disease}, volume = {}, number = {}, pages = {}, doi = {10.1094/PDIS-04-25-0798-PDN}, pmid = {40445869}, issn = {0191-2917}, abstract = {Grapevine viroids are the smallest pathogens affecting viticulture. Infected grapevines may show symptoms such as leaf yellowing, mottling, stunted growth, reduced fruit quality, and overall vine decline. Asymptomatic viroid infections in grapevines can still decrease grapevine productivity, thereby posing a hidden economic threat to viticulture (Wolpert et al., 1996; Wu et al., 2023). This study aimed to detect three widely distributed viroid species of the Pospiviroidae family: Grapevine yellow speckle viroid 1 (GYSVd-1), Grapevine yellow speckle viroid 2 (GYSVd-2), and Hop stunt viroid (HSVd). The study focused on grapevine (Vitis vinifera) cultivars 'Saperavi' and 'Rkatsiteli' cultivated in Kazakhstan. Three fields in Shirin village and one field in Tyulkubas village (each about 600 ha) in Almaty region were tested for the presence of viroids due to a decline in yield observed despite the negative tests for common viruses (past 3 years). Symptoms typical for viral infections were observed sporadically without a consistent pattern of infection. Total 17 samples from Shirin (July 2023) and 14 from Tyulkubas (June 2024) with visible symptoms were collected randomly. Validated primers were used to identify GYSVd-1 (mF/mR1, 250 bp) (Hajizadeh et al. 2012) GYSVd-2 (P1/P2, 375 bp) (Jiang et al. 2009) and HSVd (78P/83M, 312 bp) (Sano et al. 2001) using conventional RT-PCR. Among the analyzed samples, in Shirin village, 6 samples tested positive for GYSVd-1, 15 for GYSVd-2, and 15 for HSVd, including 2 positive for both HSVd and GYSVd-1. In Tyulkubas village, 2 samples were positive for GYSVd-1 and 12 for HSVd; GYSVd-1 positive samples als were positive for HSVd, including 8 positive for both HSVd and GYSVd-2 and 6 positive for three viroids. Amplicons for each viroid were further sequenced using the Sanger's method on ABI 3500 Genetic Analyser with BigDye v.3.1 kit and using MinION sequencer with the Rapid Barcoding Kit 96 V14 (Oxford Nanopore Technologies) according to the manufacturer's protocol. The obtained reads were mapped to reference sequences from GenBank-GYSVd-1 NC_001920.1, HSVd NC_001351.1, and GYSVd-2 MG780425.1-using Minimap v.2.2.0 with default parameters in Geneious software. Sequencing produced total 2253 reads for GYSVd-1 (average length 159 bp, range 42-296), 2095 for GYSVd-2 (203.6 bp, 49-578), and 1235 for HSVd (218.5 bp, 53-440). Of these, 947 (42.0%) were been mapped to GYSVd-1, 1778 (84.9%) to GYSVd-2, and 678 (54.9%) to HSVd. Genome coverage was 62.3% (GYSVd-1), 98.1% (GYSVd-2), and 73.8% (HSVd), with mean depths of 889X, 1282X, and 659X, respectively. Each viroid resulted a single contig corresponding to the target amplicon. No reads corresponding to other viral or bacterial agents have been identified. NCBI BLASTn search resulted total 141 hits with coverage 59-68% and identity 98.69-99.35% for GYSVd-1; 128 hits with coverage 82-100% and identity 97.59-100% for GYSVd-2; 157 hits with coverage 99-100% and identity 95.49-97.29%; no not-specific matches were identified for three viroids. The assembled viroid sequences obtained using nanopore sequencing have been uploaded into NCBI database (accessions PV341024-PV341026). Viroids GYSVd-1,2 and HSVd have been detected for the first time in Kazakhstan. The results indicate the need for further studies to estimate impact of these viroids on viticulture and lay a basis for their monitoring in the country.}, }
@article {pmid40443183, year = {2025}, author = {Gonçalves, F and Teixeira, MI and Rego, F and Magalhães, B}, title = {The role of spiritual care management - Needs and resources in people with amyotrophic lateral sclerosis: Insights from a mixed-methods study.}, journal = {Palliative &amp; supportive care}, volume = {23}, number = {}, pages = {e111}, doi = {10.1017/S1478951525000495}, pmid = {40443183}, issn = {1478-9523}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/therapy ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; Qualitative Research ; Adult ; *Spirituality ; Psychometrics/methods/instrumentation ; *Spiritual Therapies/methods/standards ; }, abstract = {OBJECTIVES: To explore the spiritual needs and resources of People with Amyotrophic Lateral Sclerosis (PALS) at different stages of its trajectory and to characterize the experiences of the current state of the disease.<br><br>METHODS: A convergent mixed-methods study was conducted using qualitative and quantitative approaches. Participants were assessed using the clinical and sociodemographic data, ALSFRS-R (function assessment), and the GES Questionnaire to evaluate spiritual needs and resources. Data were collected through in-person or online interviews, transcribed and coded. The qualitative analysis was based on the content analysis method. Statistical analysis was performed using SPSS software. Both datasets were integrated during data analysis.<br><br>RESULTS: Twenty-four patients were interviewed, with a duration of the illness ranging from 1 year to 12&#xa0;years. Participants were at different stages of functional dependence. Analyzing the open questions of the GES questionnaire, six categories were established related to the inner world of PALS: Concern, Nuisance, Help, Support, Safety, and Valorization. Contrary to what was hypothesized, no correlations were found between functionality and the spiritual dimensions. Spiritual needs and resources tend to vary with age, with younger ages presenting a more fragile spiritual dimension overall. Also, the intrapersonal and interpersonal dimension seems to play a central role in the lives of PALS. A negative correlation was identified between the feeling of connection to a supreme/transcendent reality and the level of educational qualifications.<br><br>SIGNIFICANCE OF RESULTS: Spirituality often provides crucial emotional support, meaning, and resilience during challenging times. Despite its importance, it is often overlooked in clinical settings. The study emphasizes the need for personalized, holistic care, which should include spiritual care support, regardless of the functional state, highlighting the importance of addressing both intrapersonal and interpersonal domains, resources and needs from early phases. Allowing to create a structured care plan that meets patients' individual spiritual needs, that can contribute to a better QoL and reduce suffering.}, }
@article {pmid40441800, year = {2025}, author = {Mehmood, N and Riaz, A and Ghuffar, S and Anwaar, S and Jabeen, N and Shaheen, I and Qasim, M and Khan, SS and Rauf, M and Anwar, T and Qureshi, H and Abusalim, GS and Zaman, W and Ansari, MJ and Iqbal, R}, title = {Epidemiology and genetic characterization of Alternaria alternata causing leaf spot in Fragaria × ananassa.}, journal = {Fungal biology}, volume = {129}, number = {4}, pages = {101589}, doi = {10.1016/j.funbio.2025.101589}, pmid = {40441800}, issn = {1878-6146}, mesh = {*Fragaria/microbiology ; *Alternaria/genetics/isolation &amp; purification/classification/pathogenicity ; *Plant Diseases/microbiology ; Phylogeny ; Pakistan/epidemiology ; Incidence ; DNA, Fungal/genetics/chemistry ; Prevalence ; Sequence Analysis, DNA ; Plant Leaves/microbiology ; DNA, Ribosomal Spacer/genetics/chemistry ; }, abstract = {Alternaria leaf spot (ALS), caused by Alternaria alternata, is a major disease threatening strawberry (Fragaria × ananassa) production globally, including in Pakistan. This study investigated the incidence and prevalence of ALS in key strawberry-producing regions of Pakistan and characterized the pathogen using morphological and molecular techniques. Surveys were conducted during the 2014-2015 and 2015-2016 seasons across 182 farms in Punjab, Khyber Pakhtunkhwa, and Islamabad. Disease prevalence was 100% across all regions, with incidence rates ranging from 17.25% in cooler Islamabad to 55% in Mardan, KPK. Pathogenicity tests confirmed A. alternata as the causal agent. Morphological traits and sequencing of the ITS and endoPG genes further validated its identity. Phylogenetic analysis showed close genetic relatedness to known A. alternata isolates. This is the first comprehensive report of ALS in strawberries in Pakistan, confirming A. alternata as the primary pathogen. The widespread occurrence and high incidence highlight the urgent need for effective control measures. Integrated disease management, including resistant cultivars and targeted fungicide use, is strongly recommended. Further research should investigate environmental factors influencing disease spread and severity to support long-term sustainable management of ALS in strawberry cultivation.}, }
@article {pmid40441681, year = {2025}, author = {Sarasate, M and Córdoba-Izquierdo, A and Farrero, E and López-Lisbona, R and Díez-Ferrer, M and Trias-Sabrià, P and Plana, M and Povedano, M and Santos, S and Prats, E}, title = {Effect of Noninvasive Ventilation on the Upper Airway in Patients With Amyotrophic Lateral Sclerosis: The Role of Upper-Airway Endoscopy.}, journal = {Respiratory care}, volume = {}, number = {}, pages = {}, doi = {10.1089/respcare.12791}, pmid = {40441681}, issn = {1943-3654}, abstract = {Background: Upper-airway obstruction (UAO) in amyotrophic lateral sclerosis (ALS) may reduce the efficacy of noninvasive ventilation (NIV). NIV can cause or worsen this obstruction, further worsening the disease prognosis. This study aims to describe UAO in ALS patients using upper-airway endoscopy (UA-End) during spontaneous breathing (SB) and NIV and to evaluate the usefulness of UA-End in adjusting NIV parameters to correct any observed obstruction. Methods: This prospective study (2017-2019) involved subjects with ALS and indications for NIV. After optimizing ventilation following standardized procedures, an awake UA-End was performed, first during SB and then during NIV. Endoscopic assessments included identification of the site of UAO using the VOTE classification, assessment of vocal cords, and adjustments of NIV settings to correct any identified obstructions. Afterward, a post hoc analysis was conducted comparing gasometrical and nocturnal oximetry variables between the groups with and without NIV obstruction at 3 and 6 months. Results: In total, 25 subjects were enrolled. UAO was observed in 9 cases (37%) during SB, whereas 12 cases (50%) showed obstruction during NIV, 7 newly appearing. Hypopharyngeal constriction and backward movement of the epiglottis were the most frequent findings. Adjustments in NIV settings during endoscopy improved UAO in all but one case. Survival rates were similar after UA-End adjustments for subjects on NIV, both with and without UAO. Conclusions: This study is, to the best of our knowledge, the first to show the usefulness of UA-End in assessing and correcting UAO in subjects with ALS at NIV initiation. Furthermore, correction of such events through UA-End may have a positive impact on ventilation control and survival.}, }
@article {pmid40441157, year = {2025}, author = {Das, T and Zaidi, FK and Farag, M and Ruff, KM and Mahendran, TS and Singh, A and Gui, X and Messing, J and Taylor, JP and Banerjee, PR and Pappu, RV and Mittag, T}, title = {Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2025.05.011}, pmid = {40441157}, issn = {1097-4164}, abstract = {Stress granules form via co-condensation of RNA-binding proteins (RBPs) containing prion-like low-complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by amyotrophic lateral sclerosis (ALS)-associated mutations. We report that condensation- versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. These separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation, whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules.}, }
@article {pmid40441139, year = {2025}, author = {Workman, MJ and Lim, RG and Wu, J and Frank, A and Ornelas, L and Panther, L and Galvez, E and Perez, D and Meepe, I and Lei, S and Valencia, V and Gomez, E and Liu, C and Moran, R and Pinedo, L and Tsitkov, S and Ho, R and Kaye, JA and ,  and Thompson, T and Rothstein, JD and Finkbeiner, S and Fraenkel, E and Sareen, D and Thompson, LM and Svendsen, CN}, title = {Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.05.022}, pmid = {40441139}, issn = {1097-4199}, }
@article {pmid40440345, year = {2025}, author = {Krull, F and Hosseini, S and Bleyer, M and Brenig, B}, title = {Findings from transcriptomics and immunohistochemistry indicate an autoimmune disease targeting brainstem inhibitory interneurons in bovine spastic paresis.}, journal = {PloS one}, volume = {20}, number = {5}, pages = {e0324633}, pmid = {40440345}, issn = {1932-6203}, mesh = {Animals ; Cattle ; *Brain Stem/metabolism/pathology/immunology ; *Interneurons/metabolism/pathology/immunology ; *Transcriptome ; *Cattle Diseases/genetics/immunology/pathology/metabolism ; *Autoimmune Diseases/veterinary/genetics/metabolism/pathology/immunology ; Immunohistochemistry ; Gene Expression Profiling ; *Muscle Spasticity/veterinary/genetics/immunology/pathology/metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {Bovine spastic paresis (BSP) is a progressive neuromuscular disease of unknown origin that causes persistent stiffness of the hind limbs. The symptoms are similar to those of human motor neuron diseases such as primary (PLS) or amyotrophic lateral sclerosis (ALS). BSP occurs worldwide in cattle production with an estimated prevalence of <1%. For Germany, this means that around 20,000 Holstein cattle are affected. BSP is generally considered a hereditary disease, but there is no prevention through breeding programs. As a result, BSP not only affects animal welfare but also leads to economic losses in milk and beef production. Here, we used transcriptomics to analyse the brainstem, spinal cord and affected gastrocnemius muscle tissue of eight animals affected by BSP and eight control animals from slaughterhouses to gain new insights into the molecular mechanisms underlying BSP. We found that the expression of several genes was significantly different in animals affected by BSP compared to control animals. Specific genes for inhibitory neurons were downregulated in the brainstems of the affected animals, namely CCK (cholecystokinin), NPY (neuropeptide Y), and SST (somatostatin). These inhibitory neurotransmitters influence cerebral movement control, among other processes. Furthermore, OOSP2 (oocyte secreted protein 2) was found to be significantly upregulated in the affected animals in all tissues. This expression could best be explained by the presence of T-follicular-helper cells which, through interleukin 21, can trigger a TH-2-dominated immune response and lead to autoimmune encephalitis. Further cases were sampled for confirmation and we detected cell infiltrates of activated microglia and T-cells in the brainstem using immunohistochemistry. Microglial foci were significantly more abundant in animals affected by BSP than control animals. We conclude that BSP is caused by an autoimmune reaction directed against inhibitory interneurons in the brainstem and is due to a combination of genetics and environmental influences. This may result in lost controlling influence on the upper motor neurons via extrapyramidal pathways and therefore triggers the specific symptoms of motor neuron disease.}, }
@article {pmid40439916, year = {2025}, author = {Porel, P and Hunjan, G and Kaur, N and Sharma, V and Kaur, M and Mittal, Y and Kaur, R and Aran, KR}, title = {Unlocking the neuroprotective potential of peptide nucleic acids 5 (PNA5) in neurological diseases: molecular mechanisms to therapeutic approaches.}, journal = {Metabolic brain disease}, volume = {40}, number = {5}, pages = {213}, pmid = {40439916}, issn = {1573-7365}, mesh = {Humans ; *Peptide Nucleic Acids/therapeutic use/pharmacology ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Blood-Brain Barrier/drug effects/metabolism ; }, abstract = {Peptide nucleic acids (PNAs) are synthetic nucleic acid analogues offering distinct structural and functional advantages over conventional RNA and DNA, positioning them as powerful molecules in molecular biology. Recently, PNAs have gained significant attention for their potential in the prevention and management of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), spinal cord injury (SCI), depression, and anxiety. PNA5, a specific PNA variant, is highly expressed in neocortical association regions, particularly in primates, and plays a critical role in high-level cognitive functions such as reasoning, decision-making, and problem-solving. It can form stable, sequence-specific hybridizations with nucleic acids, resist nuclease degradation, and efficiently cross cellular membranes, making them ideal candidates for targeting disease-related genes in the brain. PNA5 has shown neuroprotective properties by improving cognitive function, reducing neuroinflammation, and preserving the integrity of the blood-brain barrier (BBB). Additionally, it supports critical processes such as neural migration, axon guidance, and synaptogenesis, which are vital for maintaining proper brain function. This review explores the mechanisms by which PNAs, particularly PNA5, exert therapeutic effects in neurological disorders. It highlights their role in gene modulation, protein regulation, and potential strategies for enhancing PNA delivery to the central nervous system (CNS) and its related disorders.}, }
@article {pmid40439808, year = {2025}, author = {Singh, H and Gupta, R and Gupta, M and Ahmad, A}, title = {Aging-induced alterations in microglial cells and their impact on neurodegenerative disorders.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {515}, pmid = {40439808}, issn = {1573-4978}, mesh = {Humans ; *Microglia/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Aging/pathology/metabolism ; Animals ; Brain/metabolism/pathology ; Cellular Senescence ; }, abstract = {Senescence causes deterioration in the functioning and physiology of an organism. Microglia, the standing resident immune brain cells transform from neuroprotective to neurotoxic with age. Rapid process motility and cellular migration of microglia in the developing brain, and other characteristics are regarded to be crucial for immunological defense and tissue repair. As they mature, microglia not only differ in their morphology but also in their functioning. However, the exact mechanism related to the atrophies caused by aged microglia or their role in neurodegenerative diseases is still uncertain. The aim of this updated review is to provide insights of how aging microglial cells change and how this influences the development of neurodegenerative diseases. As life expectancy rises, there is an increase in the accumulation of iron, ROS/NOS, protein misfolding and insufficient clearing of debris. This is attributed to the age-dependent alterations in the genes linked to energy metabolism, mitochondrial and lysosome function, and neuroinflammation. Aging microglia often shifts towards a pro-inflammatory state with a reduction of anti-inflammatory cytokines. Aging microglia fail to clear amyloid-beta plaques, accelerates tau-pathology and enhances the chronic neuroinflammation, exacerbating the α-synuclein aggregation. These changes significantly impacted the onset of various neurogenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease etc. However, it is important to note that these microglial aging effects might not be perceived as absolute, due to various limitations such as microglial heterogeneity, intercellular complexity across brain regions and variability in human aging owing to genetic and epigenetic variations. Regardless of this the future perspective of such insights are of immense relevance as novel therapeutic approaches can be formulated if the molecular and cellular mechanisms of aging microglial perturbations are understood. Future research should focus on restoring microglial homeostasis to mitigate the effects of aging on the brain and slowing the progression of neurodegenerative diseases.}, }
@article {pmid40438583, year = {2025}, author = {Li, H and Peng, Y and Wu, Y and Chen, Y and Li, J and He, Y and Wang, H and Luo, C and Mo, Z}, title = {Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1541442}, pmid = {40438583}, issn = {1663-9812}, abstract = {BACKGROUND: Methamphetamine (MA) is one of the most harmful synthetic drugs, yet the mechanisms underlying its addiction and relapse remain incompletely understood. This study investigates how cardiomyocyte-derived exosomes carrying miRNAs facilitate heart-brain crosstalk and contribute to MA dependence.<br><br>MATERIALS AND METHODS: A conditioned place preference (CPP) model of MA dependence was established in rats. High-throughput sequencing were employed to identify candidate miRNAs in cardiac exosomes and brain tissues. Behavioral assessments, real-time PCR, nanoparticle tracking analysis, in vivo imaging, in vitro uptake assays, network pharmacology, and dual-luciferase reporter assays were used to explore the role of cardiomyocyte-derived exosomes in MA dependence.<br><br>RESULTS: MA induced significant CPP in rats. miR-181a-5p was markedly upregulated in cardiac exosomes and brain tissue, with higher levels observed in cardiac exosomes. In vivo biodistribution showed that cardiomyocyte-derived exosomes cross the blood-brain barrier and accumulate in the brain. In vitro uptake assays demonstrated that SH-SY5Y cells internalized these exosomes, leading to increased miR-181a-5p expression. Tail vein injections of miR-181a-5p-enriched exosomes enhanced MA CPP behavior in rats. Network pharmacology revealed 108 potential targets of miR-181a-5p, enriched in processes such as steroid biosynthesis, amide metabolism, and apoptosis, involving pathways related to the endoplasmic reticulum, MAPK signaling, and amyotrophic lateral sclerosis. Molecular docking identified stable interactions between MA and 12 targets, including HSP90B1, TNF, and MAP2K1, with miR-181a-5p binding to the 3'-UTR regions of these targets. Dual-luciferase assays confirmed the negative regulation of six targets by miR-181a-5p.<br><br>CONCLUSION: This study reveals that cardiomyocyte-derived exosomes transport miR-181a-5p, facilitating heart-brain crosstalk and exacerbating MA CPP behavior in rats. These effects are mediated through the regulation of key brain targets, including HSP90B1, TNF, and MAP2K1, providing new insights into the molecular mechanisms of MA addiction and potential therapeutic targets.}, }
@article {pmid40437235, year = {2025}, author = {Modafferi, S and Farina, S and Esposito, F and Brandi, O and Di Salvio, M and Della Valle, I and D'Uva, S and Scarian, E and Cicio, G and Riccardi, A and Pisati, F and Garbelli, A and Santini, T and Pansarasa, O and Morlando, M and D'Ambrosi, N and Cozzolino, M and Cestra, G and d'Adda di Fagagna, F and Gioia, U and Francia, S}, title = {DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {40437235}, issn = {1476-5403}, support = {RIPREI2023_7c8ae10d783c//Istituto Superiore di Sanit&#xe0; (ISS)/ ; PRIN 2020 CXFL4T//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; MNESYS (PE0000006)//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041 CN3 RNA//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PNRR-CN3//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2021 DDR&amp;ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2016 DDRNA&amp;ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2021 DDR&amp;ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; 2016 DDRNA&amp;ALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; DBA.AD005.225-NUTRAGE-FOE2021//Consiglio Nazionale delle Ricerche (National Research Council)/ ; Flagship Project Interomics//Consiglio Nazionale delle Ricerche (National Research Council)/ ; TELORNAGING-835103//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; AIRC-IG(21762)//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; AIRC 5&#xd7;1000//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; GGP17111//Fondazione Telethon (Telethon Foundation)/ ; POR FESR 2014-2020//Regione Lombardia (Region of Lombardy)/ ; Ricerca Corrente 2022 - 2024//Ministero della Salute (Ministry of Health, Italy)/ ; Ricerca Corrente 2022 - 2024//Ministero della Salute (Ministry of Health, Italy)/ ; }, abstract = {Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUS[P525L], co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUS[P525L] CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In Drosophila melanogaster, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS CIs include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.}, }
@article {pmid40436457, year = {2025}, author = {Peace, A and White, DA and Hackney, G and Bradburn, M and Norman, P and White, S and Al-Chalabi, A and Baird, W and Beever, D and Cade, J and Coates, E and Cooper, C and Ezaydi, N and Halliday, V and Maguire, C and Shaw, PJ and Stavroulakis, H and Waterhouse, S and Young, TA and McDermott, CJ and , }, title = {Randomised controlled trial with parallel process evaluation and health economic analysis to evaluate a nutritional management intervention, OptiCALS, for patients with amyotrophic lateral sclerosis: study protocol.}, journal = {BMJ open}, volume = {15}, number = {5}, pages = {e096098}, doi = {10.1136/bmjopen-2024-096098}, pmid = {40436457}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diet therapy/economics ; United Kingdom ; Randomized Controlled Trials as Topic ; Ireland ; Cost-Benefit Analysis ; Energy Intake ; Quality of Life ; Nutrition Therapy/methods ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating illness that leads to muscle weakness and death usually within around 3 years of diagnosis. People with ALS (pwALS) often lose weight due to raised energy requirements and symptoms of the disease presenting significant challenges to taking adequate oral diet, with those who lose more weight being at a greater chance of earlier death. There is also some evidence to suggest that a higher calorie diet may benefit the disease course in pwALS, but further research is needed.<br><br>METHODS AND ANALYSIS: Two armed, parallel group, superiority, open labelled, randomised controlled trial, with internal pilot, to assess the effectiveness of an early high calorie diet on functional outcomes in ALS, comprising two treatment arms: (1) standard care, (2) standard care with additional active management using the OptiCALS complex intervention to achieve a high calorie diet (initially randomised 1:1, then 1:2 following a protocol amendment). Using a food first approach, pwALS will be encouraged and supported to follow a diet that meets an individualised calorie target from food before prescribing oral nutritional supplements. 259 pwALS will be recruited from up to 20 ALS centres across the United Kingdom and Ireland and followed up for a period of 12 months. Primary outcome is functional change measured over 12 months, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Secondary end points include measures of functional health, quality of life, calorie intake and weight, as well as time to gastrostomy and survival. A health economic analysis and process evaluation will also be undertaken. Participant recruitment is expected to complete in September 2025, and participant follow-up is expected to complete in September 2026. The results of this study are expected in March 2027.<br><br>ETHICS AND DISSEMINATION: The trial was approved by Greater Manchester-North West Research Ethics Committee, reference 20/NW/0334 on 8 September 2020. We will publish the study findings in peer-reviewed academic journals and present at local, national and international conferences where possible.<br><br>TRIAL REGISTRATION NUMBER: ISRCTN30588041.}, }
@article {pmid40436400, year = {2025}, author = {Onder, F and Kumova, D and Ağın, A}, title = {[Carcinom-assoziierte Retinopathie im Zusammenhang mit Lungen- und Nierenzellkarzinom: Paraneoplastischer Sehverlust als Erstmanifestation].}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2623-5813}, pmid = {40436400}, issn = {1439-3999}, }
@article {pmid40436373, year = {2025}, author = {Vosough, M and Drees, F and Sieber, G and Stach, TL and Beisser, D and Probst, AJ and Boenigk, J and Schmidt, TC}, title = {Integrative Analysis of Nontargeted LC-HRMS and High-Throughput Metabarcoding Data for Aquatic Environmental Studies Using Combined Multivariate Statistical Approaches.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.5c00539}, pmid = {40436373}, issn = {1520-6882}, abstract = {Significant progress in high-throughput analytical techniques has paved the way for novel approaches to integrating data sets from different compartments. This study leverages nontarget screening (NTS) via liquid chromatography-high-resolution mass spectrometry (LC-HRMS), a crucial technique for analyzing organic micropollutants and their transformation products, in combination with biological indicators. We propose a combined multivariate data processing framework that integrates LC-HRMS-based NTS data with other high-throughput data sets, exemplified here by 18S V9 rRNA and full-length 16S rRNA gene metabarcoding data sets. The power of data fusion is demonstrated by systematically evaluating the impact of treated wastewater (TWW) over time on an aquatic ecosystem through a controlled mesocosm experiment. Highly compressed NTS data were compiled through the implementation of the region of interest-multivariate curve resolution-alternating least-squares (MCR-ALS) method, known as ROIMCR. By integrating ANOVA-simultaneous component analysis with structural learning and integrative decomposition (SLIDE), the innovative SLIDE-ASCA approach enables the decomposition of global and partial common, as well as distinct variation sources arising from experimental factors and their possible interactions. SLIDE-ASCA results indicate that temporal variability explains a much larger portion of the variance (74.6%) than the treatment effect, with both contributing to global shared space variation (41%). Design structure benefits include enhanced interpretability, improved detection of key features, and a more accurate representation of complex interactions between chemical and biological data. This approach offers a greater understanding of the natural and wastewater-influenced temporal patterns for each data source, as well as reveals associations between chemical and biological markers in an exemplified perturbed aquatic ecosystem.}, }
@article {pmid40433509, year = {2025}, author = {Baek, SH and Tae, WS and Park, JW and Kim, BJ}, title = {Assessment of the glymphatic dysfunction in amyotrophic lateral sclerosis using the diffusion tensor imaging along the perivascular spaces index: a pilot study.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1570327}, pmid = {40433509}, issn = {1663-4365}, abstract = {BACKGROUND: The glymphatic system plays a critical role in clearing interstitial waste from the brain. Dysfunction of this system has been linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The diffusion tensor imaging-along the perivascular space (DTI-ALPS) index has emerged as a potential neuroimaging biomarker for evaluating glymphatic function. This study investigates whether glymphatic function differs in individuals with ALS compared to those with Parkinson's disease (PD) and normal controls (NCs), using the DTI-ALPS index.<br><br>METHODS: This study included 35 ALS patients, 35 age- and sex-matched PD patients, and 13 NCs. Diffusion tensor imaging (DTI) was conducted, and the DTI-ALPS index was calculated. Clinical assessments included demographic data, disease duration, cognitive status, and functional scales. Group comparisons and correlation analyses were performed to assess the relationship between the DTI-ALPS index and clinical parameters.<br><br>RESULTS: The ALS group exhibited a significantly lower right-side DTI-ALPS index than the NC group (p = 0.037), while no differences were observed between the ALS and PD groups. The DTI-ALPS index was negatively correlated with age in ALS and PD groups but showed no correlation with clinical measures in the ALS group. Women in the ALS group had a significantly higher DTI-ALPS index than in men.<br><br>CONCLUSION: Glymphatic dysfunction may contribute to the pathogenesis of ALS, as evidenced by a reduced DTI-ALPS index compared to NCs. However, its clinical relevance and specificity for ALS remain uncertain. Further studies with larger cohorts are warranted to validate these findings.}, }
@article {pmid40432760, year = {2025}, author = {Simkin, RL and Rhymes, ER and Lang, Q and Birsa, N and Sleigh, JN}, title = {Dissection and Whole-Mount Immunofluorescent Staining of Mouse Hind Paw Muscles for Neuromuscular Junction Analysis.}, journal = {Bio-protocol}, volume = {15}, number = {10}, pages = {e5315}, pmid = {40432760}, issn = {2331-8325}, abstract = {The neuromuscular junction (NMJ) is a peripheral synaptic connection between a lower motor neuron and skeletal muscle fibre that enables muscle contraction in response to neuronal stimulation. NMJ dysfunction and morphological abnormalities are commonly observed in neurological conditions, including amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, and spinal muscular atrophy. Employing precise and reproducible techniques to visualise NMJs in mouse models of neuromuscular disorders is crucial for uncovering aspects of neuropathology, revealing disease mechanisms, and evaluating therapeutic approaches. Here, we present a method for dissecting the deep lumbrical and flexor digitorum brevis (FDB) muscles of the mouse hind paw and describe the process of whole-mount immunofluorescent staining for morphological analysis of NMJs. Similar whole-mount techniques have been applied to other muscles, such as the diaphragm; however, dense connective tissue in adult samples often impedes antibody penetration. Moreover, large hind limb muscles, including the gastrocnemius and tibialis anterior, are commonly used to examine NMJs but require embedding and cryosectioning. These additional steps increase the complexity and duration of the protocol and can introduce sectioning artefacts, including transection of NMJs and disruption of morphology. Using small hind paw muscles enables whole-mounting, which completely eliminates the requirement for embedding and cryosectioning. As a result, the entire neuromuscular innervation pattern can be visualised, allowing a more accurate assessment of NMJ development, denervation, and regeneration in mouse models of neurological disease and nerve injury, which can be applied across all postnatal ages. Key features • Small muscles of the mouse hind paw, i.e., lumbrical and FDB muscles, can be rapidly dissected for whole-mount immunofluorescent analysis without the need for cryosectioning. • This protocol allows visualisation of the entire neuromuscular innervation pattern using axonal (anti-tubulin βIII), pre-synaptic (anti-synaptophysin), and post-synaptic (α-bungarotoxin) markers. • Whole-mount immunofluorescence of hind paw muscles enables assessment of developmental, degenerative, and regenerative phenotypes in young and adult mice across disease and injury models. • High-throughput analysis can be performed using NMJ-Analyser or NMJ-morph to evaluate diverse morphological features of the NMJ.}, }
@article {pmid40431734, year = {2025}, author = {Kim, DH and Kim, JH and Jeon, MT and Kim, KS and Kim, DG and Choi, IS}, title = {The Role of TDP-43 in SARS-CoV-2-Related Neurodegenerative Changes.}, journal = {Viruses}, volume = {17}, number = {5}, pages = {}, doi = {10.3390/v17050724}, pmid = {40431734}, issn = {1999-4915}, support = {25-BR-02-03//Korea Brain Research Institute/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *COVID-19/complications/metabolism/virology/pathology ; *SARS-CoV-2/physiology ; *Neurodegenerative Diseases/metabolism/virology/pathology/etiology ; Virus Replication ; Animals ; }, abstract = {The coronavirus disease 2019 (COVID-19) pandemic has been linked to long-term neurological effects with multifaceted complications of neurodegenerative diseases. Several studies have found that pathological changes in transactive response DNA-binding protein of 43 kDa (TDP-43) are involved in these cases. This review explores the causal interactions between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and TDP-43 from multiple perspectives. Some viral proteins of SARS-CoV-2 have been shown to induce pathological changes in TDP-43 through its cleavage, aggregation, and mislocalization. SARS-CoV-2 infection can cause liquid-liquid phase separation and stress granule formation, which accelerate the condensation of TDP-43, resulting in host RNA metabolism disruption. TDP-43 has been proposed to interact with SARS-CoV-2 RNA, though its role in viral replication remains to be fully elucidated. This interaction potentially facilitates viral replication, while viral-induced oxidative stress and protease activity accelerate TDP-43 pathology. Evidence from both clinical and experimental studies indicates that SARS-CoV-2 infection may contribute to long-term neurological sequelae, including amyotrophic lateral sclerosis-like and frontotemporal dementia-like features, as well as increased phosphorylated TDP-43 deposition in the central nervous system. Biomarker studies further support the link between TDP-43 dysregulation and neurological complications of long-term effects of COVID-19 (long COVID). In this review, we presented a novel integrative framework of TDP-43 pathology, bridging a gap between SARS-CoV-2 infection and mechanisms of neurodegeneration. These findings underscore the need for further research to clarify the TDP-43-related neurodegeneration underlying SARS-CoV-2 infection and to develop therapeutic strategies aimed at mitigating long-term neurological effects in patients with long COVID.}, }
@article {pmid40431070, year = {2025}, author = {Trebol-Aizpurua, E and Eceiza, MV and Jimenez-Martinez, C and Marí, AI and Royuela, M and Zabalza, A and Gil-Monreal, M}, title = {Resistance to Amino Acid Biosynthesis Inhibiting-Herbicides in Amaranthus palmeri Populations from Aragon (Spain).}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, doi = {10.3390/plants14101505}, pmid = {40431070}, issn = {2223-7747}, support = {2020 117723-RB-I00//Spanish Ministry of Science and Innovation/ ; PhD fellowship//Basque Government/ ; Investigo programme//Public University of Navarre-Government of Navarre/ ; postgraduate research fellowship (call 2024)//Sociedad Espa&#xf1;ola de Malherbolog&#xed;a/ ; }, abstract = {Amaranthus palmeri is a highly problematic agricultural weed due to its rapid growth, high seed production, and strong tendency to develop herbicide resistance. In Spain, the initial colonization of A. palmeri began in 2007, when populations were detected at various locations in the province of Lleida (Catalonia). Since then, new infestations have been reported in other regions of the country, primarily infesting maize fields. Although resistance to glyphosate or to acetolactate synthase (ALS) inhibitors has been documented in several populations from Catalonia and Extremadura, little is known about the resistance profile of populations from Aragon. The main objective of this study was to characterize the putative resistance of five populations from Aragon to 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors (glyphosate) and ALS inhibitors (nicosulfuron and imazamox). Sensitivity to both mechanisms of action was measured by root growth in vertical plates and shikimate accumulation for glyphosate. Target-site resistance was evaluated by analyzing EPSPS and ALS gene copy numbers and ALS gene mutations. The populations showed high variability, with no multiple resistance detected. The Bujaraloz population showed moderate resistance to glyphosate due to EPSPS gene amplification. In three populations, mutations in the ALS gene conferring resistance were detected. The Trp574Leu mutation was detected in approximately half of the individuals from the Albelda, Tamarite de Litera, and Caspe populations. In the latter, the Pro197Thr mutation was also present. This study reveals significant genetic variability within each population and provides evidence for the spread of herbicide resistance across different regions of Spain.}, }
@article {pmid40430989, year = {2025}, author = {Li, Z and Sun, X and Yu, S and Sun, H and Lian, L and Peng, X and Jin, T and Liu, W and Wang, H}, title = {Baseline Sensitivity of Echinochloa crus-galli (L.) P.Beauv. and Leptochloa chinensis (L.) Nees to Flusulfinam, a New 4-Hydroxyphenylpyruvate Dioxygenase (HPPD)-Inhibiting Herbicide in Rice, in China.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, doi = {10.3390/plants14101425}, pmid = {40430989}, issn = {2223-7747}, support = {ZR2024QC067//Shandong Provincial Natural Science Foundation/ ; 32202353//National Natural Science Foundation of China/ ; 2021CXGC010811//Key R&amp;D Program of Shandong Province, China/ ; 2023YFD1400501//National Key R&amp;D Program of China/ ; }, abstract = {Flusulfinam is a 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide applied post-emergence (POST) to control Echinochloa crus-galli (L.) P.Beauv., Leptochloa chinensis (L.) Nees, Digitaria sanguinalis (Linn.) Scop. and other annual weeds in directly seeded and transplanted paddy fields in China, registered in September 2024. Notably, compared with other HPPD inhibitors in rice, flusulfinam exhibits consistently high safety in both japonica and indica rice varieties. Meanwhile, flusulfinam has no target-site cross-resistance with traditional acetolactate synthase (ALS)-inhibiting, acetyl-CoA carboxylase (ACCase)-inhibiting, and auxin herbicides. Moreover, as the only heterocyclic-amide-structured herbicide in the HPPD inhibitors, it poses a low risk of metabolic cross-resistance with the other HPPD inhibitors, making it a promising candidate for managing herbicide-resistant weeds in rice fields. In this study, the baseline sensitivity to flusulfinam of E. crus-galli and L. chinensis in paddy fields in China was established using dose-response assays between June and October 2023. Thirty-nine populations of E. crus-galli and forty-three populations of L. chinensis, collected from rice fields across various major rice-producing regions in China, exhibited susceptibility to flusulfinam. The GR50 values ranged from 0.15 to 19.39 g active ingredient (a.i.) ha[-1] for E. crus-galli and from 7.82 to 49.92 g a.i. ha[-1] for L. chinensis, respectively, far below the field recommended rate of flusulfinam. Meanwhile, the GR50 values of E. crus-galli and L. chinensis to flusulfinam were both distributed as a unimodal curve, with baseline sensitivity (GR50b) of 6.48 g a.i. ha[-1] and 22.38 g a.i. ha[-1], respectively. The SI50 value showed 129.27-fold and 6.38-fold variability in flusulfinam sensitivity among the 39 E. crus-galli field populations and 43 L. chinensis filed populations, while the variability declined to 2.99-fold and 2.23-fold when the SI50b value was used. This study substantiated the efficacy of flusulfinam against E. crus-galli and L. chinensis in Chinese paddy fields and furnished a benchmark for monitoring temporal variations in the susceptibility of field populations of E. crus-galli and L. chinensis to flusulfinam.}, }
@article {pmid40429802, year = {2025}, author = {Carnaroli, M and Deriu, MA and Tuszynski, JA}, title = {Computational Search for Inhibitors of SOD1 Mutant Infectivity as Potential Therapeutics for ALS Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {10}, pages = {}, doi = {10.3390/ijms26104660}, pmid = {40429802}, issn = {1422-0067}, mesh = {*Superoxide Dismutase-1/genetics/chemistry/antagonists &amp; inhibitors/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; *Mutation ; Protein Multimerization ; }, abstract = {Familial amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons. Among the main genetic causes of ALS, over 200 mutations have been identified in the Cu/Zn superoxide dismutase (SOD1) protein, a dimeric metalloenzyme essential for converting superoxides from cellular respiration into less toxic products. Point mutations in SOD1 monomers can induce protein misfolding, which spreads to wild-type monomers through a prion-like mechanism, leading to dysfunctions that contribute to the development of the disease. Understanding the structural and functional differences between the wild-type protein and its mutated variants, as well as developing drugs capable of inhibiting the propagation of misfolding, is crucial for identifying new therapeutic strategies. In this work, seven SOD1 mutations (A4V, G41D, G41S, D76V, G85R, G93A, and I104F) were selected, and three-dimensional models of SOD1 dimers composed of one wild-type monomer and one mutated monomer were generated, along with a control dimer consisting solely of wild-type monomers. Molecular dynamics simulations were conducted to investigate conformational differences between the dimers. Additionally, molecular docking was performed using a library of ligands to identify compounds with high affinity for the mutated dimers. The study reveals some differences in the mutated dimers following molecular dynamics simulations and in the docking of the selected ligands with the various dimers.}, }
@article {pmid40429767, year = {2025}, author = {Bokulic Panichi, L and Stanca, S and Dolciotti, C and Bongioanni, P}, title = {The Role of Oligodendrocytes in Neurodegenerative Diseases: Unwrapping the Layers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {10}, pages = {}, doi = {10.3390/ijms26104623}, pmid = {40429767}, issn = {1422-0067}, mesh = {Humans ; *Oligodendroglia/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism/etiology ; Animals ; Myelin Sheath/metabolism/pathology ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis/motor neuron disease, and multiple sclerosis, are characterized by progressive loss of neuronal structure and function, leading to severe cognitive, motor, and behavioral impairments. They pose a significant and growing challenge due to their rising prevalence and impact on global health systems. The societal and emotional toll on patients, caregivers, and healthcare infrastructures is considerable. While significant progress has been made in elucidating the pathological hallmarks of these disorders, the underlying cellular and molecular mechanisms remain incompletely understood. Increasing evidence implicates oligodendrocytes and their progenitors-oligodendrocyte progenitor cells (OPCs)-in the pathogenesis of several NDs, beyond their traditionally recognized role in demyelinating conditions such as MS. Oligodendrocytes are essential for axonal myelination, metabolic support, and neural circuit modulation in the central nervous system. Disruptions in oligodendrocyte function and myelin integrity-manifesting as demyelination, hypomyelination, or dysmyelination-have been associated with disease progression in various neurodegenerative contexts. This review consolidates recent findings on the role of OPCs in NDs, explores the concept of myelin plasticity, and discusses therapeutic strategies targeting oligodendrocyte dysfunction. By highlighting emerging research in oligodendrocyte biology, this review aims to provide a short overview of its relevance to neurodegenerative disease progression and potential therapeutic advances.}, }
@article {pmid40429496, year = {2025}, author = {Watt, NA and Hockley, N and Armitage, JA}, title = {Exploring the Risk: Peripheral Retinal Degenerations in Young Australian Adults.}, journal = {Journal of clinical medicine}, volume = {14}, number = {10}, pages = {}, doi = {10.3390/jcm14103501}, pmid = {40429496}, issn = {2077-0383}, abstract = {Background/Objectives: Peripheral retinal degenerations (PRDs) are structural anomalies in the outer regions of the retina, typically emerging in adolescence and early adulthood. Early detection is crucial, as some PRDs can lead to sight-threatening complications, such as retinal detachment, if left unmanaged. Due to a paucity of research regarding PRDs and their association with axial length (AL) and refractive error (RE) in young Australian adults, this study aimed to investigate the prevalence of PRDs in this population and establish whether AL and RE could help predict the likelihood of PRD occurrence. Methods: A cross-sectional study was conducted on a mixed population (n = 221) of Australian adults aged 18 to 40. Demographic data, RE, AL, and a series of ultra-widefield (UWF) retinal images were obtained from participants' undilated eyes using the Zeiss Clarus[TM] 500. Results: The overall PRD prevalence was 8.15% (n = 442 eyes). Binary logistic regression revealed that a longer AL was a more significant factor in increasing the risk of PRD development across all myopia classifications compared to emmetropia than RE. The likelihood of a PRD was 50% at an AL of 26.9 mm and -6.50D of myopia, and 95% at 29.6 mm and -11.00D. Conclusions: PRD prevalence was lower than reported in other global studies, perhaps reflecting the diverse ethnic makeup of the cohort. While our study supports the conventional understanding that longer ALs, and high myopia are key risk factors for developing a PRD, it also provides new insights into the likelihood of detecting a PRD at a given AL or RE in a mixed population. This information is crucial for eye care practitioners, enabling early identification of at-risk individuals and screening for PRDs that may increase the risk of retinal detachment.}, }
@article {pmid40428860, year = {2025}, author = {Laucius, O and Drūteika, J and Vanagas, T and Balnytė, R and Radžiūnas, A and Vaitkus, A}, title = {Ultrasonography of the Vagus Nerve for ALS Patients: Correlations with Clinical Data and Dysfunction of the Autonomic Nervous System.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {5}, pages = {}, doi = {10.3390/medicina61050902}, pmid = {40428860}, issn = {1648-9144}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnostic imaging ; Male ; Female ; *Vagus Nerve/diagnostic imaging/physiopathology ; Middle Aged ; Aged ; Ultrasonography/methods ; *Autonomic Nervous System/physiopathology ; Prospective Studies ; Cohort Studies ; }, abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons, leading to the rapid decline of motor function. In recent years, dysfunction of the autonomic nervous system (ANS) has also been increasingly recognized as a contributing factor in various neurodegenerative diseases, including ALS. This study is the second publication from our ALS research cohort at Kaunas Clinics. Our previous work examined ultrasonographic changes in the phrenic nerve as a supplementary diagnostic approach for ALS. Materials and Methods: In the present study, we investigated ultrasonographic alterations of the vagus nerve within the same ALS cohort, aiming to explore correlations with ANS involvement. We performed high-resolution ultrasonography of the vagus nerve (VN), collected clinical data, conducted heart rate monitoring, and evaluated respiratory function. Results: We prospectively included 32 ALS patients meeting "Gold Coast" criteria and 64 age- and sex-matched control patients. The average onset of ALS was 57.97 ± 9.22 years, and the duration of the disease was15.41 ± 9.04 months. For ALS patients, we found significantly reduced vagus nerve cross-sectional area (CSA) at the level of the carotid artery bifurcation bilaterally compared to controls (right VN 1.86 ± 0.21 vs. 2.07 ± 0.18 mm[2], p < 0.001; left VN 1.69 ± 0.21 vs. 1.87 ± 0.21 mm[2], p < 0.001). Reduced values of the left VN positively correlated with the reduced values of FEV1% and sO2. Conclusions: Our findings revealed a significant bilateral reduction in vagus nerve size in ALS patients compared to controls, suggesting that vagal atrophy may serve as a potential marker of autonomic dysfunction in ALS.}, }
@article {pmid40428407, year = {2025}, author = {Škarica, M and Acsadi, G and Živković, SA}, title = {Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies.}, journal = {Genes}, volume = {16}, number = {5}, pages = {}, doi = {10.3390/genes16050585}, pmid = {40428407}, issn = {2073-4425}, mesh = {Humans ; *Olivopontocerebellar Atrophies/genetics/pathology ; *Cerebellar Diseases/genetics/pathology ; }, abstract = {Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders.}, }
@article {pmid40428327, year = {2025}, author = {Papapanagiotou, AP and Alvanou, MV and Giantsis, IA and Vasilakoglou, I and Eleftherohorinos, IG}, title = {Characterization of the Giant Foxtail's (Setaria faberi) ALS Gene and Its Enhanced Metabolism-Based Cross-Resistance to Nicosulfuron and Rimsulfuron.}, journal = {Genes}, volume = {16}, number = {5}, pages = {}, doi = {10.3390/genes16050505}, pmid = {40428327}, issn = {2073-4425}, mesh = {*Acetolactate Synthase/genetics/metabolism/antagonists &amp; inhibitors ; *Sulfonylurea Compounds/pharmacology ; *Herbicide Resistance/genetics ; *Pyridines/pharmacology ; Herbicides/pharmacology ; *Setaria Plant/genetics/drug effects/enzymology ; *Plant Proteins/genetics/metabolism ; Zea mays/genetics/drug effects ; }, abstract = {BACKGROUND: Weed herbicide resistance is a serious problem in crop protection globally. Giant foxtail (Setaria faberi R.A.N. Herrm.) populations cannot be controlled by acetolactate synthase (ALS)-inhibiting herbicides in a few corn (Zea mays L.) monoculture fields.<br><br>METHODS: Five putative resistant giant foxtail populations, originating from corn monoculture fields in northeastern Greece, were evaluated for possible evolution of ALS-inhibitor resistance (nicosulfuron, rimsulfuron). The resistance ratio, the underlying resistance mechanism, and its impact on competitive ability against corn were studied.<br><br>RESULTS: The whole-plant rate-response assays showed that these populations were resistant (R) to the sulfonylureas nicosulfuron and rimsulfuron, but susceptible (S) to imidazolinone imazamox, triketone 4-hydroxyphenylpyruvate dioxygenase inhibitor tembotrione, and acetyl-CoA carboxylase inhibitor cycloxydim. The sequencing of the ALS gene did not reveal the presence of resistance-associated point mutations, indicating that the resistance was probably not target-site mediated. This was confirmed by the application of piperonyl butoxide two hours before nicosulfuron application, which reversed the resistance in all R giant foxtail populations, supporting the evidence of enhanced metabolism-mediated resistance. The competition study between corn and R or S giant foxtail populations indicated no stable trend reduction in corn traits, suggesting that the resistance mechanism was not associated with the competitive ability of the R populations. The novel ALS genotype in S. faberi, characterized for the first time and submitted to the GenBank database with accession number PV016837, indicated a closer genetic relationship with the S. viridis ALS gene than with S. italica.<br><br>CONCLUSIONS: Five giant foxtail populations have evolved metabolism-based resistance to the ALS-inhibiting herbicides nicosulfuron and rimsulfuron.}, }
@article {pmid40428092, year = {2025}, author = {Vaccarino, F and Quattrocchi, CC and Parillo, M}, title = {Susceptibility-Weighted Imaging (SWI): Technical Aspects and Applications in Brain MRI for Neurodegenerative Disorders.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, doi = {10.3390/bioengineering12050473}, pmid = {40428092}, issn = {2306-5354}, abstract = {Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient-echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson's disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington's disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications.}, }
@article {pmid40427878, year = {2025}, author = {Batterman, SA and Islam, MK and Jang, DG and Feldman, EL and Goutman, SA}, title = {Life Course Exposure to Cyanobacteria and Amyotrophic Lateral Sclerosis Survival.}, journal = {International journal of environmental research and public health}, volume = {22}, number = {5}, pages = {}, doi = {10.3390/ijerph22050763}, pmid = {40427878}, issn = {1660-4601}, support = {1R01NS127188-04D4/NH/NIH HHS/United States ; 1K23ES027221-02D2/NH/NIH HHS/United States ; 3P30ES017885-03D3/NH/NIH HHS/United States ; 1R01ES030049-03A3/NH/NIH HHS/United States ; (no number)//Scott L. Pranger ALS Clinic Fund/ ; (no number)//NeuroNetwork for Emerging Therapies/ ; (no number)//Andrea and Lawrence Wolfe Brain Health Initiative/ ; (no number)//Robert and Katherine Jacobs Environmental Health Initiative Fund/ ; (no number)//Coleman Therapeutic Discovery Fund/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/mortality/epidemiology ; Humans ; *Cyanobacteria ; *Environmental Exposure ; *Microcystins/toxicity ; Middle Aged ; *Harmful Algal Bloom ; Female ; Male ; Aged ; Adult ; }, abstract = {Cyanobacterial harmful algal blooms (cyanoHABs) occur worldwide and can cause ingestion and inhalation exposure to microcystin and other potent toxins. This study develops life course exposure measures for cyanobacteria for application in population studies and then associates these measures with the survival of individuals with amyotrophic lateral sclerosis (ALS). The exposure measures utilize an individual's residence history, date of disease onset, and satellite data from the Cyanobacteria Assessment Network. Residence duration for selected exposure windows referenced to disease onset date was used to weight cyanobacteria concentrations in water bodies within 0.25 to 10 km of each residence. Different concentration metrics, buffer sizes, and exposure windows were evaluated. The 2.5 and 5 km buffers best balanced the likelihood and plausibility of exposure while still resolving exposure contrasts. Over their lifetime, most study participants lived within 5 km of cyanobacteria blooms, and the exposure was associated with up to 0.89 years shorter survival, with significant interactions for individuals reporting swimming, fishing, and private wells. Our findings suggest a new and modifiable risk factor for ALS survival, and a need to confirm exposures and epidemiological findings. These cyanoHAB exposure estimates can facilitate population studies that can discover new relationships with neurodegenerative and other diseases.}, }
@article {pmid40427436, year = {2025}, author = {Minuti, A and Raffaele, I and Scuruchi, M and Lui, M and Muscarà, C and Calabrò, M}, title = {Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {5}, pages = {}, doi = {10.3390/antiox14050554}, pmid = {40427436}, issn = {2076-3921}, support = {Current Research Funds 2025 (RRC-2025-23686388)//Ministero della Salute/ ; }, abstract = {Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy-processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases.}, }
@article {pmid40426973, year = {2025}, author = {Ivantsik, O and Exarchos, TP and Vrahatis, AG and Vlamos, P and Krokidis, MG}, title = {Exploring Protein Misfolding in Amyotrophic Lateral Sclerosis: Structural and Functional Insights.}, journal = {Biomedicines}, volume = {13}, number = {5}, pages = {}, doi = {10.3390/biomedicines13051146}, pmid = {40426973}, issn = {2227-9059}, support = {TAEDR-0535850.//This work was partially supported by the European Union-Next Generation EU, Greece 2.0 Na-tional Recovery and Resilience Plan Flagship program TAEDR-0535850./ ; }, abstract = {Protein functionality depends on its proper folding, making protein misfolding crucial for the function of proteins and, by extension, cells and the whole organism. Increasing evidence supports the role of protein misfolding in the pathogenesis of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive disease diagnosed at a prevalence of 5 cases per 100,000, with approximately 2-3 patients per 100,000 diagnosed each year. To date, there is no cure, and the disease usually leads to death within 2 to 5 years from diagnosis. There are two types of the disorder: familial ALS (fALS), accounting for approximately 10% of cases, and sporadic (sALS), accounting for the remaining 90%. The hallmark of ALS, regardless of type, is the protein aggregates found in patients' tissues. This suggests that the disruption of proteostasis plays a critical role in the development of the disease. Herein, we stress the distinct factors that lead to protein misfolding and aggregate formation in ALS. Specifically, we highlight several triggering factors affecting protein misfolding, namely mutations, errors in the processes of protein production and trafficking, and failures of folding and chaperone machinery. Gaining a deeper understanding of protein aggregation will improve our comprehension of disease pathogenesis and potentially uncover new therapeutic approaches.}, }
@article {pmid40426848, year = {2025}, author = {Spargo, TP and Iacoangeli, A and Ryten, M and Forzano, F and Pearce, N and Al-Chalabi, A}, title = {Modelling Population Genetic Screening in Rare Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {13}, number = {5}, pages = {}, doi = {10.3390/biomedicines13051018}, pmid = {40426848}, issn = {2227-9059}, abstract = {Importance: Genomic sequencing enables the rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants, given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low, despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but is less well-understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation. Observations: We explore the probability of subsequent disease following genetic screening of several variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), comparing these results with screening for phenylketonuria, which is well-established. The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD when testing repeat expansions, for which the test had sub-optimal performance (sensitivity = 99% and specificity = 90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1 when testing pathogenic SNVs (sensitivity = 99.96% and specificity = 99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%). Conclusions and Relevance: We show that risk following a positive screening test result can be strikingly low for rare neurological diseases, even for fully penetrant variants such as HTT, if the test has sub-optimal performance. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols with very high sensitivity and specificity, and a careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings.}, }
@article {pmid40426669, year = {2025}, author = {Eisen, A}, title = {Amyotrophic Lateral Sclerosis: Recent Considerations for Diagnosis, Pathogenesis and Therapy.}, journal = {Brain sciences}, volume = {15}, number = {5}, pages = {}, doi = {10.3390/brainsci15050498}, pmid = {40426669}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS/MND) is considered a uniquely human complex neurodegenerative disorder, presenting with a variety of clinical phenotypes, which include frontotemporal dementia [...].}, }
@article {pmid40426231, year = {2025}, author = {Bergh, S and Casadei, N and Gabery, S and Simonsson, O and Duarte, JMN and Kirik, D and Nguyen, HP and Petersén, &#xc5;}, title = {TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {119}, pmid = {40426231}, issn = {2051-5960}, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *Hypothalamus/pathology/metabolism ; Mice, Transgenic ; Mice ; Humans ; Neurons/pathology/metabolism ; Male ; Orexins/metabolism ; Hypothalamic Hormones/metabolism ; Melanins/metabolism ; Pituitary Hormones/metabolism ; Oxytocin/metabolism ; *Behavior, Animal/physiology ; Disease Models, Animal ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.}, }
@article {pmid40424919, year = {2025}, author = {Yamazaki, H and Takamatsu, N and Matsubara, T and Tani, M and Fukushima, K and Yoshida, T and Osaki, Y and Oki, R and Fujita, K and Nodera, H and Izumi, Y}, title = {Evaluation of the diagnostic performance of brachial plexus ultrasound in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {175}, number = {}, pages = {2110741}, doi = {10.1016/j.clinph.2025.2110741}, pmid = {40424919}, issn = {1872-8952}, abstract = {OBJECTIVE: This study aimed to assess the diagnostic performance of brachial plexus cross-sectional area (BP-CSA) measured by nerve ultrasound (NUS) for differentiating amyotrophic lateral sclerosis (ALS) from controls.<br><br>METHODS: A retrospective, cross-sectional study was conducted including patients with ALS and control patients who underwent NUS evaluation of the BP-CSA and the cervical nerve root CSA (C-CSA). Reference values for BP-CSA were built using reference cohort. Receiver operating characteristic curve analysis was performed in independent discovery and validation cohorts to assess the diagnostic performance of BP-CSA.<br><br>RESULTS: A total of 244 patients (114 ALS and 130 controls) were included. BP-CSA significantly correlated with body weight (coefficient&#xa0;=&#xa0;0.50, p&#xa0;<&#xa0;0.001). After adjusting for body weight, BP-CSA values were significantly lower in patients with ALS than controls (p&#xa0;<&#xa0;0.001). Adjusted BP-CSA showed superior diagnostic performance compared to C-CSA, with area under the curve values of 0.75 (95&#xa0;% CI: 0.64-0.86) and 0.78 (95&#xa0;% CI: 0.68-0.88) in the discovery and validation cohorts, respectively.<br><br>CONCLUSIONS: BP-CSA, when adjusted for body weight, shows reliable performance in diagnosing ALS.<br><br>SIGNIFICANCE: This study highlights the clinical value of BP-CSA as a potential ALS diagnostic biomarker and underscores its superiority over cervical nerve root measurements.}, }
@article {pmid40424855, year = {2025}, author = {Mrkela, M and Rodrigues, M and Naidoo, S and Devaux, JBL and Kirk, SE and Vinnakota, C and Buchanan, CM and Mulroy, D and Fraser, H and Jacobsen, JC and Wyatt, H and Drake, K and Parker, E and Potter, H and Henden, L and McCann, EP and Williams, KL and Henders, AK and Roxburgh, RH and Scotter, EL}, title = {The genetics of motor neuron disease in New Zealand.}, journal = {Journal of the neurological sciences}, volume = {474}, number = {}, pages = {123472}, doi = {10.1016/j.jns.2025.123472}, pmid = {40424855}, issn = {1878-5883}, abstract = {Motor neuron disease (MND) is a group of adult-onset neurodegenerative diseases characterised by progressive motor neuron degeneration, of which amyotrophic lateral sclerosis (ALS) is the most common. MND is clinically heterogeneous with complex etiology, caused by or associated with over 40 different genes and multiple environmental risk factors. New Zealand has one of the highest global incidence and mortality rates of MND, however the reasons are unknown. We sought to identify the frequencies of genetic variants in known MND-linked genes among people with MND in New Zealand. We enrolled 184 participants: 149 with a clinical diagnosis of MND (128 sporadic, 21 familial) and 35 clinically unaffected but at-risk individuals. Participants' DNA was screened for genetic variation in 46 MND-associated genes using Sanger sequencing, Illumina SNP microarray, repeat-primed PCR for C9orf72, and an Invitae gene panel. Clinical phenotypes mirrored European trends: males and spinal-onset cases had earlier disease onset. Thirty-three participants (17.9%) carried known pathogenic variants: 24 had C9orf72 repeat expansions, and 9 had pathogenic SOD1 variants (p.(Ile114Thr) and p.(Glu101Gly)). All New Zealand SOD1 p.(Ile114Thr) cases (n = 4) were distantly related to each other and to over 30 Australian cases with the same variant. Variants of interest were found in 14 participants with the splicing variants DCTN1:c.279+1G>C and ATP13A2:c.2412G>A, p.(Lys804=) subject to further study. Notably, 48.4% of pathogenic variants were in pre-symptomatic, unaffected individuals with family history, highlighting the importance of offering cascade testing and symptom surveillance for families, particularly as gene-specific treatments emerge.}, }
@article {pmid40422218, year = {2025}, author = {Saxena, S and Arnold, WD}, title = {Current Challenges in Elucidating ALS Disease Mechanisms and Therapeutic Advances.}, journal = {Cells}, volume = {14}, number = {10}, pages = {}, pmid = {40422218}, issn = {2073-4409}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/genetics ; }, abstract = {As a researcher and a physician working together to combat amyotrophic lateral sclerosis (ALS), we are acutely aware of both the urgent need for innovation and the persistent divide between laboratory discoveries and clinical care [...].}, }
@article {pmid40422183, year = {2025}, author = {Verde, EM and Secco, V and Ghezzi, A and Mandrioli, J and Carra, S}, title = {Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.}, journal = {Cells}, volume = {14}, number = {10}, pages = {}, doi = {10.3390/cells14100680}, pmid = {40422183}, issn = {2073-4409}, support = {SUMOsolvable//AriSLA/ ; AHA MCA 2022//Giovanni Armenise-Harvard Foundation and AirAlzh/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/metabolism/pathology/genetics ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Animals ; Protein Processing, Post-Translational ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes and pathomechanisms and are referred to as the ALS-FTD spectrum. A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility. This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form. Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.}, }
@article {pmid40421380, year = {2025}, author = {Park, S and Park, SK and Blair, P and Liebman, SW}, title = {An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases.}, journal = {Microbial cell (Graz, Austria)}, volume = {12}, number = {}, pages = {119-130}, pmid = {40421380}, issn = {2311-2638}, abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1∆ aah1∆ yeast model of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from liquid-like droplets toward a more amyloid-like state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like droplets rather than amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1∆ aah1∆ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine and TDP-43 fiber interactions as seen for other heterologous fibers. This work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.}, }
@article {pmid40420932, year = {2025}, author = {Farsakoury, R and Nashwan, AJ}, title = {Revitalizing upper blepharoplasty: Preserving volume.}, journal = {World journal of clinical cases}, volume = {13}, number = {15}, pages = {100563}, pmid = {40420932}, issn = {2307-8960}, abstract = {Blepharoplasty is a frequently performed aesthetic surgery today aimed at enhancing eyelid appearance and correcting age-related changes. The traditional method of subtraction blepharoplasty, which involved removing fat and excess skin, is now considered outdated. This letter explores Gorgy et al's commentary on Miotti et al's study, highlighting a shift in upper eyelid blepharoplasty towards a more conservative, volume-preserving approach. The study systematically reviewed 10 publications, including three retrospective studies, five comparative studies, and two clinical trials. It emphasizes the trend towards preserving the patient's natural anatomy and focusing on enhancement rather than alteration. However, the study's limitations, such as the lack of long-term comparative research, a relatively small sample size, and a single-center design, indicate that further research with extended follow-up is necessary to validate the safety and effectiveness of these techniques. The focus is increasingly on preserving and augmenting volume in upper blepharoplasty rather than removing tissue.}, }
@article {pmid40420561, year = {2025}, author = {Harkey, BA and Distefano, S and Pagliaro, JA and Heyd, L and Chase, M and Igne, C and Yu, H and Sherman, AV and Dagostino, D and Tustison, E and Changkuon, G and Hall, M and Kittle, G and Connolly, MR and Giacomelli, E and Scirocco, E and Berry, JD and Babu, S and Shefner, J and Macklin, EA and Chibnik, LB and De Mattos, A and Drake, K and Kamp, C and McGarry, A and Torti, M and Small, C and Bulat, A and Cudkowicz, ME and Paganoni, S and , }, title = {Operational Development and Launch of an Adaptive Platform Trial in Amyotrophic Lateral Sclerosis: Processes and Learnings From the First Four Regimens of the HEALEY ALS Platform Trial.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28442}, pmid = {40420561}, issn = {1097-4598}, support = {//Sean M. Healey and AMG Center/ ; //Tackle ALS/ ; //ALS Finding a Cure/ ; //The ALS Association/ ; //ALS ONE/ ; //The Arthur M. Blank Family Foundation/ ; //Muscular Dystrophy Association/ ; //UCB/ ; //Biohaven Pharmaceuticals Inc/ ; //Clene Nanomedicine/ ; //Prilenia Therapeutics/ ; }, abstract = {INTRODUCTION/AIMS: Platform trials present several advantages over traditional interventional clinical trials. Here, we provide a detailed description of the operational framework of the HEALEY ALS Platform Trial.<br><br>METHODS: Platform-level procedures for regulatory oversight, safety, and site management were developed prior to trial launch. Central vendors and a single Institutional Review Board (sIRB) were used. An Investigational New Drug (IND) application was submitted for the master protocol, and each regimen was added as an amendment.<br><br>RESULTS: The HEALEY ALS Platform Trial was launched in 2020. Fifty-four geographically diverse sites from the Northeast ALS Consortium (NEALS), all highly experienced in ALS care and research, were selected. Three investigational products were selected to launch concurrently at the start of the trial as individual regimens. A fourth investigational product was selected and added to the trial after the initial launch. The Master Protocol and the first three regimens (Regimens A-C) were sIRB approved in 120&#x2009;days. sIRB amendment for Regimen D was approved in 21&#x2009;days. Enrollment for regimens A-C was completed in 15&#x2009;months, whereas Regimen D was completed in 11&#x2009;months from the start of enrollment. Results of all regimens were available within approximately 2&#x2009;years from the initial trial launch.<br><br>DISCUSSION: The HEALEY ALS Platform Trial capitalized on the benefits of the platform approach, including an adaptable operational infrastructure, concurrent enrollment into four distinct regimens, and an accelerated start-up time for a new regimen added after initial trial launch.}, }
@article {pmid40419749, year = {2025}, author = {Monteiro Neto, JR and de Souza, GF and Dos Santos, VM and de Holanda Paranhos, L and Ribeiro, GD and Magalhães, RSS and Queiroz, DD and Eleutherio, ECA}, title = {SOD1, A Crucial Protein for Neural Biochemistry: Dysfunction and Risk of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40419749}, issn = {1559-1182}, support = {201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; 201.174/2022//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; PROBRAL 88881.986154/2024-01//CAPES-DAAD/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 309635/2023-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, abstract = {Neurons are very susceptible to oxidative stress. They are the major consumers of oxygen in the brain, which is used to provide energy through oxidative phosphorylation, the major source of reactive oxygen species (ROS). In addition, compared to other tissues, neurons have lower levels of catalase and glutathione and increased susceptibility to lipid peroxidation due to the elevated levels of unsaturated fatty acids. These characteristics increasingly emphasize the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) to maintain neuronal redox homeostasis. In the last decade, SOD1 gained additional roles which are also important to the metabolism of neurons. SOD1 controls the production of ROS by the electron transport chain, activates the expression of genes involved in the protection against oxidative stress, and regulates the shift from oxidative to fermentative metabolism involved in astrocyte-neuron metabolic cooperation. Furthermore, impaired interaction between the phosphatase calcineurin and SOD1 seems to result in TDP-43 hyperphosphorylation, the main proteinopathy found in amyotrophic lateral sclerosis (ALS) patients. However, this enzyme is ubiquitously expressed, mutated, and damaged forms of SOD1 cause disease in motor neurons. In this review, we discuss the pivotal functions of SOD1 in neuronal biochemistry and their implications for ALS.}, }
@article {pmid40417702, year = {2025}, author = {Hoang, K and Prayotamornkul, S and Kuo, CY and Jang, H and Shi, L}, title = {Optical imaging of metabolic dynamics in ALS under methionine regulation.}, journal = {Journal of biomedical optics}, volume = {30}, number = {Suppl 2}, pages = {S23906}, pmid = {40417702}, issn = {1560-2281}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; *Methionine/metabolism/pharmacology ; Humans ; *Optical Imaging/methods ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; Spectrum Analysis, Raman/methods ; Cytochromes c/metabolism ; Imaging, Three-Dimensional ; Oxidation-Reduction ; }, abstract = {SIGNIFICANCE: Excessive reactive oxygen species (ROS) in dysfunctional mitochondria, combined with inefficient antioxidant defenses, can drive amyotrophic lateral sclerosis (ALS) progression. L-methionine (Met) can neutralize ROS by modulating metabolism and activating antioxidants; however, its impact on ALS remains unknown.<br><br>AIM: We aim to investigate the influence of excess Met on cellular metabolism and ROS accumulation and its role in ALS using multimodal optical imaging techniques.<br><br>APPROACH: We applied deuterium oxide-probed stimulated Raman scattering imaging to study metabolic changes of lipids, proteins, and cytochrome c and two-photon excitation fluorescence imaging to assess mitochondrial redox state (nicotinamide adenine dinucleotide and flavin adenine dinucleotide ratio) in ALS cellular models under excess Met treatment. With three-dimensional (3D) image reconstruction, we investigated morphological changes of lipid droplets (LDs) and stress granules (SGs) in ALS models.<br><br>RESULTS: Excess Met not only promoted syntheses of lipids and unsaturated lipid membranes but also reduced protein synthesis, cytochrome c oxidation, and oxidative stress. Moreover, 3D image reconstruction showed that LDs increased in volume and number to promote cellular repair, whereas SGs decreased in volume but increased in number in response to reduced cellular stress.<br><br>CONCLUSIONS: Excess Met offers a protective mechanism against oxidative stress and promotes cellular repair in ALS.}, }
@article {pmid40417478, year = {2024}, author = {Marchal, N and Janes, WE and Earwood, JH and Mosa, ASM and Popescu, M and Skubic, M and Song, X}, title = {Integrating Multi-sensor Time-series Data for ALSFRS-R Clinical Scale Predictions in an ALS Patient Case Study.}, journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium}, volume = {2024}, number = {}, pages = {788-797}, pmid = {40417478}, issn = {1942-597X}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; *Monitoring, Ambulatory/methods ; Pilot Projects ; }, abstract = {Clinical tools for tracking functional decline in amyotrophic lateral sclerosis (ALS) rely on in-clinic guided assessments, such as the gold standard ALS Functional Rating Scale Revised (ALSFRS-R) instrument, thus limiting the frequency of collection and potentially delaying needed treatments. As such, ALS clinicians may miss subtle yet critical shifts inpatient health -pointing to the needfor objective and continuous capturing of day-to-day functional status. In-home health sensors could supplement clinical instruments with more frequent, quantitative measurements as early indicators of change. Using the XGBoost regressor in base learning, we explore interpolation techniques for aligning monthly ALSFRS-R assessment targets with high frequency sensor-based health features. We evaluated 9 interpolation models, which demonstrate superior prediction of ALSFRS-R scores compared to traditional clinical scale estimates based on linear slope. This pilot work provides a practical approach of modeling mixed-frequency data and shows the potential of using sensor-based health estimates as sensitive prognostic markers.}, }
@article {pmid40415670, year = {2025}, author = {Uskun, E and Turkmenel, N and Kutluhan, S}, title = {Cross-cultural adaptation and psychometric evaluation of a Turkish version of the Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2507177}, pmid = {40415670}, issn = {2167-9223}, abstract = {Objective: This study aimed to evaluate the validity and reliability of the Turkish version of the Amyotrophic Lateral Sclerosis Specific Quality of Life Instrument Short Form (ALSSQOL-SF), a quality-of-life scale originally developed by Simons et al., for Turkish Amyotrophic Lateral Sclerosis (ALS) patients. Methods: Using a rigorous six-step translation process, the scale was adapted without altering any items to maintain linguistic and cultural equivalence. The study included 100 patients diagnosed with ALS, aged 18 years and older, and native Turkish speakers. Results: Psychometric evaluations revealed strong content validity (CVI: 100%) and high internal consistency (Cronbach's alpha: 0.86 for the overall scale, 0.74-0.95 for subscales). Item-total correlation coefficients, except for three items, exceeded 0.20, and removing these items did not improve the scale's reliability, preserving the scale's integrity. Construct validity was supported by significant correlations with the Short Form 12 Health Survey Questionnaire (SF-12) and ALS Functional Rating Scale Revised (ALSFRS-R), confirming the scale's ability to assess physical and mental health in ALS patients. Exploratory factor analysis showed a 6-factor structure consistent with the original structure. Conclusion: Turkish version of ALSSQOL-SF (ALSSQOL-SF-Tr) is a reliable and valid instrument for assessing the quality of life in Turkish ALS patients. Its application in clinical and research settings can help evaluate patient needs and improve disease management.}, }
@article {pmid40415381, year = {2025}, author = {Pretalli, JB and Vernerey, D and Evrard, P and Pozet, A and Clairet, AL and Benoist, S and Karoui, M and Cotte, E and Heyd, B and Lakkis, Z and , }, title = {Intraoperative indocyanine green fluorescence angiography in colorectal surgery to prevent anastomotic leakage: A single-blind phase III multicentre randomized controlled trial (FLUOCOL-01/FRENCH 21/GRECCAR 19 intergroup trial).}, journal = {Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland}, volume = {27}, number = {5}, pages = {e70119}, doi = {10.1111/codi.70119}, pmid = {40415381}, issn = {1463-1318}, support = {PHRC-K-20-044//Programme Hospitalier de Recherche Clinique-Cancer/ ; //French Ministry of Health/ ; }, mesh = {Humans ; *Indocyanine Green ; *Anastomotic Leak/prevention &amp; control/etiology ; *Fluorescein Angiography/methods ; Single-Blind Method ; *Intraoperative Care/methods ; Anastomosis, Surgical/adverse effects/methods ; Multicenter Studies as Topic ; Female ; Male ; *Colorectal Neoplasms/surgery ; Randomized Controlled Trials as Topic ; Coloring Agents ; Clinical Trials, Phase III as Topic ; France ; Colon/surgery/blood supply ; Colorectal Surgery/methods ; }, abstract = {AIM: Anastomotic leak (AL) is a major problem in colorectal surgery, and its prevention is crucial for patient safety. The scientific literature shows that optimal anastomotic perfusion is essential for anastomotic healing. However, in cases of left colon or rectal cancer requiring high vessel ligation for oncological reasons, anastomotic blood supply relies mainly on the pericolic arterial arcades. Consequently, assessing anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green might be relevant to reduce the risk of AL. Although evidence of its positive impact on the risk of AL is growing in the literature, most studies are descriptive prospective cohorts or retrospective comparative series with controversial findings. Furthermore, no other studies specifically address left-sided colon or high rectal tumours. FLUOCOL-1 is a large multicentre randomized controlled trial (RCT) that aims to demonstrate that assessing anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green will reduce ALs in left-sided or high anterior resections with intraperitoneal anastomosis METHOD: FLUOCOL-1 is a French multicentre, single-blind, randomized, two-arm, phase III superiority clinical trial. Patients will be randomized in a 1:1 ratio to either the intervention group (FLUO+) or the control group (FLUO-). A total of 1010 patients will be randomized. The primary endpoint is the occurrence of an AL within 90 days postsurgery. AL is defined as any anastomotic dehiscence with leakage into the pelvic cavity diagnosed by imaging or surgical exploration, or any isolated pelvic organ-space infection with no evidence of fistula, as defined by the International Study Group of Rectal Cancer.<br><br>DISCUSSION: Prevention of AL is one of the most important questions to be addressed in colorectal surgery. The FLUOCOL-1 multicentre RCT described herein aims to demonstrate that assessment of anastomotic perfusion using intraoperative fluorescence angiography with indocyanine green will reduce ALs in certain resections with intraperitoneal anastomosis.}, }
@article {pmid40414828, year = {2025}, author = {Kim, MS and Yoo, SH and Kim, KH and Cho, B and Lee, SY}, title = {Telemedicine Experiences of People Living with Amyotrophic Lateral Sclerosis at Home in South Korea.}, journal = {Yonsei medical journal}, volume = {66}, number = {6}, pages = {366-373}, doi = {10.3349/ymj.2024.0145}, pmid = {40414828}, issn = {1976-2437}, support = {RS-2021-KH120239//Patient-Centered Clinical Research Coordinating Center (PACEN)/Korea ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea ; *Telemedicine ; Middle Aged ; Female ; Male ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; Home Care Services ; }, abstract = {PURPOSE: Telemedicine is advantageous in providing medical care to patients with mobility difficulties. This single-center study aimed to report on the provision of video televisits to people living with amyotrophic lateral sclerosis (pALS, ALS) who were registered with a home-based medical care (HBMC) team in a tertiary hospital in South Korea.<br><br>MATERIALS AND METHODS: A retrospective cross-sectional study was conducted for pALS provided with video televisits by the HBMC team between July 2020 and February 2023. The patients' demographics, disease status, mobility level, and supportive care equipment were investigated. The main issues discussed at televisits were investigated.<br><br>RESULTS: During the 32-month study period, video televisits were provided to 69 (81.2%) of the 85 pALS registered with the HBMC team. Their median (interquartile range) age was 66 (57-71) years, and 66.7% were aged 60 years or older. At the time of the televisits, 71.0% were non-ambulatory and 27.5% were at an assisted ambulatory level. Furthermore, 82.6% were receiving nutritional support with a nasogastric or gastrostomy tube, and 78.3% had received either non-invasive positive pressure ventilation (43.5%) or tracheostomy invasive ventilation (34.8%). Common issues addressed on televisits were disease-related symptoms (100%), management of supportive care equipment (92.8%), acute health issues (52.2%), and advance care planning (ACP) including goal of care discussion (14.5%).<br><br>CONCLUSION: Video telemedicine is feasible for pALS, including older adults with limited mobility due to muscle weakness or reliance on various supportive care equipment. Video televisits allow for a variety of discussions, ranging from acute health issues to ACP.}, }
@article {pmid40414644, year = {2025}, author = {Manusha, S and Varsha, N and Varshini, R and Sivamani, Y and Pokkuluri, KS and Elayaperumal, S}, title = {Altered microbiome influence on the enteric neuromuscular system in amyotrophic lateral sclerosis (ALS).}, journal = {International review of neurobiology}, volume = {180}, number = {}, pages = {95-123}, doi = {10.1016/bs.irn.2025.04.006}, pmid = {40414644}, issn = {2162-5514}, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/physiopathology ; Humans ; *Gastrointestinal Microbiome/physiology ; *Enteric Nervous System/physiopathology/microbiology ; *Dysbiosis/physiopathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease marked by the degeneration of motor neurons, leading to muscle weakness and paralysis. While the cause of ALS is uncertain, research indicates that changes in the gut microbiome may influence the disease's progression. This chapter explores how alterations in gut microbiota affect the enteric neuromuscular system (ENS) in ALS. In ALS patients, disrupted gut microbiota are linked to the brain-gut axis, impacting both gastrointestinal function and neuronal health. Studies show that microbial changes are associated with inflammation, immune instability, and neurodegeneration, which exacerbate the disease. Gastrointestinal issues like constipation and dysphagia in ALS are tied to ENS dysregulation. Understanding the connections between the gut microbiome, ENS, and central nervous system (CNS) may lead to novel therapies targeting neurodegeneration and microbial dysbiosis in ALS.}, }
@article {pmid40414240, year = {2025}, author = {Suzuki, N and Nishiyama, A and Ebihara, S and Aoki, M}, title = {Jacifusen for FUS-ALS: molecular effects and clinical outcomes in a case series.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)01038-4}, pmid = {40414240}, issn = {1474-547X}, }
@article {pmid40414239, year = {2025}, author = {Shneider, NA and Harms, MB and Korobeynikov, VA and Rifai, OM and Hoover, BN and Harrington, EA and Aziz-Zaman, S and Singleton, J and Jamil, A and Madan, VR and Lee, I and Andrews, JA and Smiley, RM and Alam, MM and Black, LE and Shin, M and Watts, JK and Walk, D and Newman, D and Pascuzzi, RM and Weber, M and Neuwirth, C and Da Cruz, S and Soriano, A and Lane, R and Henry, S and Mathews, J and Jafar-Nejad, P and Norris, D and Rigo, F and Brown, RH and Miller, S and Crean, R and Bennett, CF}, title = {Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)00513-6}, pmid = {40414239}, issn = {1474-547X}, abstract = {BACKGROUND: Pathogenic variants of fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (FUS-ALS), with evidence of gain of function. Jacifusen is an antisense oligonucleotide targeting FUS pre-mRNA, previously shown to delay neurodegeneration in a mouse model and potentially slow functional decline in a first-in-human study. Here, we sought to further evaluate use of jacifusen as a treatment for FUS-ALS.<br><br>METHODS: This expanded access programme was conducted through a series of single-patient investigational new drug applications at five sites (four hospitals in the USA and one in Switzerland). Participants carried a FUS variant and had clinical evidence of motor neuron disease onset or electrophysiological abnormalities, if not a diagnosis of ALS. Participants were ineligible if chronically ventilated with tracheostomy. Enrolled sequentially, participants received serial intrathecal injections of jacifusen over 2&#xb7;8-33&#xb7;9 months. Based on multiple ascending doses of jacifusen (from 20 mg to 120 mg), successive protocols were modified as safety and other data were acquired, with the last participants enrolled receiving 120 mg doses monthly from the start of their treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and standard cerebrospinal fluid (CSF) metrics. Concentration of neurofilament light chain (NfL) in CSF was used as a biomarker of axonal injury and neurodegeneration, and the ALS Functional Rating Scale-Revised (ALSFRS-R) score was used as an overall measure of motor function. Biochemical analysis and immunohistochemical staining were done on post-mortem CNS tissues to quantify FUS protein expression and assess the burden of FUS pathology.<br><br>FINDINGS: Between June 11, 2019, and June 2, 2023, we recruited 12 participants (median age 26 years [range 16-45]; seven [58%] were female and five [42%] were male) into the expanded access programme. Transient elevations in cell counts or total protein concentration in CSF (six [50%] participants) were unrelated to treatment duration. The most common adverse events were back pain (six [50%]), headache (four [33%]), nausea (three [25%]), and post-lumbar puncture headache (three [25%]). Two participant deaths were recorded during the programme, both thought to be unrelated to the investigational drug. The concentration of NfL in CSF was reduced by up to 82&#xb7;8% after 6 months of treatment. Although most participants had continued functional decline (as measured by ALSFRS-R) after starting treatment with jacifusen, one showed unprecedented, objective functional recovery after 10 months, and another remained asymptomatic, with documented improvement in electromyographic abnormalities. Biochemical and immunohistochemical analysis of CNS tissue samples from four participants showed reduced FUS protein levels and an apparent decrease in the burden of FUS pathology.<br><br>INTERPRETATION: The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial.<br><br>FUNDING: ALS Association, Project ALS, Ionis Pharmaceuticals, Tow Foundation, Nancy D Perlman and Thomas D Klingenstein Innovation Fund for Neurodegenerative Disease, National Institutes of Health, Angel Fund for ALS Research, Cellucci Fund for ALS Research, Max Rosenfeld ALS Fund, University of Minnesota, and the Muscular Dystrophy Association.}, }
@article {pmid40413670, year = {2025}, author = {Montero-Odasso, M and Pieruccini-Faria, F and Black, SE and Binns, MA and Freedman, M and Grimes, DA and Hegele, RA and Haddad, SH and Lang, AE and Masellis, M and Mandzia, J and Beaton, D and Ramirez, J and Roberts, AC and McIlroy, W and Pasternak, SH and Zinman, L and Abrahao, A and Swartz, RH and Symons, S and Tan, B and Tartaglia, C and Son, S and Sakurai, R and Dilliott, A and Cornish, BF and Hezam, A and Strong, MJ and ,  and Bartha, R}, title = {Association between vascular risk factors burden and neurodegenerative diseases: results from ONDRI.}, journal = {Journal of neurology}, volume = {272}, number = {6}, pages = {418}, pmid = {40413670}, issn = {1432-1459}, mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Neurodegenerative Diseases/epidemiology/diagnostic imaging/pathology ; Risk Factors ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Cerebrovascular Disorders/epidemiology/diagnostic imaging ; Cognitive Dysfunction/epidemiology/diagnostic imaging ; Aged, 80 and over ; Cohort Studies ; Ontario/epidemiology ; Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; }, abstract = {BACKGROUND: Vascular risk factors are common in older adults and contribute to brain damage, can manifest as increased white matter hyperintensities (WMH), and associated with future risk of stroke and dementia. However, their prevalence, effect across different neurodegenerative diseases, and association with WMH remains underexplored.<br><br>OBJECTIVE: To investigate the association between vascular risk burden, and brain white matter integrity, across five neurodegenerative conditions.<br><br>METHODS: Cross-sectional study including 520 participants from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) cohorts: 126 with amnestic Mild Cognitive Impairment/Alzheimer's Disease (MCI/AD), 53 with Frontotemporal Dementia (FTD), 161 with Cerebrovascular Disease (CVD), 140 with Parkinson's Disease (PD), and 40 with Amyotrophic Lateral Sclerosis (ALS), along with 41 cognitively healthy controls. A vascular risk index (VRI, range 0-5) assessed hypertension, diabetes, dyslipidemia, obesity (BMI&#x2009;&#x2265;&#x2009;30), and smoking history. Macro (WMH volume) and micro (Diffusion tensor imaging) white matter integrity were evaluated using 3-Tesla MRI. Associations were analyzed using multinomial logistic regression and ANCOVA, adjusting for age, sex, education, and APOE &#x3b5;4 allele status.<br><br>RESULTS: Vascular risk factors, particularly hypertension and hypercholesterolemia, were more prevalent in the disease cohorts than controls. A higher VRI was significantly associated with MCI/AD (1.5-fold, p =&#x2009;0.05), FTD (1.7-fold, p =0&#x2009;.02), and CVD (2.6-fold, p&#x2009;<&#x2009;0.005) cohorts. High VRI was associated with reduced macro and microstructural white matter integrity in the pooled sample (macro: p =&#x2009;0.005; micro: p =&#x2009;0.003), and separately in CVD (macro: p =&#x2009;0.04; micro: p =&#x2009;0.002). APOE &#x3b5;4 status only mildly attenuated these associations.<br><br>CONCLUSION: Vascular risk burden is prevalent in neurocognitive syndromes including MCI/AD, FTD and CVD, and impacts white matter integrity. Future studies are needed to explore if vascular risk management may mitigate the consequences of neurodegeneration in these clinical groups.}, }
@article {pmid40413526, year = {2025}, author = {Hawley, ZCE and Li, X and Bodnar, D and Gu, Y and Luo, Y and Ferretti, D and Sheehy, A and Driscoll, R and Zavodszky, MI and Cao, S and Isaza, I and Jandreski, L and Liu, Y and Carlile, T and Lo, SC and Grimard, A and Bourque, S and Utturkar, A and Desmarais, S and Arnold, HM and Huh, D and Guilmette, E and Kwon, DY}, title = {Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1[C71G] ALS mouse model.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {116}, pmid = {40413526}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; *Profilins/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Ataxin-2/genetics/metabolism ; Humans ; Spinal Cord/pathology/metabolism ; Gene Knockdown Techniques ; Muscle, Skeletal/pathology/metabolism ; Male ; Motor Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and muscle atrophy. Hyperphosphorylated aggregation of the RNA-binding protein, TDP-43, in the motor cortex and spinal cord are defining molecular features of ALS, suggesting TDP-43 dysfunction underlies disease pathogenesis. This phenomenon, however, has been difficult to recapitulate endogenously in animal models, impeding characterization of TDP-43 pathobiology in neurodegeneration. In this study, we report age-dependent accumulation of TDP-43 pathology in the spinal cord and progressive muscle-related deficits in transgenic mice expressing the ALS-associated PFN1[C71G] mutant protein. We show that transgenic neuronal expression of PFN1[C71G] induces early hyperphosphorylation of endogenous TDP-43 in the spinal cord that augments over time, preceding accumulation of insoluble non-phosphorylated TDP-43 and the manifestation of muscle denervation and motor dysfunction. Sustained knockdown of Atxn2 in the central nervous system (CNS) in pre-symptomatic PFN1[C71G] mice by AAV-driven expression of an artificial microRNA (AAV-amiR-Atxn2) reduces aberrant TDP-43 in the spinal cord, while delaying neurodegeneration and improving muscle and motor function. RNA-sequencing analysis of spinal cord samples from PFN1[C71G] mice and ALS donors show shared patterns of transcriptional perturbation, including a pro-inflammatory gene signature that is attenuated by AAV-amiR-Atxn2. Notably, impaired regulation of the PFN1[C71G] skeletal muscle transcriptome exceeds that of the spinal cord and is also improved by Atxn2 reduction in the CNS. Lastly, we find significant gene co-expression network homology between PFN1[C71G] mice and human ALS, with shared dysregulation of modules related to neuroinflammation and neuronal function and uncover novel hub genes that provide biological insight into ALS and potential drug targets that can be further investigated in this mouse model.}, }
@article {pmid40413303, year = {2025}, author = {Yang, W and Luo, Z and Tang, X and Guo, J and Chen, X and Dong, Y and Sun, YM and Fan, D and Xu, K and Chen, Y and Zhang, M}, title = {Protein Structure-based FUS Mutational Subtypes Are Associated With Protein Mislocalization in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40413303}, issn = {1559-1182}, support = {32301018//National Natural Science Foundation of China/ ; 82071430, 82371878//National Natural Science Foundation of China/ ; 2021YFA1302200//National Key Research and Development Program of China/ ; 22ZR1466400//Shanghai Municipal Natural Science Foundation General Program/ ; }, abstract = {The mislocalization of RNA-binding proteins (RBPs) from nucleus to cytoplasm and the formation of aggregates are hallmarks of neurodegeneration. Amyotrophic lateral sclerosis (ALS) disease-causing mutations in the fused in sarcoma (FUS) gene, encoding an RNA-binding protein, cluster at the C-terminal proline/tyrosine-nuclear localization signal (PY-NLS) domain, which is crucial for mediating nucleus-cytoplasm translocation by binding to Transportin-1. However, the mechanisms underlying heterogeneous protein mislocalization and age at onset (AAO) of ALS cases carrying FUS PY-NLS mutations remain unclear. Here, we screened FUS mutations in 416 ALS patients, and identified 12 patients carrying four FUS mutations at the p.R521 locus of PY-NLS domain (p.R521P, p.R521C, p.R521G, p.R521H), exhibiting highly variable AAO (20-56 years). AlphaFold-2 predicted protein structures classified FUS p.R521 mutants into alpha-helix containing (p.R521C, p.R521H) and alpha-helix disrupted (p.R521P, p.R521G) subgroups. Isothermal titration calorimetry experiment showed that the FUS alpha-helix disrupted subgroup had a reduced binding affinity with transportin-1, which is essential for mediating the nucleus-cytoplasm translocation. Furthermore, immunofluorescence in HEK-293 T and SH-SY5Y cells revealed more protein mislocalization in the FUS alpha-helix disrupted subgroup compared to the alpha-helix containing subgroup. FUS mislocalization status is also significantly associated with ALS AAO. Finally, the alpha-helix structure based FUS-ALS subgroups exhibited significantly different AAO (P = 0.036) in our cohort, but not in a Chinese cohort including published dataset. In summary, we showed highly diverse phenotypes in ALS patients with FUS R521 mutants, and implicated a link between genetic mutation related C-terminal structure with the status of FUS protein mislocalization.}, }
@article {pmid40413059, year = {2025}, author = {Lopes, AMDS and Giacomini, S and Ulahannan, A and Darnac, C and Bugeia, S and Gutknecht, G and Colomer-Lahiguera, S and Spurrier-Bernard, G and Latifyan, S and Addeo, A and Michielin, O and Eicher, M}, title = {Acceptability of an Electronic Patient-Reported Outcomes-Based Model of Care to Monitor Symptoms Related to Cancer Treatment with Immune Checkpoint Inhibitors: Results from the IePRO Randomized Controlled Trial.}, journal = {Seminars in oncology nursing}, volume = {}, number = {}, pages = {151903}, doi = {10.1016/j.soncn.2025.151903}, pmid = {40413059}, issn = {1878-3449}, abstract = {OBJECTIVES: This study analyzed the acceptability of an electronic patient-reported outcomes measures-based model of care (IePRO MoC) and the usability of its complementary ePROM mobile app to monitor and manage symptoms related to immune checkpoint inhibitors. In this MoC, symptoms reported by patients treated at an outpatient clinic were reviewed by oncology triage nurses who provided symptom management interventions by telephone.<br><br>METHODS: As part of a larger intervention trial (ClinicalTrials.gov.NCT05530187) we conducted an abductive, semantic thematic analysis through semistructured interviews of patients participating in the intervention arm. Acceptability was deduced from Sekhon et al's (2017) Theoretical Framework of Acceptability completed with inductively generated themes. Usability analysis was guided by the mHealth App Usability Questionnaire's domains by Zhoul et al (2019).<br><br>RESULTS: A total of 17 interviews were performed. The IePRO MoC was reported to be an acceptable intervention. Patients expressed feeling safe and empowered due to continuous monitoring and timely support from nurses. Personalized support motivated patients to use the MoC throughout treatment. Some questioned the predefined response options of the app, and the standardized approach regarding notifications and monitoring requirements. Despite high app usability, some expressed discomfort from being frequently reminded of their illness and being confronted with questions about their sexuality and other intimate themes.<br><br>CONCLUSIONS: The feedback loop between patients and nurses facilitated the acceptability of the IePRO MoC. The app's usability further facilitated adherence to the MoC. A more personalized approach regarding the frequency of assessments and the way symptoms are conveyed is recommended to decrease discomfort and support the implementation of similar MoCs in the future.}, }
@article {pmid40412392, year = {2025}, author = {Yan, X and Kuster, D and Mohanty, P and Nijssen, J and Pombo-García, K and Garcia Morato, J and Rizuan, A and Franzmann, TM and Sergeeva, A and Ly, AM and Liu, F and Passos, PM and George, L and Wang, SH and Shenoy, J and Danielson, HL and Ozguney, B and Honigmann, A and Ayala, YM and Fawzi, NL and Dickson, DW and Rossoll, W and Mittal, J and Alberti, S and Hyman, AA}, title = {Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2025.04.039}, pmid = {40412392}, issn = {1097-4172}, abstract = {Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.}, }
@article {pmid40412267, year = {2025}, author = {Tian, H and Huang, N and Chen, C and Yu, H and Ge, C}, title = {Flavor profiles and genetic basis differences of Lacticaseibacillus paracasei isolates from different isolations in fermented milk.}, journal = {International journal of food microbiology}, volume = {440}, number = {}, pages = {111274}, doi = {10.1016/j.ijfoodmicro.2025.111274}, pmid = {40412267}, issn = {1879-3460}, abstract = {Lacticaseibacillus paracasei from diverse traditional fermented foods exhibit unique flavor profiles in dairy products. In this study, 101 Lacticaseibacillus isolates were categorized into four distinct classes, with those originating from fermented dairy products demonstrating the highest flavor diversity. Multivariate statistical analyses identified diacetyl, acetoin, and 2-nonanone as key volatile compounds characterizing ketone-type isolates. Further examination of two ketone-type isolates and one non-ketone-type isolate, isolated from kurut, sour porridge, and Huangjiu mash respectively, revealed their specific abilities to produce ketones, lactones, and alcohols. Genome comparison of ketone-type and non-ketone-type L. paracasei isolates revealed disparities in the cit gene cluster, als, and but genes within the citrate metabolic pathway. These findings provide novel insights into the flavor diversity and help identify potential key genes involved in flavor formation in L. paracasei isolates, thereby facilitating the application of L. paracasei isolates in fermented dairy products.}, }
@article {pmid40411682, year = {2025}, author = {Jain, S and Das, D and Mukherjee, A and Roy, I}, title = {Inhibition of PolyGA Dipeptide Repeat Protein Aggregation by Nucleic Acid Aptamers in C9 Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Models.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40411682}, issn = {1559-1182}, support = {BT/PR30896/BRB/10/1747/2018//Department of Biotechnology/ ; }, abstract = {Hexanucleotide (GGGGCC) repeat expansion in non-coding region of C9ORF72 is the main genetic cause of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Gain of toxic function, via RNA or proteins, or loss of function via haploinsufficiency, are probable mechanisms of disease progression. Expanded GGGGCC repeat codes for dipeptide repeat (DPR) proteins which form inclusions in the brain. Among all the dipeptides, aggregates formed by polyGA sequence are the most toxic. In this work, inhibition of aggregation of polyGA DPRs using aptamers has been explored as a therapeutic strategy to delay disease progression. Target-specific, high-affinity RNA aptamers were selected against monomeric (GA)30. Selected aptamers showed significant inhibition of aggregation of (GA)30 in vitro. Inhibitory RNA sequences were seen to form typical secondary structures which was missing in a non-inhibitory sequence. Some of the RNA aptamers showed increased solubilisation of DPRs formed by (GA)30 and (GA)60 in a neuronal cell model of ALS-FTD. Decreased aggregation was accompanied by lower oxidative stress and improved cell survival. Importantly, expression level of one of the markers of autophagy was significantly enhanced in the presence of aptamers, explaining lower aggregation observed in these cells. Thus, aptamers may be developed as potential therapeutic agents in C9 ALS-FTD.}, }
@article {pmid40411245, year = {2025}, author = {Giacobbe, A and Hiana, J and Wang, O and Benatar, M and Wicks, P and Mascias Cadavid, J and Jhooty, S and McDermott, C and Pattee, G and Bertorini, T and Heiman-Patterson, T and Ratner, D and Barkhaus, P and Carter, G and Jackson, C and Denson, K and Brown, A and Armon, C and Sun, Y and Nguyen, A and Bedlack, R and Li, X}, title = {ALSUntangled #79: alpha-lipoic acid.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2025.2507166}, pmid = {40411245}, issn = {2167-9223}, abstract = {Alpha-lipoic acid (ALA) is a naturally occurring fatty acid. It serves as an essential cofactor for enzymatic reactions in mitochondrial energy production, is a potent antioxidant and has anti-inflammatory effects, which are plausible mechanisms in slowing ALS progression. In ALS preclinical studies, ALA slowed motor function decline and improved survival. There were self-reported cases of improved muscle strength in ALS patients when ALA was taken with numerous additional supplements, making it difficult to discern its efficacy. One small, 6-month open-label study showed improved quality of life, fatigue, and mood after participants took it with B vitamins and amino acids for the first 3 months. So far, no clinical trials have been published in people living with amyotrophic lateral sclerosis (PALS). Given the insufficient clinical data, we cannot endorse ALA and will support more research on its efficacy in slowing ALS progression.}, }
@article {pmid40409555, year = {2025}, author = {Ma, G and Ruan, X and Yang, B and Li, N and Su, D and Sun, S and Chen, S and Xu, K and Ying, Z and Wang, H}, title = {Abnormal regulation of membrane-less organelles contributes to profilin1-associated ALS.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {110259}, doi = {10.1016/j.jbc.2025.110259}, pmid = {40409555}, issn = {1083-351X}, abstract = {Profilin 1 (PFN1) is a key cytoskeletal protein that regulates actin dynamics by incorporating monomeric actin into linear filaments. PFN1 deletion or mutations have been linked to numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of PFN1 to neurodegenerative pathologies is poorly understood. Recent studies have implicated the role of aberrant cellular membrane-less organelles (MLOs) in neurodegenerative pathogenesis. Here, we demonstrate that PFN1 is involved in the assembly of MLOs, including Cajal bodies and Stress granules. Specifically, depletion of PFN1 leads to abnormal Cajal body accumulation and accelerated maturation into a gel-like state, consequently dysregulating snRNP biogenesis and impairing pre-mRNA splicing efficiency in both neuronal and non-neuronal cells. Similarly, we show that PFN1 knockdown accelerates the assembly of Stress granules in stressed cells. Furthermore, we demonstrate that the ALS-linked PFN1-C71G mutant exhibits a loss of function in the context of MLO biogenesis. We further reveal that the PFN1 deficiency-induced Cajal body dysregulation, but not Stress granule assembly, is caused by cellular actin filament depolymerization. Importantly, the actin filament agonist CN04 rescues Cajal body properties in PFN1-depleted cells. Taken together, our findings shed light on the role of PFN1 in MLO biogenesis and suggest its involvement in neurodegenerative pathogenesis.}, }
@article {pmid40409351, year = {2025}, author = {Collins, K and Hoellein, A}, title = {Undifferentiated Myopathies.}, journal = {The American journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.amjmed.2025.05.026}, pmid = {40409351}, issn = {1555-7162}, }
@article {pmid40409314, year = {2025}, author = {,  and , }, title = {Safety and efficacy of trehalose in amyotrophic lateral sclerosis (HEALEY ALS Platform Trial): an adaptive, phase 2/3, double-blind, randomised, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {24}, number = {6}, pages = {500-511}, doi = {10.1016/S1474-4422(25)00173-5}, pmid = {40409314}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Trehalose/therapeutic use/adverse effects/administration &amp; dosage ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Treatment Outcome ; *Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; Edaravone/therapeutic use ; }, abstract = {BACKGROUND: Trehalose is a disaccharide that activates autophagy pathways in animal models of neurodegenerative diseases, with the potential to catalyse clearance of toxic, misfolded proteins in motor neurons and slow disease progression in amyotrophic lateral sclerosis (ALS). We aimed to evaluate the safety and efficacy of trehalose in individuals with ALS.<br><br>METHODS: The HEALEY ALS Platform Trial is a perpetual, adaptive, phase 2/3, randomised, double-blind, multi-regimen trial conducted at 60 geographically diverse sites in the USA. In the current regimen, adults with clinically possible, probable, laboratory-supported probable, or definite ALS, defined by the revised El Escorial criteria, were randomly allocated (3:1), stratified by use of edaravone and riluzole, to receive trehalose 0&#xb7;75 g per kg intravenously weekly over 24 weeks, or matching placebo. The primary outcome was a composite of the relative rate of disease progression, as measured by the Revised ALS Functional Rating Scale (ALSFRS-R), and survival over 24 weeks, estimated in a Bayesian shared-parameter model. The study included prespecified stopping rules for futility; interim analyses occurred every 12 weeks. The primary outcome was analysed according to the intention-to-treat principle in all participants in the trehalose group, the placebo group within the regimen, and placebo groups from other contributing regimens; the safety analysis population was comprised of all participants who initiated treatment. This study is registered with ClinicalTrials.gov, NCT05136885.<br><br>FINDINGS: Between Feb 21, 2022, and Feb 17, 2023, 1021 participants were screened for the platform trial and 171 were assigned to the trehalose regimen. Of these, 161 participants met eligibility criteria, with 120 randomly allocated to trehalose and 41 to regimen-specific placebo. 164 participants randomly allocated to placebo in other regimens were added for analysis (totalling 205 placebo recipients). The disease rate ratio for change in ALSFRS-R and survival was 0&#xb7;87 (95% credible interval 0&#xb7;665-1&#xb7;102, posterior probability of superiority 0&#xb7;877). Serious adverse events occurred in 19 (16%) participants in the trehalose group and three (7%) participants in the regimen-only placebo group, leading to premature discontinuations in 14 (12%) versus one (2%), respectively. Fatal treatment-emergent adverse events occurred in seven participants in the trehalose group and none in the regimen-only placebo group. No death was considered related to the trial drug. The most common cause of death was respiratory failure, consistent with the natural history of ALS.<br><br>INTERPRETATION: Trehalose was well tolerated but there was no evidence to suggest a difference in ALS disease progression compared with placebo in this study. No statistical benefit was seen in secondary clinical or biomarker measures, suggesting that trehalose at this dosage is unlikely to be efficacious for treatment of ALS.<br><br>FUNDING: AMG Charitable Foundation, Tackle ALS, the ALS Association, ALS Finding a Cure, the Muscular Dystrophy Association, ALS ONE, the Arthur M Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative, and other community fundraising initiatives and donors. Study drug and partial regimen-related funding was provided by Seelos.}, }
@article {pmid40409302, year = {2025}, author = {Fan, D}, title = {Innovative trial designs in amyotrophic lateral sclerosis: balancing efficiency and precision.}, journal = {The Lancet. Neurology}, volume = {24}, number = {6}, pages = {473-474}, doi = {10.1016/S1474-4422(25)00150-4}, pmid = {40409302}, issn = {1474-4465}, }
@article {pmid40407667, year = {2025}, author = {Pérez-Bonilla, M and Díaz Borrego, P and Mora-Ortiz, M and Fernández-Baillo, R and Muñoz-Alcaraz, MN and Mayordomo-Riera, FJ and Girela López, E}, title = {Relationship Between Voice Analysis and Functional Status in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Audiology research}, volume = {15}, number = {3}, pages = {}, doi = {10.3390/audiolres15030053}, pmid = {40407667}, issn = {2039-4330}, abstract = {Background: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons, with bulbar dysfunction manifesting in up to 80% of patients. Dysarthria, characterized by impaired speech production, is common in ALS and often correlates with disease severity. Voice analysis has emerged as a promising tool for detecting disease progression and monitoring functional status. Methods: This study investigates acoustic and biomechanical voice alterations in ALS patients and their association with clinical measures of functional independence. A descriptive observational case series study was conducted, involving 43 ALS patients and 43 age and sex matched controls with non-neurological voice disorders. Sustained vowel /a/ recordings were obtained and analyzed using Voice Clinical Systems[®] and Praat software (version 6.2.22). Biomechanical and acoustic parameters were correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) and Barthel Index scores. Results: Significant differences were observed between ALS and control groups (elevated muscle force and tension and interedge distance in non-ALS individuals). Between bulbar and spinal ALS subtypes, elevated values were observed in certain parameters in Bulbar ALS patients, indicating irregular vocal fold contact and weakened phonatory control, while spinal ALS exhibited increased values, suggesting higher phonatory muscle tension. Elevated biomechanical parameters were significantly correlated with low ALSFRS-R scores, suggesting a possible relationship between voice measures and functional decline. However, acoustic measurements showed no relationship with performance status. Conclusions: These results highlight the potential of voice analysis as a non-invasive, objective tool for monitoring ALS stage and differentiating between subtypes. Further research is needed to validate these findings and explore their clinical applications.}, }
@article {pmid40407286, year = {2025}, author = {Steenkjær, CH and Heintzelmann, MB and Obál, I and Andersen, G and Blicher, JU}, title = {An adapted Danish translation of the Center for Neurologic Study Lability scale.}, journal = {Danish medical journal}, volume = {72}, number = {5}, pages = {}, doi = {10.61409/A07240497}, pmid = {40407286}, issn = {2245-1919}, mesh = {Humans ; Denmark ; *Amyotrophic Lateral Sclerosis/psychology/complications/diagnosis ; *Multiple Sclerosis/psychology/complications/diagnosis ; *Translations ; Surveys and Questionnaires ; Female ; Male ; Middle Aged ; Adult ; Aged ; Translating ; }, abstract = {INTRODUCTION: Pathological crying and/or laughing (pseudobulbar affect (PBA)) are socially debilitating symptoms seen in many neurological diseases, such as stroke, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One method for measuring the degree of PBA is the Center for Neurologic Study-Lability Scale (CNS-LS), a seven-item questionnaire validated for quantifying symptoms and supporting PBA diagnoses in ALS and MS. The aim of this study was to provide a Danish translation of the CNS-LS inspired by international guidelines on cross-cultural translation and adaptation of self-report measurements.<br><br>METHODS: Through a six-step process, the CNS-LS was translated and back-translated by four certified translators, followed by an expert committee examination. The translation was then field-tested by interviewing patients with ALS and MS after they had completed the CNS-LS. If at least 20% of participants found an item "unclear", it would be reevaluated.<br><br>RESULTS: Twelve patients with ALS patients and 30 patients with MS were tested and interviewed. None of the questionnaire items exceeded the 20% threshold for lack of clarity.<br><br>CONCLUSION: We present a Danish translation of the CNS-LS to facilitate better diagnosis and quantification of PBA symptoms in Danish patients with ALS or MS.<br><br>FUNDING: This study received funding from the PhD fellowship grant of Neuroscience Academy Denmark.<br><br>TRIAL REGISTRATION: Not relevant.}, }
@article {pmid40406897, year = {2025}, author = {Li, J and Zi, X and Fang, J and Liang, M and Ju, M and Sun, Z and Shen, B and Zhang, X}, title = {Endoplasmic Reticulum Stress Induces Liquid-Liquid Phase Separation of GRP78 and Modulates Protein Aggregation Dynamics.}, journal = {ACS sensors}, volume = {}, number = {}, pages = {}, doi = {10.1021/acssensors.5c00807}, pmid = {40406897}, issn = {2379-3694}, abstract = {Abnormal protein aggregation is a hallmark of neurodegenerative diseases, disrupting cellular homeostasis. Glucose-regulated protein 78 (GRP78), a key endoplasmic reticulum (ER) chaperone, plays a crucial role in protein folding and the ER stress response. Recent studies suggest that GRP78 undergoes liquid-liquid phase separation (LLPS) to form dynamic condensates; however, its functional implications under pathological conditions remain unclear. In this study, we designed and synthesized two fluorescent probes (ER-Pro and Agg-Pro) for specifically labeling GRP78 and monitoring microenvironmental polarity changes during protein phase transition. By integrating fluorescence lifetime imaging microscopy and confocal microscopy, we demonstrated that GRP78 undergoes LLPS under ER stress and recruits the amyotrophic lateral sclerosis-associated mutant protein SOD1(A4V), influencing its aggregation dynamics. Further investigations revealed that SOD1(A4V) aggregation is accompanied by local polarity changes, highlighting a potential role for GRP78 LLPS in protein quality control. Our findings provide new insights into ER homeostasis regulation and the pathogenesis of neurodegenerative diseases, offering potential strategies for early diagnosis and therapeutic intervention.}, }
@article {pmid40406043, year = {2025}, author = {Wang, L and Ma, L and Gao, Z and Wang, Y and Qiu, J}, title = {Significance of gene therapy in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1515255}, pmid = {40406043}, issn = {1662-4548}, abstract = {Gene therapy is an approach that employs vectors to deliver genetic material to target cells, aiming to correct genes with pathogenic mutations and modulate one or more genes responsible for disease progression. It holds significant value for clinical applications and offers broad market potential due to the large patient population affected by various conditions. For instance, in 2023, the Food and Drug Administration (FDA) approved 55 new drugs, including five specifically for gene therapy targeting hematologic and rare diseases. Recently, with advancements in understanding the pathogenesis and development of neurodegenerative diseases (NDDs), gene therapy has emerged as a promising avenue for treating Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA), particularly in personalized medicine. Notably, the FDA has approved three clinical applications for combating SMA, utilizing viral vectors delivered via intravenous and intrathecal injections. However, gene therapy for other NDDs remains in clinical trials, necessitating improvements in viral vectors, exploration of new vectors, optimization of delivery routes, and further investigation into pathogenesis to identify novel targets. This review discusses recent advancements in gene therapy for NDDs, offering insights into developing new therapeutic strategies.}, }
@article {pmid40405710, year = {2025}, author = {Clift, A and Rowen, D and Knox, L and Griffiths, AW and McDermott, CJ}, title = {A Systematic Review of Attributes Influencing Preferences for Treatments and Interventions in People With Amyotrophic Lateral Sclerosis (ALS).}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28437}, pmid = {40405710}, issn = {1097-4598}, support = {//National Institute for Health and Care Research/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that has no cure, and treatments predominantly focus on improving quality of life. Patient-centred care is central to bringing about meaningful improvements to quality of life. This review addresses the lack of consolidated evidence on what matters most to people with ALS (pwALS) by synthesizing 44 preference-based studies covering six different treatment and intervention categories. Data-based convergent synthesis identified five overarching factors influencing preferences: ease of use, accessibility, making life easier, autonomy, and safety/reliability. Simplifying and enhancing accessibility of treatment delivery across disease stages aligns with the nature of neurodegenerative disorders such as ALS, where function declines as the disease progresses. The value in perceived and real control reflects the profound impact ALS has on an individual's independence. Safety and reliability are crucial for people with ALS and are recognized as fundamental requirements for quality healthcare. The themes identified in this review can inform the attributes of preference elicitation methods. Systematically varying the levels of these attributes elicits quantitative measures of preferences. These findings can be used to inform and develop healthcare policy and clinical practice in ALS care. Specifically, preferences related to drug treatments can then be integrated into target product profiles (TPPs) to align drug development with the needs and values of pwALS. Integrating patient preferences into clinical practice promotes patient-centred care, increasing both patient satisfaction and treatment effectiveness.}, }
@article {pmid40405476, year = {2025}, author = {Ma, C and Tian, G and Liu, Y and Wang, P and Meng, C and Liu, J and Guo, S and Qi, D}, title = {Highly Stretchable and Conductive Wrapping-Entanglement Coupling Network for All-Carbon-Based Soft Bioelectrode.}, journal = {Nano letters}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.nanolett.5c01522}, pmid = {40405476}, issn = {1530-6992}, abstract = {Carbon-based materials are ideal for MRI-compatible bioelectrodes, essential for monitoring electromyographic signals and delivering electrical stimulation in diseases like ALS and MG. However, conventional stretchable carbon electrodes struggle with balancing electrical and mechanical properties. This paper proposes a new method of using a wrapping-entanglement coupling carbon network with multiple carbon nanomaterials in a polymer matrix, achieving high conductivity (454.5 S/m, several to dozens of times higher than that of electrodes made from other carbon materials embedded in polymers) and exceptional elongation at break (>3000%, carbon-based stretchable electrodes typically have a stretch rate of <500%). This electrode demonstrates remarkable durability, withstanding over 10,000 cycles at 20% strain (carbon-based stretchable electrodes can typically withstand <2500 cycles), outperforming existing carbon-polymer electrodes. It can be conformally attached to the skin and used as multichannel electrodes for ECG and EMG monitoring, matching the performance of Ag/AgCl electrodes. Implanted in rat models, it successfully recorded electrophysiological signals while reducing MRI artifacts compared to Pt electrodes in a 9.4 T MRI scanner. This innovation offers significant potential for advanced medical diagnostics and treatments.}, }
@article {pmid40405223, year = {2025}, author = {Yoonesi, S and Abedi Azar, R and Arab Bafrani, M and Yaghmayee, S and Shahavand, H and Mirmazloumi, M and Moazeni Limoudehi, N and Rahmani, M and Hasany, S and Idjadi, FZ and Aalipour, MA and Gharedaghi, H and Salehi, S and Asadi Anar, M and Soleimani, MS}, title = {Facial expression deep learning algorithms in the detection of neurological disorders: a systematic review and meta-analysis.}, journal = {Biomedical engineering online}, volume = {24}, number = {1}, pages = {64}, pmid = {40405223}, issn = {1475-925X}, mesh = {*Deep Learning ; Humans ; *Nervous System Diseases/diagnosis ; *Facial Expression ; }, abstract = {BACKGROUND: Neurological disorders, ranging from common conditions like Alzheimer's disease that is a progressive neurodegenerative disorder and remains the most common cause of dementia worldwide to rare disorders such as Angelman syndrome, impose a significant global health burden. Altered facial expressions are a common symptom across these disorders, potentially serving as a diagnostic indicator. Deep learning algorithms, especially convolutional neural networks (CNNs), have shown promise in detecting these facial expression changes, aiding in diagnosing and monitoring neurological conditions.<br><br>OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the performance of deep learning algorithms in detecting facial expression changes for diagnosing neurological disorders.<br><br>METHODS: Following PRISMA2020 guidelines, we systematically searched PubMed, Scopus, and Web of Science for studies published up to August 2024. Data from 28 studies were extracted, and the quality was assessed using the JBI checklist. A meta-analysis was performed to calculate pooled accuracy estimates. Subgroup analyses were conducted based on neurological disorders, and heterogeneity was evaluated using the I[2] statistic.<br><br>RESULTS: The meta-analysis included 24 studies from 2019 to 2024, with neurological conditions such as dementia, Bell's palsy, ALS, and Parkinson's disease assessed. The overall pooled accuracy was 89.25% (95% CI 88.75-89.73%). High accuracy was found for dementia (99%) and Bell's palsy (93.7%), while conditions such as ALS and stroke had lower accuracy (73.2%).<br><br>CONCLUSIONS: Deep learning models, particularly CNNs, show strong potential in detecting facial expression changes for neurological disorders. However, further work is needed to standardize data sets and improve model robustness for motor-related conditions.}, }
@article {pmid40404809, year = {2025}, author = {Morando, MA and D'Alessandro, V and Spinello, A and Sollazzo, M and Monaca, E and Sabbatella, R and Volpe, MC and Gervaso, F and Polini, A and Mizielinska, S and Alfano, C}, title = {Epigallocatechin-3-gallate binds tandem RNA recognition motifs of TDP-43 and inhibits its aggregation.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {17879}, pmid = {40404809}, issn = {2045-2322}, support = {CUP F85F20000260006//Programma Operativo Nazionale Ricerca e Innovazione 2014-2020 (CCI 2014IT16M2OP005), Fondo Sociale Europeo, Azione I.1 "Dottorati Innovativi con caratterizzazione Industriale"/ ; CUP B73C21001300006//Italian Ministry of University and Research/ ; }, mesh = {*Catechin/analogs &amp; derivatives/pharmacology/chemistry/metabolism ; *DNA-Binding Proteins/metabolism/chemistry ; Humans ; Protein Binding ; *Protein Aggregates/drug effects ; *RNA Recognition Motif ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Transactive response DNA-binding Protein 43 (TDP-43) aggregation is a key pathological feature in Amyotrophic Lateral Sclerosis and related neurodegenerative diseases. This study investigates the inhibitory effects of Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, on TDP-43 aggregation. Using a combination of fluorescence assays, NMR spectroscopy, and computational modeling, we demonstrate that Epigallocatechin-3-gallate significantly delays the nucleation phase of TDP-43 aggregation process, thus inhibiting the formation of TDP-43 aggregates in vitro. Additionally, we proved a direct interaction of the compound with the RNA recognition motifs of TDP-43 and modeled the mechanism of interaction. Our findings reveal that EGCG stabilizes the RRM domains, counteracting aggregation by interfering with the early stages of the amyloidogenic pathway. Furthermore, EGCG's stability under experimental conditions was ensured using reducing agents, highlighting the importance of maintaining its reduced form for reproducible results. These insights underscore the therapeutic potential of EGCG in TDP-43 proteinopathies and provide a foundation for developing targeted treatments for ALS and related disorders.}, }
@article {pmid40403957, year = {2025}, author = {Zeng, L and Yang, J and Zhang, C and Zhu, J and Zhong, S and Liu, X and Xie, H and Wang, L and Chen, L and Zhong, M and Hua, F and Liang, W}, title = {Miro1: A potential target for treating neurological disorders.}, journal = {Neuroscience}, volume = {577}, number = {}, pages = {228-239}, doi = {10.1016/j.neuroscience.2025.05.019}, pmid = {40403957}, issn = {1873-7544}, abstract = {The Miro1 protein is a member of the mitochondrial Rho GTPase (Miro) protein family and plays a crucial role in regulating the dynamic processes of mitochondria and participating in cellular movement and mitochondrial transport. In the nervous system, it ensures adequate energy supply for normal neuronal function and synaptic transmission. Additionally, Miro1 actively participates in the regulation of mitochondrial quality control and stress responses within neurons. Its primary function is to sense intracellular stress signals to regulate mitochondrial movement and metabolism, thereby adapting to environmental changes. Multiple studies have indicated that the Miro1 protein is associated with the pathogenesis of various neurological disorders, such as Alzheimer's Disease(AD), Parkinson's Disease(PD), and Amyotrophic Lateral Sclerosis(ALS). This article reviews the mechanistic role of Miro1 in these diseases and summarizes the latest research on its involvement in neurological disorders. These efforts aim to provide unified treatment strategies for certain neurological disorders and explore the potential for treating complex neurological diseases.}, }
@article {pmid40334920, year = {2025}, author = {Perez, OD and Lin, MJ and Pomeranz, MK and Chiu, ES and Lu, CP and Petukhova, L}, title = {Response to Andersen et al's "A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.04.064}, pmid = {40334920}, issn = {1097-6787}, }
@article {pmid40403623, year = {2025}, author = {Chtourou, M and Osuna, MD and Vázquez-García, JG and De Prado, R and Lozano-Juste, J and Marín, GM and Hada, Z and Souissi, T and Torra, J}, title = {Several point mutations and metabolism confer cross-resistance to ALS-inhibiting herbicides in Tunisian wild mustard.}, journal = {Plant physiology and biochemistry : PPB}, volume = {225}, number = {}, pages = {110043}, doi = {10.1016/j.plaphy.2025.110043}, pmid = {40403623}, issn = {1873-2690}, abstract = {A growing number of weed biotypes showing resistance to acetolactate synthase (ALS)-inhibitors have been reported in several species, notably including Sinapis arvensis L. Two putative resistant (R) populations of S. arvensis from Tunisia were subjected to greenhouse and laboratory investigations to validate resistance to ALS-inhibitors and to determinate the mechanisms involved. The results indicated that both populations were resistant to four distinct ALS-inhibiting herbicides, tribenuron-methyl (TM), florasulam, flucarbazone and imazamox (IMZ), thereby confirming cross-resistance between them. The dose of (TM) required to achieve a 50 % reduction in plant growth (ED50) and 50 % mortality (LC50) in R populations of S. arvensis was found to be at least 60 times greater than the recommended field dose (18.7 g ai ha[-1]) applied in cereal crops in Tunisia, indicating a significantly elevated resistance factor. Synergist experiments using malathion as a cytochrome P450 (Cyt-P450) inhibitor demonstrated a reduction in resistance to imazamox (IMZ) in both resistant (R) biotypes, indicating that Cyt-P450 plays a partial role in the resistance mechanism. In addition, ALS gene analysis identified three key point mutations, Pro197Ala, Asp376Glu and Trp574Leu, in both R populations. The docking analysis demonstrated that Asp376Glu mutation in S. arvensis could confer cross-resistance to IMZ and TM herbicides. CAPS and dCAPS methods were developed for detecting the Trp574Leu and Asp376Glu mutations, respectively, in S arvensis and it was shown that work efficiently. Fortunately, the study also confirmed that 2,4-D still effectively controlled S. arvensis populations. This study provides valuable insights into the mechanisms underlying herbicide resistance in S.arvensis populations from Tunisia, demonstrating that both target-site resistance (TSR) and non-target-site resistance (NTSR) contribute to the species' broad-spectrum resistance against four dissimilar ALS-inhibitors.}, }
@article {pmid40403503, year = {2025}, author = {Dhapola, R and Paidlewar, M and Kumari, S and Sharma, P and Vellingiri, B and Medhi, B and HariKrishnaReddy, D}, title = {cGAS-STING and neurodegenerative diseases: A molecular crosstalk and therapeutic perspective.}, journal = {International immunopharmacology}, volume = {159}, number = {}, pages = {114902}, doi = {10.1016/j.intimp.2025.114902}, pmid = {40403503}, issn = {1878-1705}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and Frontotemporal Dementia (FTD) share key pathological features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, autophagic dysfunction, and DNA damage. By identifying cytosolic DNA and triggering the type I interferon response, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway regulates neuroinflammation. Dysregulated cGAS-STING signaling has been linked to neuroinflammation and neuronal degeneration across multiple neurodegenerative conditions. In many neurodegenerative disorders, neuroinflammation is mediated by the cGAS-STING pathway. Mitochondrial malfunction and impaired autophagy cause cytosolic DNA buildup in Huntington's, Parkinson's, and Alzheimer's diseases, which activates cGAS-STING and drives chronic inflammation. This pathway is triggered by TDP-43 pathology and nucleic acid dysregulation in ALS and FTD, which leads to neuronal destruction. Both central demyelination and peripheral immunological responses are linked to cGAS-STING activation in multiple sclerosis. Various inhibitors, such as RU.521, H-151, and naturally occurring compounds like metformin, potentially attenuate cGAS-STING-mediated neuroinflammation and associated pathologies. H-151 significantly decreased the expression of pro-inflammatory markers in murine macrophage J774 cells activated with cGAMP: TNF-α by 68 %, IFN-β by 84 %, and CXCL10 by 96 %. cGAS-STING inhibitors target neuroinflammation, offering a disease-modifying approach unlike current symptomatic treatments. However, challenges like blood-brain barrier penetration, off-target effects, and immune suppression hinder clinical translation, necessitating optimized drug delivery and immune modulation. With a focus on its potential for future clinical applications, this review explores the role of the cGAS-STING pathway in neurodegeneration and new treatment approaches.}, }
@article {pmid40401739, year = {2025}, author = {Perera, ND and De Silva, S and Tomas, D and Cuic, B and Turner, BJ}, title = {Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70045}, pmid = {40401739}, issn = {1098-1136}, support = {IG 2132//Motor Neurone Disease Research Australia/ ; 2020-2024//Stafford Fox Medical Research Foundation/ ; Early Career Researcher Grant 2020//University of Melbourne/ ; ID 2202//Bethlehem Griffiths Research Foundation Grant 2022/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1[G93A] mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.}, }
@article {pmid40401027, year = {2025}, author = {Libonati, L and Cambieri, C and Ceccanti, M and Moret, F and Di Giulio, M and Palma, E and Inghilleri, M}, title = {Twitch force in human Amyotrophic Lateral Sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1590950}, pmid = {40401027}, issn = {1664-2295}, abstract = {INTRODUCTION: This study investigated differences in muscle twitch force between slow and fast progressors of amyotrophic lateral sclerosis (ALS) to better understand disease heterogeneity and identify potential biomarkers of disease progression.<br><br>METHODS: Forty-four ALS patients were classified as slow or fast progressors based on disease progression rates. Electrophysiological assessments, including compound muscle action potential (CMAP) and muscle force measurements, were conducted. Creatine kinase (CK) levels were also evaluated.<br><br>RESULTS: Slow progressors demonstrated significantly higher muscle peak force and area under the curve (AUC) compared to fast progressors, reflecting greater muscle strength and endurance. CK levels were also elevated in slow progressors.<br><br>DISCUSSION: Despite similar CMAp values, slow progressors retained greater muscle strength, possibly due to a reduced degeneration of fast-twitch fibers and compensatory axonal sprouting. These adaptations may preserve muscle function and elevate CK levels, suggesting better muscle integrity in slow progressors.<br><br>CONCLUSION: Muscle function profiles and CK levels are promising indicators of ALS progression. These findings could enhance early detection of disease progression and lead to targeted interventions to preserve muscle function. Further research is needed to validate these results and explore the underlying functional mechanisms of disease heterogeneity.}, }
@article {pmid40400898, year = {2025}, author = {Aziz, S and Anbreen, S and Shahzad, S and Ahmed, MS and Sharma, V and Yang, J and Ali, L}, title = {Investigating nanoparticle's utilization in stem cell therapy for neurological disorders.}, journal = {American journal of stem cells}, volume = {14}, number = {1}, pages = {1-13}, pmid = {40400898}, issn = {2160-4150}, abstract = {Stem cell therapy is a promising area of regenerative medicine, offering potential treatments for various life-threatening disorders. Stem cells are classified based on their differentiation potential into totipotent, pluripotent, and multipotent stem cells. Among them, mesenchymal stem cells (MSCs) are widely used in regenerative medicine due to their tissue regeneration capabilities and ability to differentiate into multiple cell types. Stem cells are being explored for treating neurodegenerative disorders like Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). These conditions result from progressive neuronal degeneration, leading to irreversible damage. Challenges such as cell survival, immune rejection, tumor formation, and ethical concerns related to embryonic stem cells need to be addressed. Nanotechnology is emerging as a tool for enhancing stem cell therapy, improving targeted delivery and effectiveness. Nanoparticles possess the ability to create microenvironments as substrates, facilitate targeted administration, and enable real-time, precise imaging of stem cells. This review explores the integration of stem cells and nanotechnology as regenerative medicine tool for neurodegenerative disease treatment, analyzing current strategies and therapeutic approaches. Integrating nanotechnology with stem cell therapy may significantly improve targeted delivery and enhance regenerative outcomes for neurodegenerative disorders.}, }
@article {pmid40400199, year = {2025}, author = {Ramgopal, S and Callaway, CW and Martin-Gill, C and Okubo, M}, title = {Using Life-Saving Interventions to Determine Optimal Vital Sign Ranges among Adults Encountered by Emergency Medical Services.}, journal = {Prehospital and disaster medicine}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/S1049023X25001542}, pmid = {40400199}, issn = {1945-1938}, abstract = {BACKGROUND: Vital signs are an essential component of the prehospital assessment of patients encountered in an emergency response system and during mass-casualty disaster events. Limited data exist to define meaningful vital sign ranges to predict need for advanced care.<br><br>STUDY OBJECTIVES: The aim of this study was to identify vital sign ranges that were maximally predictive of requiring a life-saving intervention (LSI) among adults cared for by Emergency Medical Services (EMS).<br><br>METHODS: A retrospective study of adult prehospital encounters that resulted in hospital transport by an Advanced Life Support (ALS) provider in the 2022 National EMS Information System (NEMSIS) dataset was performed. The outcome was performance of an LSI, a composite measure incorporating critical airway, medication, and procedural interventions, categorized into eleven groups: tachydysrhythmia, cardiac arrest, airway, seizure/sedation, toxicologic, bradycardia, airway foreign body removal, vasoactive medication, hemorrhage control, needle decompression, and hypoglycemia. Cut point selection was performed in a training partition (75%) to identify ranges for heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), oxygen saturation, and Glasgow Coma Scale (GCS) by using an approach intended to prioritize specificity, keeping sensitivity constrained to at least 25%.<br><br>RESULTS: Of 18,259,766 included encounters (median age 63 years; 51.8% male), 6.3% had at least one LSI, with the most common being airway interventions (2.2%). Optimal ranges for vital signs included 47-129 beats/minute for HR, 8-30 breaths/minute for RR, 96-180mmHg for SBP, >93% for oxygen saturation, and >13 for GCS. In the test partition, an abnormal vital sign had a sensitivity of 75.1%, specificity of 66.6%, and positive predictive value (PPV) of 12.5%. A multivariable model encompassing all vital signs demonstrated an area under the receiver operator characteristic curve (AUROC) of 0.78 (95% confidence interval [CI], 0.78-0.78). Vital signs were of greater accuracy (AUROC) in identifying encounters needing airway management (0.85), needle decompression (0.84), and tachydysrhythmia (0.84) and were lower for hemorrhage control (0.52), hypoglycemia management (0.68), and foreign body removal (0.69).<br><br>CONCLUSION: Optimal ranges for adult vital signs in the prehospital setting were statistically derived. These may be useful in prehospital protocols and medical alert systems or may be incorporated within prediction models to identify those with critical illness and/or injury for patients with out-of-hospital emergencies.}, }
@article {pmid40400037, year = {2025}, author = {Harjuhaahto, S and Jokela, M and Rajendran, J and Rokka, M and Hu, B and Kvist, J and Zhang, F and Zárybnický, T and Haimilahti, K and Euro, L and Pirinen, E and Huber, N and Herukka, SK and Haapasalo, A and Kuuluvainen, E and Gopalakrishnan, S and Katajisto, P and Hietakangas, V and Burg, T and Van Den Bosch, L and Huang, X and Narendra, DP and Kuure, S and Ylikallio, E and Tyynismaa, H}, title = {Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {111}, pmid = {40400037}, issn = {2051-5960}, mesh = {Animals ; Humans ; Mice ; *Mitochondrial Proteins/genetics/metabolism ; *Creatine/metabolism ; Male ; Motor Neurons/metabolism ; Female ; Disease Models, Animal ; *Motor Neuron Disease/genetics/metabolism ; Energy Metabolism/genetics ; Mice, Transgenic ; Mutation ; Muscular Atrophy, Spinal/genetics/metabolism ; }, abstract = {Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.}, }
@article {pmid40399998, year = {2025}, author = {Xu, L and Wang, Y and Li, X and Hu, Q and Adamkova, V and Xu, J and Harris, CJ and Ausin, I}, title = {H3K4me3 binding ALFIN-LIKE proteins recruit SWR1 for gene-body deposition of H2A.Z.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {137}, pmid = {40399998}, issn = {1474-760X}, support = {URF\R1\201016//Royal Society, UK/ ; URF\R1\201016//Royal Society, UK/ ; URF\R1\201016//Royal Society, UK/ ; EP/X025306/1/ERC_/European Research Council/International ; EP/X025306/1/ERC_/European Research Council/International ; EP/X025306/1/ERC_/European Research Council/International ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; 321703059 and 32370580//National Science Foundation of China/ ; }, mesh = {*Histones/metabolism/genetics ; *Arabidopsis Proteins/metabolism/genetics ; *Arabidopsis/genetics/metabolism ; Gene Expression Regulation, Plant ; Protein Binding ; *Adenosine Triphosphatases/metabolism ; }, abstract = {BACKGROUND: The H2A.Z histone variant is highly enriched over gene bodies, playing an essential role in several genome-templated processes, including transcriptional regulation and epigenetic patterning across eukaryotes. Deposition of H2A.Z is mediated by the SWR1 remodeling complex. How SWR1 is directed to gene bodies is largely unknown.<br><br>RESULTS: Here, we show that ALFIN-LIKE (AL) proteins are responsible for H2A.Z gene body patterning in&#xa0;Arabidopsis. AL proteins encode H3K4me3-binding PHD domains, and by ChIP-seq, we confirm preferential binding of AL5 to H3K4me3 over H3K4me1/2&#xa0;in planta. We observe a global reduction in H2A.Z in&#xa0;al&#xa0;septuple mutants (al7m), especially over H3K4me3-enriched genic regions. While MBD9 recruits SWR1 to nucleosome-free regions, ALs act non-redundantly with MBD9 for deposition of H2A.Z. Notably,&#xa0;al7m&#xa0;mutants show severe developmental abnormalities and upregulation of H2A.Z gene body-enriched responsive genes.<br><br>CONCLUSIONS: Therefore, we propose a model whereby AL proteins direct gene body enrichment of H2A.Z by recruiting SWR1 to H3K4me3-containing responsive genes.}, }
@article {pmid40399476, year = {2025}, author = {Rasà, DM and Stoppa, I and Bérenger-Currias, N and Pasho, E and Ciura, S and Kabashi, E and Martinat, C and Boido, M}, title = {Stress exposure affects amyotrophic lateral sclerosis pathogenesis via PI3K/Akt and focal adhesion pathways: evidence from three experimental models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {17583}, pmid = {40399476}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/etiology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Disease Models, Animal ; Mice ; Humans ; *Focal Adhesions/metabolism ; *Signal Transduction ; Male ; Superoxide Dismutase-1/genetics/metabolism ; Female ; Motor Neurons/metabolism/pathology ; Mice, Transgenic ; *Stress, Physiological ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms and affect the disease progression in ALS-predisposed conditions. To model stress in vivo, SOD1[G93A] mice underwent a chronic unpredicted mild stress protocol. This resulted in a significant impairment in body weight gain and motor performance, in a gender-specific manner. Moreover, the gene expression of Col1a1, Col1a2 and Il6 was strongly dysregulated in motor cortex and/or spinal cord of stressed mice. To assess the direct impact of stress on MNs, NSC-34 hSOD1[G93A] cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1[WT], mutated MNs exhibited a reduced capacity to cope with stress. By performing gene expression, protein-protein interaction, gene ontology and pathway enrichment analyses, we also revealed the pivotal role of the PI3K/Akt and focal adhesion pathways (triggered by Gsk3b, Il6, Igf1 and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived TARDBP[G298S] MNs. In conclusion, our results suggest that the PI3K/Akt and focal adhesion pathways play a crucial role in stress response across different ALS-predisposed models: the study paves the way for novel therapeutic targets and highlights the relevance of a healthy lifestyle.}, }
@article {pmid40398684, year = {2025}, author = {Naufal, E and Shadbolt, C and Wouthuyzen-Bakker, M and Rele, S and Sahebjada, S and Thuraisingam, S and Babazadeh, S and Choong, PF and Dowsey, MM}, title = {Clinical prediction models to guide treatment of periprosthetic joint infections: A systematic review and meta-analysis.}, journal = {The Journal of hospital infection}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jhin.2025.04.035}, pmid = {40398684}, issn = {1532-2939}, abstract = {BACKGROUND: Several clinical prediction models that aim to guide decisions about the management of periprosthetic joint infections (PJI) have been developed. While some models have been recommended for use in clinical settings, their suitability remains uncertain.<br><br>METHODS: We systematically reviewed and critically appraised all multivariable prediction models for the treatment of PJI. We searched MEDLINE, EMBASE, Web of Science, and Google Scholar from inception until March 1st, 2024 and included studies that developed or validated models that predict the outcome of PJI. We used PROBAST (Prediction model Risk Of Bias ASsessment Tool) to assess the risk of bias and applicability. Model performance estimates were pooled via random effect meta-analysis.<br><br>RESULTS: Thirteen predictive models and seven external validations were identified. Methodological issues were identified in all studies. Pooled estimates indicated that the KLIC (Kidney, Liver, Index surgery, Cemented prosthesis, C-reactive protein) score had fair discriminative performance (pooled c-statistic 0.62, 95% CI 0.55 to 0.69). Both the &#x3c4;2 (0.02) and I2 (33.4) estimates indicated that between study heterogeneity was minimal. Meta-analysis indicated Shohat et al's model had good discriminative performance (pooled c-statistic 0.74, 95% CI 0.57 to 0.85). Both the &#x3c4;2 (0.0) and I2 (0.0) indicated that between study heterogeneity was minimal.<br><br>CONCLUSIONS: Clinicians should be aware of limitations in the methods used to develop available models to predict outcomes of PJI. As no models have consistently demonstrated adequate performance across external validation studies, it remains unclear if any available models would provide reliable information if used to guide clinical decision-making.}, }
@article {pmid40398193, year = {2025}, author = {Carra, S and Fabian, B and Taghavi, H and Milanetti, E and Giliberti, V and Ruocco, G and Shepherd, J and Vendruscolo, M and Fuxreiter, M}, title = {Virus-like particles of retroviral origin in protein aggregation and neurodegenerative diseases.}, journal = {Molecular aspects of medicine}, volume = {103}, number = {}, pages = {101369}, doi = {10.1016/j.mam.2025.101369}, pmid = {40398193}, issn = {1872-9452}, abstract = {A wide range of human diseases are associated with protein misfolding and amyloid aggregates. Recent studies suggest that in certain neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and various tauopathies, protein aggregation may be promoted by virus-like particles (VLPs) formed by endogenous retroviruses (ERVs). The molecular mechanisms by which these VLPs contribute to protein aggregation, however, remain enigmatic. Here, we discuss possible molecular mechanisms of ERV-derived VLPs in the formation and spread of protein aggregates. An intriguing possibility is that liquid-like condensates may facilitate the formation of both protein aggregates and ERV-derived VLPs. We also describe how RNA chaperoning, and the encapsulation and trafficking of misfolded proteins, may contribute to protein homeostasis through the elimination of protein aggregates from cells. Based on these insights, we discuss future potential therapeutic opportunities.}, }
@article {pmid40398050, year = {2025}, author = {Hirschbeck, SS and Sawaya, MR and Lindberg, ET and Limbach, MN and Jang, JH and Lazar Cantrell, KL and Eisenberg, DS and Do, TD}, title = {Amyloid Oligomers: Expediting Crystal Growth and Revisiting the Corkscrew Structures.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.5c00656}, pmid = {40398050}, issn = {1520-5126}, abstract = {Crystallizing soluble amyloid oligomers (AOs) presents a major challenge in studying disease-related mutations associated with amyloid diseases. The G37R mutation in superoxide dismutase 1 (SOD1) is linked to early onset amyotrophic lateral sclerosis (ALS), yet its toxic mechanism remains unclear. The transient nature and low solubility of AOs often complicate the production of high-quality crystals required for X-ray crystallography (XRC) analysis. To address these challenges, we employ native ion mobility spectrometry-mass spectrometry (IMS-MS) to screen SOD1 peptides and examine correlations between structural features that reflect AO stability, their sequence length, and specific mutations. In particular, previous studies showed that the P28K mutation in SOD1(28-38) enhances solubility, thus allowing the capture of AO corkscrew structures for both SOD1(28-38)[P28K] and SOD1(28-38)[P28K, G37R]. Building on these findings, we expanded our screening to include SOD1 peptides with longer sequences, identifying structural features in IMS-MS spectra that correlate with improved crystallization potential. This approach enabled us to distinguish the stabilizing effects of G37R from those of P28K, culminating in the successful determination of the first crystal structure of the SOD1 corkscrew containing the native proline.}, }
@article {pmid40396445, year = {2025}, author = {Hu, X and Cheng, J and Yuan, R and Zhou, Y and Rao, J and Wan, Y and Li, Y and Zhang, X and Li, R}, title = {Gold Nanoparticles: Diagnostic and Therapeutic Applications in Neurodegenerative Disorders.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-39}, doi = {10.1080/1061186X.2025.2509287}, pmid = {40396445}, issn = {1029-2330}, abstract = {Neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases, pose a significant and escalating health challenge in the context of an aging population. Gold nanoparticles (GNPs) have emerged as promising agents in the diagnostic and therapeutic realms of NDDs, due to their unique ability to enhance drug delivery across the blood-brain barrier (BBB). This paper presents a comprehensive review of the application of GNPs in the context of NDDs diagnosis and therapy, highlighting their potential to transform patient management. Additionally, we systematically address the critical challenges associated with the use of GNPs in the treatment and diagnosis of NDDs, focusing on pharmacokinetics and metabolism, toxicity, long-term biocompatibility, regulatory challenges, and cost-effectiveness. Furthermore, we synthesize ongoing clinical studies to provide a holistic perspective on the current state of research in this field. We also explore the prospective trajectories and clinical translational potential of GNPs, which may usher in a new era in the treatment of NDDs.}, }
@article {pmid40396430, year = {2025}, author = {Yang, J and Xiao, F and Liu, Y and Bai, J and Tan, S}, title = {Nerve Conduction Study and the Prognosis of Amyotrophic Lateral Sclerosis: Exploration of Additional Neuroelectrophysiological Parameters.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70209}, doi = {10.1111/ene.70209}, pmid = {40396430}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; *Neural Conduction/physiology ; Middle Aged ; Male ; Female ; Prognosis ; Aged ; Adult ; Action Potentials/physiology ; Aged, 80 and over ; Median Nerve/physiopathology ; Nerve Conduction Studies ; }, abstract = {OBJECTIVE: To investigate the correlation between nerve conduction study (NCS) parameters and the prognosis of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: NCS parameters were recorded from the median, ulnar, peroneal, tibial, and superficial peroneal nerves of 114 sporadic patients with ALS. The main endpoint was death or tracheostomy. Univariate Cox regression analysis was conducted for all the NCS parameters. Subsequently, multivariate analysis was performed using Cox stepwise regression, incorporating factors identified in the univariate analysis and known prognostic factors. Kaplan-Meier curves and log-rank tests were used for survival analysis. Receiver operating characteristic (ROC) curves were used to assess the predictive capabilities of NCS parameters.<br><br>RESULTS: The distal compound muscle action potential (dCMAP) negative peak area and the sensory nerve action potential (SNAP) amplitude of the median nerve were identified as prognostic factors for ALS. Further stratified analyses showed that larger median dCMAP negative peak area significantly correlated with better prognosis in elderly (>&#x2009;61&#x2009;years) patients with limb-onset ALS. Conversely, higher median SNAP amplitudes indicated worse prognosis in younger (&#x2264;&#x2009;61&#x2009;years) patients with limb-onset ALS.<br><br>CONCLUSION: The current study showed that the dCMAP negative peak area and SNAP amplitude of the median nerve are independent prognostic factors for sporadic ALS patients.}, }
@article {pmid40396429, year = {2025}, author = {Keipert, LM and Wurster, CD and Uzelac, Z and Dorst, J and Schuster, J and Wollinsky, K and Ludolph, A and Lulé, D}, title = {Pain in adult and adolescent patients with 5q-associated Spinal Muscular Atrophy - an often underrated phenomenon.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251325773}, doi = {10.1177/22143602251325773}, pmid = {40396429}, issn = {2214-3602}, abstract = {BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder leading to progressive muscle weakness and atrophy. Pain in SMA may be the consequence of the underlying neuromuscular disease but has hardly been investigated so far.<br><br>OBJECTIVE: To assess pain in SMA and its interaction with patient's wellbeing.<br><br>METHODS: In a prospective, cross-sectional study design, 70 adult and adolescent SMA patients (median age 30 years, IQR 21-49 years, types I-IV) were assessed at the Department of Neurology, Ulm University hospital. Pain was evaluated with a self-adapted Pain Scale, depressiveness with the ALS-Depression-Inventory-12-Items (ADI-12) and global Quality of Life (gQoL) with the Anamnestic Comparative Self-Assessment (ACSA).<br><br>RESULTS: We found an intermittent frequency of pain in 80% in SMA patients with more than half of the patients experience pain at least once a week. The mean pain intensity score estimated by pain frequency and strength was 24 on a scale of 0 to 240, indicating a frequently appearing mild to moderate pain. Pain was mostly located in the lumbar spine, hip, and thoracic spine. The pain intensity score was independent from demographics (age, gender) or clinical parameters (SMA type, physical state), but, instead, it was associated to depressiveness. Depressiveness was more prevalent in older SMA patients. gQoL was rather independent from pain intensity or physical state.<br><br>CONCLUSIONS: The study provides evidence for a prevalence of mild to moderate pain in 80% of adult and adolescent SMA patients. Pain was not simply caused by physical deficits and did not severely interfere with patients' quality of life, but, instead, was closely interrelated with patients' affective state.}, }
@article {pmid40395983, year = {2025}, author = {Beckers, J and Van Damme, P}, title = {The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2474796}, pmid = {40395983}, issn = {2769-4127}, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two extremes of a neurodegenerative disease spectrum characterised by overlapping genetic, clinical, and neuropathological features. This review covers the intricate relationship between both ALS and FTD and defects in the autophagy and endolysosomal pathway as recent evidence has pointed towards alterations in these pathways as being a root cause of disease pathogenesis. Here, we review the current knowledge on the interplay between ALS/FTD and lysosomebased proteostasis pathways and carefully asses the steps of the autophagy and endolysosomal pathways that are impaired by ALS or FTDcausing variants. Finally, we present a comprehensive overview of therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating the impact of these devastating diseases. Through this review, we aim to enhance the understanding of the pathophysiological mechanisms involving autophagy and/or the endolysosomal system that underlie the ALS-FTD spectrum and underscore the necessity for specific therapeutic approaches that target these shared vulnerabilities.}, }
@article {pmid40395632, year = {2025}, author = {Gerring, ZF and Bhalala, OG and Fearnley, LG and Oikari, LE and White, AR and Derks, EM and Watson, R and Yassi, N and Bahlo, M and Reay, WR}, title = {Drug repurposing candidates for amyotrophic lateral sclerosis using common and rare genetic variants.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf184}, pmid = {40395632}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which novel disease modifying therapies are urgently needed. Given the increasing bottlenecks in drug discovery pipelines, repurposing existing drugs for ALS may represent a path to expedite translation and improve disease outcomes. However, ALS is a heterogeneous disease for which the aetiology remains poorly characterized, complicating efforts to effectively repurpose drugs. We propose that the polygenic architecture of ALS genetic liability, which ranges from ultra-rare, high-impact variation to common frequency loci of small-individual effect, could be leveraged to prioritize drug repurposing candidates which are more generalizable to the ALS clinical population. Here, we utilize common and rare frequency ALS genetic risk with a novel approach to uncover therapeutic classes that may be prospective repurposing opportunities in ALS. The common variant-led analyses integrated both positional-based and functional gene-based tests on SNP-genotype data from a genome-wide association study of ALS and implicated mitogen-activated protein kinase signalling related downregulation through B-Raf inhibitors as a prospective target for repurposing. The rare variant-led approaches leveraged rare variant burden testing of exonic variation on whole genome-sequencing data from a subset of the common variant genome-wide association study cohort and prioritized B-vitamin related candidates, such as cobalamin and niacin. Clinical characterization of these putative repurposing opportunities revealed genetic support to existing biology for which related compounds are actively proceeding through ALS clinical studies. Moreover, leveraging transcriptomic data from ALS derived cell lines carrying a selection of pathogenic variants in genes that cause familial forms of ALS (C9orf72, SOD1, FUS and TARDBP) suggested that the action of B-Raf inhibitors may be of particular relevance to C9orf72 carriers, whilst the signal for B-vitamin signalling related targets was strongest in SOD1 carriers. In summary, we demonstrate the importance of considering the therapeutic actionability of both common and rare-variant mediated risk for ALS given the immense biological heterogeneity of this disorder. Future pre-clinical and clinical studies are now warranted to further characterize the tractability of these prioritized compounds.}, }
@article {pmid40395537, year = {2024}, author = {Zhang, J and Pan, L}, title = {Mechanistic insights into the interaction between optineurin with RAB8A.}, journal = {Autophagy reports}, volume = {3}, number = {1}, pages = {2432848}, pmid = {40395537}, issn = {2769-4127}, abstract = {OPTN (optineurin), an amyotrophic lateral sclerosis (ALS)-associated modifier, plays vital roles in autophagy and cellular vesicular transport in mammals. OPTN can associate with RAB8A and the GTPase-activating protein TBC1D17, and facilitate the negative regulation of RAB8A by TBC1D17 (TBC domain family member 17). Recently, we reported the biochemical and structural characterizations of the interactions between OPTN, RAB8A and TBC1D17. We determined the crystal structure of the leucine-zipper domain (LZD) of OPTN with the GTP-bound active RAB8A and uncovered the molecular mechanism underpinning the specific interaction of OPTN with RAB8A. Moreover, we revealed that OPTN LZD and the TBC (Tre-2/Bub2/Cdc16) domain of TBC1D17 competitively bind to active RAB8A, while the central coiled-coil domain of OPTN and the active RAB8A can simultaneously interact with TBC1D17 TBC. In summary, our study provided mechanistic insights into the interaction of OPTN with RAB8A, and revealed the interaction relationship among OPTN, RAB8A and TBC1D17.}, }
@article {pmid40395127, year = {2025}, author = {Ghannizadeh, M and Rustamzadeh, A and Homayoun, M and Aliakbari, Z and Zamani, S}, title = {Premotor cortex and frontal eye field region metabolite alteration in human amyotrophic lateral sclerosis patients: A quantitative survey.}, journal = {The neuroradiology journal}, volume = {}, number = {}, pages = {19714009251345102}, doi = {10.1177/19714009251345102}, pmid = {40395127}, issn = {2385-1996}, abstract = {IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron degeneration, leading to muscle weakness, respiratory failure, and mortality. The premotor cortex (PMC), including the frontal eye field (FEF), shows greater resistance, with limb function declining earlier than eye movement. This study utilizes magnetic resonance spectroscopy (MRS) to investigate metabolite ratio changes in these regions for potential early ALS diagnosis.Methods and MaterialsFourteen ALS patients and healthy controls underwent MRS to assess neurometabolite levels, including N-acetyl aspartate (NAA), creatine (Cr), myo-inositol (mIns), and choline (Cho) in the PMC and FEF. ELISA measured superoxide dismutase-1 (SOD1) enzyme levels. Group differences were analyzed statistically using t-tests to evaluate significant variations.ResultIn ALS patients, a significant decrease in NAA/Cr (p = .045) and an increase in mIns/Cr (p < .0001) concentrations were observed in the PMC. No significant differences in Cho/Cr (p = .215) were detected between the FEF and PMC regions in ALS patients. Compared to the control group, NAA/Cr levels in the PMC and FEF regions of ALS patients were significantly lower (p = .004, .001), while mIns/Cr values were significantly higher (p = .001). However, no significant changes were observed in the Cho/Cr ratio in the FEF between ALS patients and controls. Additionally, SOD1 enzyme levels were significantly reduced in ALS patients (p < .0001).ConclusionThe findings suggest that neurometabolites levels in the PMC and FEF may be a promising candidate for clinical and pathological changes in ALS.}, }
@article {pmid40395088, year = {2025}, author = {Zhang, S and Gu, J and Yang, Y and Li, J and Ni, L}, title = {Evolution Trend of Brain Science Research: An Integrated Bibliometric and Mapping Approach.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70451}, doi = {10.1002/brb3.70451}, pmid = {40395088}, issn = {2162-3279}, support = {2020Z388//Jiangsu Postdoctoral Research Foundation/ ; //Top Talent Support Program for young and middle-aged people of the Wuxi Health Committee/ ; M202033//Wuxi Health Commission Scientific Research Project/ ; 24CC00903//Beijing Academy of Science and Technology Think Tank Research Project/ ; ZYYB05//Wuxi Administration of Traditional Chinese Medicine/ ; }, mesh = {*Bibliometrics ; Humans ; *Biomedical Research/trends ; *Neurosciences/trends ; *Brain/physiology ; United States ; China ; }, abstract = {BACKGROUND: Brain science research is considered the crown jewel of 21st-century scientific research; the United States, the United Kingdom, and Japan have elevated brain science research to a national strategic level. This study employs bibliometric analysis and knowledge graph visualization to map global trends, research hotspots, and collaborative networks in brain science, providing insights into the field's evolving landscape and future directions.<br><br>METHODS: We analyzed 13,590 articles (1990-2023) from the Web of Science Core Collection using CiteSpace and VOSviewer. Metrics included publication volume, co-authorship networks, citation patterns, keyword co-occurrence, and burst detection. Analytical tools such as VOSviewer, CiteSpace, and online bibliometric platforms were employed to facilitate this investigation.<br><br>RESULTS: The United States, China, and Germany dominated research output, with China's publications rising from sixth to second globally post-2016, driven by national initiatives like the China Brain Project. However, China exhibited limited international collaboration compared to the United States and European Union. Key journals included Human Brain Mapping and Journal of Neural Engineering, while emergent themes centered on "task analysis," "deep learning," and "brain-computer interfaces" (BCIs). Research clusters revealed three focal areas: (1) Brain Exploration (e.g., fMRI, diffusion tensor imaging), (2) Brain Protection (e.g., stroke rehabilitation, amyotrophic lateral sclerosis therapies), and (3) Brain Creation (e.g., neuromorphic computing, BCIs integrated with AR/VR). Despite China's high output, its influence lagged in highly cited scholars, reflecting a "quantity-over-quality" challenge.<br><br>CONCLUSION: Brain science research is in a golden period of development. This bibliometric analysis offers the first comprehensive review, encapsulating research trends and progress in brain science. It reveals current research frontiers and crucial directions, offering a strategic roadmap for researchers and policymakers to navigate countries when planning research layouts.}, }
@article {pmid40394046, year = {2025}, author = {Ge, R and Chen, M and Wu, S and Huang, S and Zhou, P and Cao, M and Zhang, F and Zang, J and Zhu, Y and Li, J and Ni, G and Yang, Z and Li, Q and Pan, W and Zhang, L and Liu, M and Xuan, C and Yu, H and Zhou, J and Xie, S}, title = {DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4683}, pmid = {40394046}, issn = {2041-1723}, support = {32270892//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200613//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *RNA-Binding Protein FUS/metabolism/genetics ; Animals ; Proteolysis ; *DNA/chemistry ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Blood-Brain Barrier/metabolism ; *Oligonucleotides ; Mice ; Brain/metabolism ; Receptors, Transferrin/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; }, abstract = {Oligonucleotide-based medicine faces challenges in efficiently crossing the blood-brain barrier and rapidly reducing toxic proteins. To address these challenges, here we establish an integrated modality, brain-penetrant DNA nanoflowers incorporated with oligonucleotide-based proteolysis targeting chimeras. Using FUS as a proof-of-concept, mutations of which cause frontotemporal dementia and amyotrophic lateral sclerosis, we demonstrate that a FUS-engaging RNA oligonucleotide crosslinked to a ligand for Cereblon efficiently degrade FUS and its cytoplasmic disease-causing mutants through a ubiquitin-proteasomal pathway. The DNA nanoflower contains hundreds of oligonucleotide binding sites and transferrin receptor-engaging aptamers, allowing efficient loading of the oligonucleotide-based degrader and engaging transferrin receptors for brain delivery. A single dose intravenous injection of this modality reaches brain parenchyma within 2 h and degrades 80% FUS protein there, sustained for two weeks without noticeable toxicity. DNA nanoflower oligonucleotide-based degrader is a therapeutic strategy for neurodegenerative diseases that leverages the advantages of designer oligonucleotides and targeted protein degradation.}, }
@article {pmid40392845, year = {2025}, author = {Beccari, MS and Arnold-Garcia, O and Baughn, MW and Artates, JW and McAlonis-Downes, M and Lim, J and Leyva-Cázares, DF and Rubio-Lara, HI and Ramirez-Rodriguez, A and Bernal-Buenrostro, CN and Murgia-Bay, B and Rangel, CK and Kim, DH and Melamed, Z and Lutz, CM and Lagier-Tourenne, C and Corbett, KD and López-Erauskin, J and Cleveland, DW}, title = {Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {21}, pages = {e2502294122}, doi = {10.1073/pnas.2502294122}, pmid = {40392845}, issn = {1091-6490}, support = {T32GM008666//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32AG066596//HHS | NIH | National Institute on Aging (NIA)/ ; R01NS112503//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS124203//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35GM144121//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; N/A//NOMIS Stiftung (NOMIS Foundation)/ ; N/A//Muscular Dystrophy Association (MDA)/ ; P30NS047101//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Axons/metabolism/physiology/pathology ; *Motor Neurons/metabolism/physiology/pathology ; Mice ; *Tubulin/metabolism ; *Nerve Regeneration/physiology ; Mice, Knockout ; Protein Binding ; Neuromuscular Junction/metabolism/pathology ; Humans ; Microtubules/metabolism ; }, abstract = {Stathmin-2 (also known as SCG10) is encoded by the STMN2 gene, whose mRNA is one of the most abundantly expressed in human motor neurons. In almost all instances of ALS and other TDP-43 proteinopathies, stathmin-2 encoding mRNAs are cryptically spliced and polyadenylated in motor neurons, a pathogenic consequence of nuclear loss of function of the RNA binding protein TDP-43. While stathmin-2 has been shown to enhance regeneration after axonal injury to axons of cultured motor neurons, here, we show that after crush injury within the adult murine nervous system of wild-type or stathmin-2-null mice, the presence of stathmin-2 reduces axonal and neuromuscular junction degeneration and stimulates reinnervation and functional recovery. Mechanistically, although stathmin-2 has been proposed to function through direct binding to α/β tubulin heterodimers and correspondingly to affect microtubule assembly and dynamics, stathmin-2's role in axon regeneration after axotomy is shown to be independent of its tubulin binding abilities.}, }
@article {pmid40391540, year = {2025}, author = {Massey, C and Hobson, E and Griffiths, AW and Musson, L and McDermott, C}, title = {Exploring mechanisms of behavior change for healthcare professionals in cough and secretion management in ALS.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/17582024.2025.2506954}, pmid = {40391540}, issn = {1758-2032}, abstract = {OBJECTIVES: To explore healthcare professionals' experiences managing cough and secretion problems in Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: A qualitative study was completed with 23 individuals participating in four focus groups. Data was analyzed using reflexive thematic analysis and COM-B and theoretical domains framework (TDF) behavior change frameworks.<br><br>RESULTS: This study found that roles, responsibilities, and expectations needed to be clearly defined and that building relationships was important to support care delivery. Barriers identified included limited access to specialist care, equipment, and opportunities to gain knowledge and skills. A structured clinical assessment was highlighted to enable good-quality care. Data mapped most commonly to the environmental context/resources, knowledge, skills (TDF), and physical capability (COM-B) behavior change domains.<br><br>CONCLUSION: Cough and secretion management in ALS is complex due to the multifaceted nature of the disease. This study emphasizes the need for future development of clinical interventions to support care.}, }
@article {pmid40395512, year = {2024}, author = {Tanaka, Y and Ito, SI and Suzuki, G}, title = {TDP-43 Secretion via Extracellular Vesicles Is Regulated by Macroautophagy.}, journal = {Autophagy reports}, volume = {3}, number = {1}, pages = {2291250}, pmid = {40395512}, issn = {2769-4127}, abstract = {The pathological accumulation of the nuclear protein TDP-43 (TAR DNA-binding protein 43 kDa) in the cytoplasm is characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), and its spread through the brain and spinal cord is closely associated with the progression of these two diseases. However, the mechanisms through which the TDP-43 pathology propagates throughout the central nervous system remain unclear. We recently reported the role of (macro)autophagy in the secretion of TDP-43 via extracellular vesicles (EVs). We found that among the autophagy modulators, bafilomycin A1 (Baf) and GRN (granulin precursor) deficiency impair the formation of autolysosomes and promote the secretion of TDP-43 by EVs. TDP-43 loading on EVs involves autophagy-related proteins and the knockdown of TDP-43 augmented Baf-induced EV release. Thus, our results suggest that the loss-of-function of TDP-43 accelerates release of EVs possibly derived from autophagosomes, which may mediate cell-to-cell spread of the TDP-43 pathology.}, }
@article {pmid40395318, year = {2023}, author = {Sun, S and Wang, H and Ma, Q and Li, N and Cao, M and Tam, KY and Ying, Z}, title = {PRKN regulates inner mitochondrial membrane PHB2 during mitophagy.}, journal = {Autophagy reports}, volume = {2}, number = {1}, pages = {2164643}, pmid = {40395318}, issn = {2769-4127}, abstract = {PINK1 (PTEN induced kinase 1) and PRKN-mediated mitophagy is an important mitochondrial quality control pathway which selectively degrades damaged mitochondria and is tightly associated with neurodegenerative diseases, including Parkinson disease and amyotrophic lateral sclerosis. The current model of PINK1-PRKN-mediated mitophagy is that PRKN ubiquitinates multiple outer mitochondrial membrane (OMM) proteins, and then the ubiquitin chains on the OMM interact with autophagy receptors which bind Atg8-family protein labeled phagophores. However, little work has been focused on the PRKN-mediated ubiquitination of inner mitochondrial membrane (IMM) proteins during mitophagy. Our recent work revealed that PRKN binds and ubiquitinates PHB2 (prohibitin 2), an essential IMM protein which was previously recognized as a mitophagy receptor, after the OMM is ruptured by proteasomal degradation. Using biochemical and microscopy approaches, we found that mutations of PRKN-targeted ubiquitination sites on PHB2 decrease the recognition of damaged mitochondria by the phagophore and the clearance of damaged mitochondria. In conclusion, our findings revealed a critical role for PRKN-PHB2 interaction in mitochondrial quality control by regulating IMM-associated recognition of mitochondria by the autophagy machinery.}, }
@article {pmid40396030, year = {2022}, author = {Ichimura, Y and Komatsu, M}, title = {Considering the mechanism by which droplets of ALS-FTD-associated SQSTM1/p62 mutants cause pathology.}, journal = {Autophagy reports}, volume = {1}, number = {1}, pages = {9-13}, pmid = {40396030}, issn = {2769-4127}, abstract = {Large numbers of point mutations in SQSTM1/p62 have been identified in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). SQSTM1 interacts with ubiquitinated proteins, undergoing liquid-liquid phase separation, and the resulting SQSTM1-droplets are degraded by macroautophagy/autophagy. SQSTM1 also serves as a multiple signaling hub for processes including selective autophagy and the anti-oxidative stress response. Such diverse functions are modulated by multiple domains and regions throughout the protein. Because mutations in SQSTM1 have been identified throughout its gene, including regions encoding the domains and motifs, the effects of these mutations on disease onset have been thought to be complicated. Recently, we thoroughly investigated how 7 mutations around the LC3-interacting region and KEAP1-interacting region (amino acids 335-356) affected autophagic degradation of SQSTM1, the anti-oxidative stress response, the KEAP1-NFE2L2/Nrf2 pathway, and the dynamics of SQSTM1 droplets. We found that reduced inner fluidity of the droplets is a unique, shared defect among all mutants, suggesting a link between qualitative changes in SQSTM1 liquid droplets and ALS-FTD. In this punctum article, we discuss the mechanism whereby reduced inner fluidity of mutant SQSTM1 droplets causes ALS-FTD pathology.}, }
@article {pmid40390742, year = {2025}, author = {Franconieri, F and Fayolle, S and Raviol, P}, title = {Non-diabetic Ketoacidosis in a Patient With Amyotrophic Lateral Sclerosis: The Role of Stewart's Approach in Analyzing Acid-Base Disorders.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82585}, pmid = {40390742}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is often complicated by severe malnutrition, increasing the risk of metabolic disturbances. Non-diabetic ketoacidosis (NDKA) is a rare but serious complication, typically related to prolonged fasting or catabolic states. A 62-year-old female patient with ALS and hypothyroidism presented with pneumonia and tetraplegia. Her body mass index (BMI) was 17 kg/m[2]. Laboratory findings showed a high anion gap (AG) metabolic acidosis (pH 7.23, bicarbonate 13 mmol/L, partial pressure of carbon dioxide (pCO2) 28 mmHg) without hyperlactatemia, but with significant ketonemia (5 mmol/L), severe hypophosphatemia, and signs of systemic inflammation. Upon admission, she received an intravenous infusion of 4.2% sodium bicarbonate. The simplified strong ion difference (SID) was preserved, excluding dilutional or hyperchloremic causes. Stewart's physicochemical approach, supported by a Gamblegram, revealed an acidosis due to unmeasured fixed acids, specifically ketone bodies. In light of this, bicarbonate therapy was discontinued, and nutritional correction with glucose hydration led to rapid clinical and biochemical improvement. This case illustrates the diagnostic and therapeutic value of Stewart's model in complex acid-base disturbances and underscores the need for early nutritional assessment in ALS patients. To our knowledge, this is the first reported case of NDKA in ALS, highlighting a rare but clinically relevant metabolic complication.}, }
@article {pmid40390638, year = {2025}, author = {Oh, J and Chu, HS}, title = {Self-care mobile application for people with Amyotrophic Lateral Sclerosis: a development and usability test.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2507169}, pmid = {40390638}, issn = {2167-9223}, abstract = {OBJECTIVE: Mobile technology can significantly enhance self-care for individuals with amyotrophic lateral sclerosis (ALS). This study aims to develop and evaluate the usability of a mobile application that provides relevant information and manages disease-related data for ALS patients and their families.<br><br>METHODS: A mobile application compatible with Android and iOS platforms was developed following the four phases of the System Development Life Cycle. The content was derived from a literature review, stakeholder focus group interviews, and in-depth interviews with ALS patients, family members, and healthcare professionals. The final application was validated by experts (n&#x2009;=&#x2009;7), tested for usability by ALS patients and caregivers (n&#x2009;=&#x2009;18), and evaluated using the System Usability Scale (SUS) to assess effectiveness and user satisfaction.<br><br>RESULTS: The application includes features such as tailored health data visualization, symptom tracking, text-to-speech functionality, and access to information customized based on the overall the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, thereby supporting patient-centered care and daily disease management. The mean SUS score was 75.00&#x2009;&#xb1;&#x2009;9.57 for expert panel members and 63.75&#x2009;&#xb1;&#x2009;10.26 for the target users, indicating an acceptable level of usability.<br><br>CONCLUSIONS: The mobile application was evaluated as practical, acceptable, and feasible for ALS patients and their caregivers, with positive feedback on its usability and potential to improve self-care management.}, }
@article {pmid40389989, year = {2025}, author = {Noh, MY and Oh, SI and Kim, YE and Cha, SJ and Sung, W and Oh, KW and Park, Y and Mun, JY and Ki, CS and Nahm, M and Kim, SH}, title = {Mutations in NEK1 cause ciliary dysfunction as a novel pathogenic mechanism in amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {59}, pmid = {40389989}, issn = {1750-1326}, support = {RS-2023-00265515//Ministry of Science and ICT/ ; RS-2023-00265515//Ministry of Science and ICT/ ; 24-BR-02-04//Ministry of Science and ICT/ ; 25-BR-04-01//Ministry of Science and ICT, South Korea/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *NIMA-Related Kinase 1/genetics/metabolism ; *Cilia/metabolism/pathology/genetics ; Mutation/genetics ; Female ; Male ; Middle Aged ; Motor Neurons/metabolism ; Fibroblasts/metabolism ; Adult ; }, abstract = {BACKGROUND: Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear.<br><br>METHODS: We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand the disease contribution of NEK1 variants in ALS, we performed a series of functional studies using patient fibroblasts focusing on primary cilia and microtubule-related phenotypes. In addition, these findings were validated in iPSC-derived motor neurons (iPSC-MNs).<br><br>RESULTS: NIMA-related kinase 1 (NEK1), a gene encoding a serine/threonine kinase involved in cell cycle regulation, has been identified as a risk gene for amyotrophic lateral sclerosis (ALS). Here, we report that mutations in NEK1 cause primary ciliary abnormality, cell cycle re-entry, and disrupted tubulin acetylation in ALS. We analyzed the whole-exome sequences of 920 Korean patients with sporadic ALS and identified 16 NEK1 variants in 23 patients. We found that two novel variants, p.E853Rfs*9 and p.M1?, reduced NEK1 expression, resulting in loss-of-function (LOF) and one synonymous splicing variant (p.Q132=) exhibited an aberrant isoform lacking exon 5. All three NEK1 variants exhibited abnormal primary ciliary structure, impaired sonic hedgehog signaling, and altered cell-cycle progression. Furthermore, the ALS-linked variants induced intracellular calcium overload followed by Aurora kinase A (AurA)-histone deacetylase (HDAC)6 activation, resulting in ciliary disassembly. These defects were restored by treatment with the intracellular Ca[2+] chelator, BAPTA. We also found that NEK1 variants cause decreased &#x3b1;-tubulin acetylation, mitochondrial alteration, and impaired DNA damage response (DDR). Notably, drug treatment to inhibit HDAC6 restored the NEK1-dependent deficits in patient fibroblasts. And, we confirmed that data found in patient fibroblasts were reproduced in iPSC-MNs model.<br><br>CONCLUSIONS: Our results suggest that NEK1 contributes to ALS pathogenesis through the LOF mechanism, and HDAC6 inhibition provides an attractive therapeutic strategy for NEK1 variants associated ALS treatment.}, }
@article {pmid40389567, year = {2025}, author = {Wu, WL and Gong, XX and Qin, ZH and Wang, Y}, title = {Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases-an update.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {40389567}, issn = {1745-7254}, abstract = {Glutamate excitotoxicity is intricately linked to the pathogenesis of neurodegenerative diseases, exerting a profound influence on cognitive functions such as learning and memory in mammals. Glutamate, while crucial for these processes, can lead to neuronal damage and death when present in excessive amounts. Our previous review delved into the cascade of excitotoxic injury events and the underlying mechanisms of excitotoxicity. Building on that foundation, this update summarizes the latest research on the role of excitotoxicity in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as new cutting-edge techniques applied in the study of excitotoxicity. We also explore the mechanisms of action of various excitotoxicity inhibitors and their clinical development status. This comprehensive analysis aims to enhance our understanding of the nexus between excitotoxicity and neurodegenerative diseases, offering valuable insights for therapeutic strategies in these conditions.}, }
@article {pmid40389397, year = {2025}, author = {Schweingruber, C and Nijssen, J and Mechtersheimer, J and Reber, S and Lebœuf, M and O'Brien, NL and Mei, I and Hedges, E and Keuper, M and Benitez, JA and Radoi, V and Jastroch, M and Ruepp, MD and Hedlund, E}, title = {Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4633}, pmid = {40389397}, issn = {2041-1723}, support = {2020-01049//Vetenskapsr&#xe5;det (Swedish Research Council)/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism/genetics/pathology ; Humans ; Single-Cell Analysis ; Induced Pluripotent Stem Cells/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mutation ; Sequence Analysis, RNA ; Axons/metabolism ; C9orf72 Protein/genetics/metabolism ; Animals ; }, abstract = {Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.}, }
@article {pmid40328418, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Kaltchenko et al's "Dupilumab and neuropsychiatric outcomes in pediatric atopic dermatitis: A real-world cohort analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.02.101}, pmid = {40328418}, issn = {1097-6787}, }
@article {pmid40389223, year = {2025}, author = {Heimbuch, S and Tischler, L and Beyer, A and Jordan, Y and Pfeuffer, N and Krause, H and van den Berg, N}, title = {Telemedizin in der Pädiatrie - Akzeptanz und Zufriedenheit aus Elternperspektive.}, journal = {Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany))}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2543-3179}, pmid = {40389223}, issn = {1439-4421}, abstract = {The telemedical networking of children's clinics of varying sizes and specializations can support healthcare close to home, especially in rural regions with structural limitations. A Regional Tele-Paediatric Network was implemented in Mecklenburg-Western Pomerania and North Brandenburg (innovation fund project RTP-Net). This study examines the question of how participating parents accepted and evaluated this form of care.Parents of paediatric patients at a participating clinic were invited to take part in the study during the observation period 02.2021 to 03.2023 study. A mixed-methods approach was used that comprised a standardized questionnaire. The interviews were transcribed, categorized according to Kuckartz and subjected to descriptive evaluation. Between 12.2023 to 02.2024, telephone interviews were conducted with parents who had agreed to be recontacted.A total of 507 cases (403 patients) were included in the RTP-Net. Data from 138 questionnaires were analyzed. 74.5% of parents found that the use of telemedicine was helpful for the treatment of their child; 88.1% could imagine that telemedicine could supplement paediatric healthcare in the future. Parents interviewed over the telephone (n=11) rated telemedicine services positively. The main advantages mentioned were saving in time and distance, availability of specialist expertise and avoidance of long waiting times. There were concerns about the lack of physical contact between telemedicine doctor and patient.Parents show a high level of acceptance of telemedicine and trust in the provision of telemedical services. Telemedicine can help parents to avoid the burden of long journeys and waiting times and improve access to specialist medical expertise. In order to improve the acceptance and satisfaction of parents, it is important to inform them about the results if the telemedical advice was based on a doctor-to-doctor consultation.Die telemedizinische Vernetzung von Kinder-Kliniken unterschiedlicher Größen und Spezialisierungen kann insbesondere in ländlichen Regionen mit strukturellen Einschränkungen eine wohnortnahe Versorgung unterstützen. In Mecklenburg-Vorpommern und Nord-Brandenburg wurde ein Regionales Telepädiatrisches Netzwerk (Innovationsfondsprojekt RTP-Net) implementiert. In dieser Publikation wird der Frage nachgegangen, wie teilnehmende Eltern diese Versorgungsform akzeptierten und bewerteten.Der Mixed-Methods-Ansatz umfasste einen deskriptiv ausgewerteten standardisierten Fragebogen für Eltern, die ihr Kind im Beobachtungszeitraum 02.2021 bis 03.2023 in einer teilnehmenden Klinik vorstellten und an der Studie teilnahmen. Zwischen 12.2023 und 02.2024 wurden telefonische Interviews mit Eltern geführt, die einer Wiederkontaktierung zugestimmt hatten. Die Interviews wurden transkribiert und inhaltlich strukturierend nach Kuckartz kategorisiert und ausgewertet.Es wurden 507 Fälle (403 Patienten) in das RTP-Net eingeschlossen. Daten aus 138 Elternfragebögen wurden analysiert. 74,5% der befragten Eltern fanden, dass die Nutzung der Telemedizin hilfreich für die Behandlung ihres Kindes war. 88,1% von ihnen können sich vorstellen, dass Telemedizin die pädiatrische Versorgung zukünftig ergänzt. Es wurden elf Telefoninterviews geführt. Diese Eltern schätzten telemedizinische Angebote positiv ein. Als Vorteile galten v. a. die Weg- und Zeitersparnis, die Verfügbarkeit spezialfachärztlicher Expertise und die Vermeidung langer Wartezeiten. Bedenken bestanden in Bezug auf den fehlenden physischen Kontakt zwischen Telemedizinarzt und Patient. Um die Akzeptanz und Zufriedenheit der Eltern zu verbessern, ist es wichtig, diese über das Resultat zu informieren, wenn die telemedizinische Maßnahme als Arzt-zu-Arzt-Konsultation erfolgte.Auf Seiten der Eltern ist eine hohe Akzeptanz telemedizinischer Angebote und Vertrauen in die telemedizinische Leistungserbringung gegeben. Durch Telemedizin können Belastungen der Eltern durch lange Anfahrtswege und Wartezeiten vermieden werden und der Zugang zu spezialfachärztlicher Expertise verbessert werden.}, }
@article {pmid40389171, year = {2025}, author = {Das, D and Das, A and Bhattacharya, K and Koch, KP and Deuri, DJ and Saikia, D and Chanu, NR and Deka, S}, title = {Xanthones as Neuroprotective Agents: A Comprehensive Review of Their Role in the Prevention and Treatment of Neurodegenerative Diseases.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {102772}, doi = {10.1016/j.arr.2025.102772}, pmid = {40389171}, issn = {1872-9649}, abstract = {Over the recent years, numerous research efforts have been focused toward xanthones, a class of heterocyclic compounds characterized by a three-ring core structure and a diverse range of biological activities. Despite extensive studies, no xanthone-based molecule has successfully progressed through clinical trials to reach pharmaceutical applications. Xanthones belong to the class of secondary metabolites that exist naturally, found in various plant species, and their structural diversity has been further expanded through synthetic modifications to enhance their pharmacological efficacy. This review provides a comprehensive description of the therapeutic potential of xanthone derivatives within the scope of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuroinflammation. Existing literature has been rigorously examined to highlight the pharmacological relevance of xanthones in these disorders. Additionally, the pathophysiological aspects of each disease are discussed in detail to establish a mechanistic understanding of how xanthone derivatives may exert neuroprotective effects. Furthermore, the SAR of xanthones is explored to elucidate key molecular features responsible for their bioactivity, providing insights into rational drug design. By synthesizing and critically analyzing the existing research, this review is focused in highlighting the therapeutic relevance of xanthones in neurodegenerative diseases and their potential as lead candidates for further drug development.}, }
@article {pmid40389143, year = {2025}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Wang, S and Wang, J and Feng, H}, title = {COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis.}, journal = {Brain research}, volume = {}, number = {}, pages = {149707}, doi = {10.1016/j.brainres.2025.149707}, pmid = {40389143}, issn = {1872-6240}, abstract = {Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.}, }
@article {pmid40389086, year = {2025}, author = {Pu, K and Yang, S and Sheng, R and Chen, J and Dai, Y and Wood, IC and Zhong, Z and Xu, S}, title = {Chuanxiong-Danggui herb pair alleviated cognitive deficits of APP/PS1 mice by promoting mitophagy.}, journal = {Journal of ethnopharmacology}, volume = {}, number = {}, pages = {119988}, doi = {10.1016/j.jep.2025.119988}, pmid = {40389086}, issn = {1872-7573}, abstract = {Disruption of receptor-mediated mitophagy contributes to neuronal damage in Alzheimer's disease (AD). Chuanxiong-Danggui herb pair (CDHP) is classic herbal pair applied to treating neurodegenerative diseases including AD, Amyotrophic Lateral Sclerosis, Parkinson's disease. Though studies have demonstrated the neuroprotective effects of CDHP, the underlying mechanisms by which CDHP attenuates neuronal impairment of AD remains to be elucidated.<br><br>AIM OF THE STUDY: The objective of this work was to investigate the anti-AD mechanism of CDHP in APP/PS1 mice.<br><br>MATERIALS AND METHODS: Behavioral assessments were conducted on C57BL/6J and APP/PS1 mice following CDHP treatment, alongside an evaluation of neuronal morphology in the hippocampal region. In vitro, HT-22 cells were induced by A&#x3b2;25-35 before being treated with CDHP. The mechanisms of CDHP were investigated using transmission electron microscopy, Golgi staining, immunofluorescence, siRNA, and Western blot analysis.<br><br>RESULTS: Results from the passive avoidance test and the Morris water maze (MWM) indicated that CDHP significantly mitigated cognitive deficits of APP/PS1 mice, accompanied by a reduction of pathological damage in the CA1 and CA3 regions of hippocampus. Further testing found that a significant reduction in dendritic spines density was rescued by CDHP. Synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) were elevated in the CDHP group, while A&#x3b2; (&#x3b2;-amyloid) plaques deposition was significantly reduced. Simultaneously, CDHP markedly inhibited neuronal apoptosis through a decrease of the levels of Cleaved Caspase-12 and enhanced expression of Bcl-2/Bax, both in vivo and in vitro. Additionally, CDHP improved mitochondrial morphology and function in the AD model by decreasing abnormal mitochondria and increasing the expression of COXIV. Transmission electron microscopy (TEM) revealed that clear mitophagy-autophagosomes were nearly absent in APP/PS1 mice, while the expression of p62 and LC3B were elevated following CDHP treatment. Furthermore, CDHP increased the expression of the FUNDC1 and PGAM5 in APP/PS1 mice and AD-like cell models.<br><br>CONCLUSION: These findings suggest that CDHP mitigated cognitive dysfunction in APP/PS1 mice by enhancing mitophagy to reduce neuronal injury.}, }
@article {pmid40388677, year = {2025}, author = {de Vries, BS and de Boer, EMJ and Brugman, F and Van Damme, P and Veldink, JH and van Es, MA and van den Berg, LH}, title = {Primary Lateral Sclerosis: Implications for Diagnostic Criteria From a Natural History Study in the Netherlands.}, journal = {Neurology}, volume = {104}, number = {11}, pages = {e213461}, doi = {10.1212/WNL.0000000000213461}, pmid = {40388677}, issn = {1526-632X}, mesh = {Humans ; Female ; Middle Aged ; Male ; *Motor Neuron Disease/diagnosis/epidemiology/physiopathology ; Aged ; Netherlands/epidemiology ; Disease Progression ; Amyotrophic Lateral Sclerosis/diagnosis ; Follow-Up Studies ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is a rare disease characterized by upper motor neuron (UMN) degeneration. We aimed to elucidate the natural history in patients with UMN syndromes suggestive of PLS and validate the most recent diagnostic (consensus) criteria.<br><br>METHODS: A validation study of a long-term follow-up cohort was conducted, including adults with UMN syndromes and disease durations &#x2265;6 months. Patients were assessed at baseline (T1), at 3 years (T2), and when possible after 13 years (T3). Diagnostic categorization followed the 2020 PLS consensus criteria. Main outcomes included diagnostic classification at follow-up and survival.<br><br>RESULTS: The study comprised 86 patients (34 women [40%], mean age 58.9 &#xb1; 10.1 years), of whom 43 met the PLS consensus criteria at baseline (6 probable, 37 definite). Eight patients had a disease duration <2 years, and 35 patients presented with UMN symptoms localized to 1 region (1 bulbar, 34 legs). Change of initial diagnosis occurred in 14% of patients with PLS, and 49% of patients presenting with UMN symptoms in 1 region progressed to PLS. Seven patients developed amyotrophic lateral sclerosis (ALS), and for 7 patients, diagnosis was revised to hereditary spastic paraplegia (HSP). Survival was shorter for patients with a disease duration <4 years. In the probable PLS group, 33% converted to ALS. Converters had a steeper Amyotrophic Lateral Sclerosis Functional Rating Scale slope (p = 0.023) and shorter symptom duration (p < 0.001) at inclusion. Of patients presenting with leg symptoms, diagnosis was revised between T2 and T3 in 29%. Introducing a 4-year minimal disease duration for PLS diagnosis and categorization based on regions involved resulted in 86% of PLS diagnoses remaining within the PLS category, 5% transitioning to ALS (slow variant), and 9% to HSP. Survival was longest for patients presenting with symptoms confined to arms and legs or legs only, followed by those with bulbar involvement at baseline, while patients with disease durations between 6 months and 4 years exhibited the shortest survival.<br><br>DISCUSSION: Our findings suggest that a diagnosis of PLS should be deferred until 4 years after symptom onset because shorter durations correlate with higher ALS conversion rates and shorter survival. Categorization by regional involvement may facilitate more effective monitoring of patients with UMN syndromes.}, }
@article {pmid40388191, year = {2025}, author = {De Marchi, F and Lombardi, I and Bombaci, A and Diamanti, L and Olivero, M and Perciballi, E and Tornabene, D and Vulcano, E and Ferrari, D and Mazzini, L}, title = {Recent therapeutic advances in the treatment and management of amyotrophic lateral sclerosis: the era of regenerative medicine.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1080/14737175.2025.2508781}, pmid = {40388191}, issn = {1744-8360}, abstract = {INTRODUCTION: Despite decades of research, effective disease-modifying treatments for Amyotrophic Lateral Sclerosis (ALS) remain scarce, with riluzole and edaravone offering only limited benefits. The emergence of regenerative medicine, including stem cell therapy, gene-based interventions, and bioengineering strategies, presents a new frontier for ALS treatment.<br><br>AREAS COVERED: This review is based on a comprehensive literature search using PubMed, Scopus and clinical trials databases on the recent therapeutic advancements in ALS, giving particular focus to regenerative medicine. The article includes coverage of stem cell-based therapies, including mesenchymal stem cells, neural stem cells, and induced pluripotent stem cells; all of which may offer potential neuroprotective and immunomodulatory effects. Gene therapy, particularly antisense oligonucleotides targeting ALS-related mutations, has gained traction, with tofersen becoming the first FDA-approved genetic therapy for ALS. The article also covers emerging approaches such as extracellular vesicles, immune-modulating therapies, and bioengineering techniques, including CRISPR-based gene editing and cellular reprogramming, that hold promise for altering disease progression.<br><br>EXPERT OPINION: While regenerative medicine provides hope for ALS patients, significant challenges remain. Biomarkers will play a crucial role in guiding personalized treatment strategies, ensuring targeted and effective interventions. Future research should prioritize optimizing combinatory approaches, integrating different therapy strategies to maximize patient outcomes. Although regenerative medicine is still in its early clinical stages, its integration into ALS treatment paradigms could redefine disease management and potentially alter its natural course.}, }
@article {pmid40386966, year = {2025}, author = {Honig, A and Dayan, R and Knaani, A and Levine, H and Gotkine, M}, title = {Military Service Roles and ALS Among Veterans: A Matched Case-Control Study.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70079}, pmid = {40386966}, issn = {2328-9503}, abstract = {While military service is an established risk factor for amyotrophic lateral sclerosis (ALS), it remains unclear whether this association is linked to combat. We conducted a matched case-control study comparing 191 ALS patients who were veterans of the Israeli Defense Forces (IDF) with known military service type and 1910 matched controls. The ALS group had higher rates of combat service (46.0% vs. 22.7%) and parachuting (10.5% vs. 1.1%) in comparison with controls (p < 0.001 for both). In a multivariate model, combat service was associated with ALS (odds ratio 2.49, confidence interval [1.49-4.16], p < 0.01). The higher prevalence of combat roles among ALS patients expands our understanding of military service factors that contribute to ALS risk.}, }
@article {pmid40385899, year = {2025}, author = {Panganiban, ELC and Rosales, RL}, title = {Multiple System Atrophy (Cerebellar Type) With Overlapping Progressive Muscular Atrophy Features and Genetic Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) Amyotrophic Lateral Sclerosis Variant: A Case Report.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82509}, pmid = {40385899}, issn = {2168-8184}, abstract = {Multiple system atrophy (MSA) is a progressive disease with Parkinsonism, dysautonomia, and cerebellar symptoms wherein patients can present with a broad range of confusing and overlapping findings attributable to various neuroanatomical substrates. Although possible, weakness is an unusual primary complaint, warranting further work-up for another neurodegenerative disease. The involvement of the more central structures, such as the locus coeruleus, pontine micturition center, and the cerebellum, can explain the wide range of symptoms. While Onuf's nucleus contributes to the urinary symptoms, anterior horn cells can implicate a motor neuron disease. Taking the varied neuroanatomical substrates into consideration, patients can present with a plethora of dysregulated motor symptoms. The authors share the course of a patient with clinically established MSA-cerebellar type and lower motor neuron disease findings at par with progressive muscular atrophy (PMA), but tested positive for an ERBB4 gene mutation, which is linked to an amyotrophic lateral sclerosis (ALS) variant. A 65-year-old Chinese female manifested with bilateral leg weakness and urinary incontinence. Over the next five years, she developed recurrent pre-syncopal attacks, asymmetric limb tremors, memory lapses, laughing fits, and a staccato-like voice. Medical management with anti-Parkinsonism drugs did not help her condition. Repeated annual non-contrast enhanced cranial magnetic resonance imaging (MRI) revealed gradual cerebellar atrophy, and an eventual prominent "hot-cross bun" sign. Because of episodes of orthostatic hypotension, with a systolic blood pressure as low as 50 mmHg, she gradually became bedridden with progressive arm weakness and sleep issues. These prompted her admission. Saccadic dysmetria and ataxic dysarthria aided in the diagnosis of MSA-cerebellar type, while motor neuron disease findings included tongue fasciculation, asymmetric leg atrophy, and polyminimyoclonus, suggestive of PMA. Neurophysiological studies confirmed this, while whole genome sequencing yielded an ERBB4 gene ALS variant of uncertain significance. She remained compliant with physical therapy during her admission. Although she was prescribed fludrocortisone for symptomatic relief and a two-week course of edaravone, she was discharged with minimal improvement and wheelchair-bound. However, the patient eventually expired two years afterward due to systemic complications. Although suspicion for a certain movement disorder can be initially made with physical examination, diagnostics can shed further light on the patient's pathology, exemplifying the uniqueness of this case report and how varying neurodegenerative movement disorders can coexist in a single patient.}, }
@article {pmid40385805, year = {2025}, author = {Moutinho, A and Fontes, J and Ferreira, L and Lopes, J and Martins, F and Mega, S and Gil, M and Barros, F and Correia, AM}, title = {Sepsis Alerts in the Pre-hospital Setting: An Observational Retrospective Study of Emergency Medical Services' Response in Portugal (2020-2023).}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82528}, pmid = {40385805}, issn = {2168-8184}, abstract = {Background Sepsis is a life-threatening condition that demands prompt recognition and intervention to enhance patient outcomes. Early identification and timely treatment, particularly in the prehospital setting, are essential. Objective This study aims to characterize sepsis pre-alerts issued by the Portuguese Emergency Medical Services (EMS) early warning system between May 2020 and December 2023, focusing on adult patients. It provides an overview of the alert system and examines associated clinical data, therapeutic interventions, and hospital referrals. Methods A retrospective analysis was conducted on sepsis pre-alerts from the Portuguese EMS database. Data collected included patient demographics, comorbidities, National Early Warning Score (NEWS), interventions administered, and outcomes. Results A total of 537 sepsis alerts were identified, with a median patient age of 83 years. The majority of patients had significant cardiovascular and neurological comorbidities. The average NEWS was 11.74. Advanced Life Support (ALS) or Integrated Life Support (ILS) teams were required in 76.9% (N=413) of cases. Interventions included intravenous fluid administration in 49.3% (N=265), oxygen therapy in 46.2% (N=248), and vasopressor use in 3.9% (N=14). Conclusions Effective prehospital sepsis management is crucial for improving patient outcomes. Challenges such as delayed hospital transfers, often due to regional constraints, highlight the need for enhanced integration between EMS and hospital care. Future efforts should focus on optimizing early sepsis management, fostering collaboration between EMS and hospital teams, and exploring the feasibility of prehospital antibiotic administration.}, }
@article {pmid40385376, year = {2025}, author = {Chamoun, S and Imrell, S and Upate, Z and Kläppe, U and Öijerstedt, L and Yazdani, S and Andersson Franko, M and Foucher, J and Azizi, L and Lovik, A and Samuelsson, K and Press, R and Fang, F and Svennberg, E and Juto, A and Ingre, C}, title = {Plasma troponin T reflects lower motor neuron involvement on electromyography in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {3}, pages = {fcaf177}, pmid = {40385376}, issn = {2632-1297}, abstract = {Cardiac troponin T (cTnT) is elevated in neuromuscular conditions without apparent cardiac disease, including Amyotrophic Lateral Sclerosis (ALS). The reason for this increase is unclear. Since cTnT is found in both cardiomyocytes and skeletal muscle cells, we aimed to investigate the latter as a possible cTnT source. We examined the correlation of cTnT in venous blood to lower motor neuron (LMN) involvement on Electromyography (EMG). A positive correlation between EMG findings and cTnT levels would indicate that cTnT is a biomarker for LMN involvement in ALS. This observational cohort study was conducted on a tertiary referral centre for neuromuscular diseases in Stockholm, Sweden. Consecutive patients with ALS were included. EMG was performed during diagnostic work-up, and high-sensitive cardiac troponin T (hs-cTnT), plasma creatine kinase (CK), and serum neurofilament light (NfL) were analysed within 6 months of the EMG. King's stage and score on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) closest to hs-cTnT sampling were noted. In total, 50 ALS patients diagnosed between 1 January 2014 and 31 December 2018 were included and followed until death, invasive ventilation, or the 14 August 2024. Hs-cTnT correlated positively with the number of muscular regions involved (τ = 0.283, P = 0.009) and percentage of muscles involved on EMG (ρ = 0.367, P = 0.009). Hs-cTnT was associated with the percentage of muscles involved in EMG in the adjusted linear regression. Patients with higher hs-cTnT had more advanced King's stage, both when numerical hs-cTnT and subgrouping high (≥15 nanogram/L) versus normal hs-cTnT was used (τ = 0.253, P = 0.021 and U = 197.5, P = 0.022, respectively). Hs-cTnT was neither correlated to ALSFRS-R total score (ρ = -0.176, P = 0.220 and U = 249.5, P = 0.233, respectively) nor ALSFRS-R excluding respiratory domain score (ρ = -0.069, P = 0.632 and U = 280.5, P = 0.558, respectively). High versus normal hs-cTnT did not predict survival (univariate analysis, HR = 1.824, P = 0.060). Numerical hs-cTnT was associated with shorter survival (univariate analysis, HR = 1.635, P = 0.017) but not after adjusting for age at diagnosis (HR = 1.413, P = 0.105). This study illustrates that ALS patients with higher hs-cTnT have more spread disease as evidenced by the positive correlation between hs-cTnT and both EMG and King's stage. This is not true for established biomarkers of muscle damage (CK) and neuroaxonal damage (NfL). These findings need to be confirmed in larger studies but suggest that hs-cTnT is a biomarker of LMN involvement in patients with ALS and could be used in clinical trials.}, }
@article {pmid40384653, year = {2025}, author = {Bai, C and Leng, Y and Xiao, H and Li, L and Cui, W and Li, T and Dong, Y and Zheng, J and Cai, X}, title = {A deep-learning model for predicting post-stroke cognitive impairment based on brain network damage.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {5}, pages = {3964-3981}, pmid = {40384653}, issn = {2223-4292}, abstract = {BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common and severe complication following acute lacunar stroke (ALS). Due to the limitations of current assessment tools and imaging methods, the early diagnosis of PSCI within 3 months of ALS remaining challenging. This study aimed to develop an effective, reliable, and accurate deep-learning method to predict PSCI within 3 months of ALS.<br><br>METHODS: In total, 100 ALS patients were enrolled in the study, of whom 39 were diagnosed with PSCI and 61 were non-PSCI. First, we quantified three-dimensional (3D) gray-matter damage and white-matter tract disconnection, providing both regional damage (RD) and structural disconnection (SDC) higher-dimensional insights into brain network disruption. Second, we developed a novel deep-learning model based on ResNet18, integrating 3D RD, SDC, and diffusion-weighted imaging (DWI) to provide a comprehensive analysis of brain network integrity and predict PSCI. Finally, we compared the performance of our method with other methods, and visualized brain network damage associated with PSCI.<br><br>RESULTS: Our model showed strong predictive performance and had a mean accuracy (ACC) of 0.820&#xb1;0.024, an area under the curve (AUC) of 0.795&#xb1;0.068, a sensitivity (SEN) of 0.746&#xb1;0.121, a specificity (SPE) of 0.869&#xb1;0.044, and a F1-score (F1) of 0.760&#xb1;0.050 in the five-fold cross-validation, outperforming existing models. In the PSCI patients, brain network damage significantly affected the salience, default mode, and somatic motor networks.<br><br>CONCLUSIONS: This study not only established a model that can accurately predict PSCI, it also identified potential targets for symptom-based treatments, offering new insights into PSCI.}, }
@article {pmid40384575, year = {2025}, author = {Vogt, C and Weber, M and Schneider, U and Neuwirth, C}, title = {Quinine Sulfate for Muscle Cramps in Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind Crossover Trial.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28440}, pmid = {40384575}, issn = {1097-4598}, support = {//Swiss ALS foundation/ ; //H&#xe4;nseler AG/ ; }, abstract = {INTRODUCTION/AIMS: Many patients with amyotrophic lateral sclerosis (ALS) experience muscle cramps during the course of the disease. This study aimed to evaluate the efficacy of orally administered quinine sulfate for muscle cramps in ALS patients.<br><br>METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial in ALS patients experiencing daily muscle cramps. After a two-week run-in period, patients were assigned to receive 250&#x2009;mg quinine sulfate once daily, followed by a placebo or vice versa. Each treatment period lasted 2&#x2009;weeks and was followed by a 4-week washout period. Patients used a daily diary to rate muscle cramp intensity on the numeric rating scale (NRS) and record muscle cramp frequency. The primary outcome measure was change in cramp intensity; coprimary outcome measures were number of muscle cramps during daytime and nighttime.<br><br>RESULTS: Data from four women and three men were included in the analysis, all of whom reported a notable reduction in cramp intensity and frequency, leading them to continue the medication. Quinine sulfate was well-tolerated, with two patients reporting mild tinnitus. Cramp intensity was significantly reduced by 48% (p&#x2009;=&#x2009;0.042). Further, the number of daytime muscle cramps declined significantly (p&#x2009;=&#x2009;0.024).<br><br>DISCUSSION: Our findings suggest the potential efficacy of quinine sulfate in reducing muscle cramp intensity and frequency in ALS patients. However, the small sample size (n&#x2009;=&#x2009;7) limits generalizability. Larger, multicenter studies are needed to confirm these results and fully assess its safety, serious adverse events, and therapeutic potential.}, }
@article {pmid40384352, year = {2025}, author = {Yuan, Y and Fu, Y and Wang, X and Hu, F and Zhao, Q and He, C and Tang, L and Li, Y and Bu, Y and Song, X and Liu, Q and Liu, Z and Xu, R and Cao, W and Zhang, Y and Yi, X and Wang, J and Chen, BT}, title = {Shape Alterations of Subcortical Nuclei Correlate With Amyotrophic Lateral Sclerosis Progression.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70495}, doi = {10.1002/brb3.70495}, pmid = {40384352}, issn = {2162-3279}, support = {81300981//National Natural Science Foundation of China/ ; 81671120//National Natural Science Foundation of China/ ; 82171431//National Natural Science Foundation of China/ ; U22A20377//National Natural Science Foundation of China/ ; 2021ZD0201803//Science and Technology Innovation 2030/ ; 2020LNJJ13;2022LNJJ09//Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya hospital)/ ; 2022JJ30979//Natural Science Foundation of Hunan Province/ ; 2021YFA0805202//National Key Research and Development Program of China/ ; 2022M713536//China Post-Doctoral Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; Male ; Female ; Disease Progression ; Middle Aged ; Magnetic Resonance Imaging/methods ; Aged ; Brain Stem/pathology/diagnostic imaging ; Neuroimaging/methods ; Basal Ganglia/pathology/diagnostic imaging ; Adult ; Thalamus/pathology/diagnostic imaging ; Brain/pathology/diagnostic imaging ; Prospective Studies ; }, abstract = {BACKGROUND: Neuroimaging has been increasingly used to assess brain structural alterations in patients with amyotrophic lateral sclerosis (ALS). We aimed to investigate alterations in brain sub-cortical structures and to identify potential neuroimaging biomarkers for disease progression for patients with ALS.<br><br>METHODS: A total of 61 patients with ALS were prospectively enrolled and were divided into three subgroups according to disease progression, i.e., fast, intermediate, and slow progression. Sixty-one matched healthy controls (HCs) were also recruited. All participants acquired a brain structural magnetic resonance imaging scan for subcortical volumetric and shape analyses. Neuropsychological testing and functional assessment were performed.<br><br>RESULTS: Patients with fast progression showed significant shape alterations in basal ganglia and brainstem as compared to the HCs group. In ALS patients with fast progression, shape contractions with atrophic changes were noted in bilateral nucleus accumbens, left caudate, left thalamus, and brainstem; while shape expansion with hypertrophy was noted in the left caudate, left thalamus, and left pallidum (all p < 0.05). There were significant positive correlations of the shape changes of the left thalamus with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALS-FRS-R) total and limb scores and with disease duration (all p < 0.05). There were positive correlations of left pallidum with anxiety or with disease duration, and of left nucleus accumbens with ALS-FRS-R total or bulbar score, and of brainstem with mini-mental state examination score (all p < 0.05).<br><br>CONCLUSION: Extensive shape alterations of subcortical nuclei were noted in patients with fast progression of ALS, implicating subcortical shape being a potential neuroimaging biomarker for ALS progression.}, }
@article {pmid40384011, year = {2025}, author = {Changqing, L and Leying, Y and Caiyun, M and Hebao, W and Laiguo, H and Xiaojiang, Z}, title = {Causal Relationships Between the Gut Microbiota, Inflammatory Cytokines, and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70571}, doi = {10.1002/brb3.70571}, pmid = {40384011}, issn = {2162-3279}, support = {//Philosophy and Social Sciences Foundation of the Anhui Higher Education Institutions of China/ ; //Provincial Quality Engineering Project of Higher Education Institutions of Anhui Province/ ; //Natural Science Foundation of the Higher Education Institutions of Anhui Province/ ; 202310367042//National College Students Innovation and Entrepreneurship Training Program/ ; //innovation and entrepreneurship training program for college students/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/microbiology ; Humans ; Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics/physiology ; *Cytokines/metabolism/genetics ; Genome-Wide Association Study ; Inflammation ; }, abstract = {BACKGROUND: The relationship between gut microbiota (GM) and amyotrophic lateral sclerosis (ALS) is well-documented. However, the causal nature of this association and the potential mediating role of inflammatory cytokines (ICs) have yet to be elucidated.<br><br>METHODS: We performed Mendelian randomization (MR) analyses utilizing data derived from genome-wide association studies (GWAS) of GM, ICs, and ALS. Initially, we conducted bidirectional two-sample MR analysis to determine the causal relationships between GM, ICs, and ALS. Subsequently, a two-step MR mediation analysis was performed to investigate the role of ICs as mediators. The primary statistical approach was the inverse variance weighted (IVW) method.<br><br>RESULTS: Through MR analysis, we identified one positive causal relationship and three negative causal relationships between GM and ALS. There was one positive association and one negative association between ICs and ALS. In addition, ICs do not appear to mediate the pathway from GM to ALS.<br><br>CONCLUSION: This study established a causal relationship between GM, ICs, and ALS, suggesting that ICs do not function as mediators in the pathway from GM to ALS. These findings provide new perspectives on potential ALS prevention and treatment strategies.}, }
@article {pmid40383997, year = {2025}, author = {Foucher, J and Wellander, T and Lovik, A and Öijerstedt, L and Juto, A and Fang, F and Ingre, C}, title = {Venous Bicarbonate as a Prognostic Biomarker and Proposed Proxy for Vital Capacity to Be Used as an Eligibility Criterion in Amyotrophic Lateral Sclerosis Clinical Trials.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70570}, doi = {10.1002/brb3.70570}, pmid = {40383997}, issn = {2162-3279}, support = {//Ulla-Carin Lindquists stiftelse f&#xf6;r ALS-forskning/ ; //Neuro Sweden/ ; /CC/CDC HHS/United States ; //R01TS000324-02-01/ ; //Demensf&#xf6;rbundet/ ; //Svenska Frimurarorden/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/physiopathology/diagnosis/mortality ; Male ; Female ; Middle Aged ; Biomarkers/blood ; Prognosis ; *Bicarbonates/blood ; Aged ; Vital Capacity/physiology ; Sweden ; Registries ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: Clinical trials for people living with ALS (pALS) all list vital capacity (VC) as an important eligibility criterion. However, VC measures are challenging to perform among pALS, especially bulbar pALS. Additionally, since the disease rapidly changes, the VC can change in a short duration of time, making it unreliable.<br><br>OBJECTIVE: We aimed to investigate the association of venous bicarbonate with VC as an alternative criterion for trial eligibility. We also wanted to examine whether venous bicarbonate could be used as a prognostic biomarker for survival in ALS.<br><br>METHODS: We included pALS from the Swedish ALS/MND Registry between January 1, 2019 and July 31, 2022. pALS had to have serum bicarbonate values and ALSFRS-R available close to diagnosis. Spearman correlations, Kaplan-Meier curves, and Cox proportional hazard regressions were used to assess the associations of venous bicarbonate with VC, other clinical characteristics, and survival.<br><br>RESULTS: Among the 117 pALS included in the study, we observed a negative correlation between venous bicarbonate and VC among spinal and bulbar pALS (&#x3c1; = -0.346, p = 0.002 and &#x3c1; = -0.367, p = 0.024, respectively). Venous bicarbonate negatively correlated with ALSFRS-R (&#x3c1; = -0.377, p < 0.001), specifically among bulbar pALS (&#x3c1; = -0.595, p < 0.001), but positively correlated with KING's stage (&#x3c1; = 0.248, p = 0.007). High level of venous bicarbonate appeared to be associated with shorter survival.<br><br>CONCLUSIONS: Venous bicarbonate appears to be a prognostic biomarker for survival among pALS. This cheap and easily accessible measure could potentially be an alternative for VC as an eligibility criterion in ALS trials.}, }
@article {pmid40383620, year = {2025}, author = {Ibáñez-Cervantes, JL and Vargas-de León, C and Veléz-Reséndiz, JM and Fernández-Sánchez, V and Saavedra-Bravo, R and Bandala, C and Olvera-Gómez, I and Mancilla-Ramírez, J and Ibáñez-Cervantes, G}, title = {Association of ALS genes in strains of the genus Candida with cervical cytological alterations.}, journal = {Indian journal of medical microbiology}, volume = {54}, number = {}, pages = {100795}, doi = {10.1016/j.ijmmb.2025.100795}, pmid = {40383620}, issn = {1998-3646}, mesh = {Humans ; Female ; Adult ; Mexico ; *Candidiasis, Vulvovaginal/microbiology/pathology ; Middle Aged ; *Candida/genetics/isolation &amp; purification/classification/enzymology ; *Cervix Uteri/pathology/microbiology ; Young Adult ; *Fungal Proteins/genetics ; Polymerase Chain Reaction ; Candida albicans/genetics/isolation &amp; purification ; Aged ; }, abstract = {PURPOSE: Fungi are an important cause of human infection and include infections caused by Candida species. Vaginal candidiasis is a mycosis caused by several species of the genus Candida. In Mexico, it is considered the only mycosis that must be reported to health authorities. The participation and/or contribution of Candida ALS genes to the presence of cervical cytological alterations is currently unknown. The purpose of this study was to elucidate the frequency of Candida ALS genes and their association with clinical characteristics.<br><br>METHODS: The number of randomly selected samples was 697, of which 53 were Candida positive. Samples were selected from women attending gynaecological outpatient clinics for cervical cancer screening at Hospital Juarez de Mexico. These strains were identified, and genomic DNA was obtained from each isolate. Molecular assays were performed by endpoint PCR amplification of ALS genes.<br><br>RESULTS: The predominant Candida species identified in the study were Candida tropicalis and Candida albicans. ALS1 12 (22.6&#xa0;%) and ALS3 19 (35.8&#xa0;%) genes were found. ALS2, ALS4, ALS5, ALS6, ALS7, and ALS9 genes were not detected. ALS1 was the gene that was associated with patients using corticosteroids.<br><br>CONCLUSIONS: Vulvovaginitis remains one of the most prevalent conditions in patients in their 20s and 30s, and it is a real public health problem. Further studies are needed to determine the direct involvement of the identified ALS genes in the pathogen's ability to adhere and how it causes transient change in vaginal cytology.}, }
@article {pmid40382904, year = {2025}, author = {Montemerlo, AE and Azcarate, SM and Camiña, JM and Messina, G}, title = {Development of a chemometrics-assisted electrochemical sensor applied to gallic acid quantification in food samples.}, journal = {Food chemistry}, volume = {487}, number = {}, pages = {144737}, doi = {10.1016/j.foodchem.2025.144737}, pmid = {40382904}, issn = {1873-7072}, abstract = {Gallic acid (GA) is an abundant natural phenolic compound found in foods such as tea, fruits, and beverages. Quantifying GA remains a key research area in analytical chemistry. Traditional methods, such as liquid chromatography, are time-consuming, highlighting the need for faster and more efficient techniques to quantify GA concentration. This study proposes an approach based on the MCR-ALS algorithm to model second-order voltammetric data obtained by varying the scan rate. Data preprocessing and subsequent mathematical modeling enabled the quantification of GA with a detection limit of 5.9 mg L[-1], below the stipulated concentrations for the analyte in various food matrices. Quantification was achieved even in the presence of unmodeled interferences, leveraging the second-order capabilities of multivariate calibration methods. This approach allows for accurate results to be obtained in a direct, fast, and reliable manner, representing a breakthrough in food industry quality control and opening new perspectives for food quality assessment.}, }
@article {pmid40381433, year = {2025}, author = {Begh, MZA and Zehravi, M and Bhuiyan, MAK and Molla, MR and Raman, K and Emran, TB and Ullah, MH and Ahmad, I and Osman, H and Khandaker, MU}, title = {Recent advances in stem cell approaches to neurodegeneration: A comprehensive review with mechanistic insight.}, journal = {Pathology, research and practice}, volume = {271}, number = {}, pages = {156013}, doi = {10.1016/j.prp.2025.156013}, pmid = {40381433}, issn = {1618-0631}, abstract = {The progressive nature of neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, presents substantial problems because current treatments are still obscure. Stem cell-based treatments are emerging as a viable solution to address the significant gaps in treating these severe diseases. This study provides a comprehensive analysis of the latest advancements in stem cell research, focusing on the treatment of NDs. Various types of stem cells, such as adult, induced pluripotent, and embryonic stem cells, and their potential applications in immunomodulation, neurotrophic factor release, and neuronal development are also discussed. Recent clinical studies reveal outcomes, challenges, and solutions, with advancements in disease-specific neural cell production, gene editing, and improved stem cell transplantation transport strategies. The review discussed future perspectives on developing more effective stem cell-based interventions. Biomaterials are being used for cell distribution and personalized medicine techniques to improve treatment outcomes, while exploring stem cell treatments for NDs and identifying areas for further research.}, }
@article {pmid40381165, year = {2025}, author = {Esperante, I and Banzan, C and Munuera, JZ and Lima, A and Hunt, H and De Kloet, ER and Deniselle, MCG and De Nicola, AF and Meyer, M}, title = {The Selective Glucocorticoid Receptor Modulator Cort125329 Decreases Neuroinflammation and Gliosis and Enhances Myelination in the Wobbler Model of Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40381165}, issn = {1559-1182}, support = {PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PIP 2017PIP 2019 #11220170100002CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; PICT 2021 00389//Ministry of Science, Technology and Innovative Production of Argentina/ ; AFDN grant//CORCEPT Therapeutics/ ; AFDN grant//CORCEPT Therapeutics/ ; AFDN grant//CORCEPT Therapeutics/ ; AFDN grant//CORCEPT Therapeutics/ ; AFDN grant//CORCEPT Therapeutics/ ; AFDN grant//CORCEPT Therapeutics/ ; 20020170100224BA)//Universidad de Buenos Aires/ ; 20020170100224BA)//Universidad de Buenos Aires/ ; }, abstract = {The Wobbler mouse is a genetic model of familial amyotrophic lateral sclerosis. Wobblers show spinal cord neurodegeneration associated with gliosis, neuroinflammation, and demyelination. Like human neurodegenerative diseases, Wobblers show high levels of corticosterone in the blood and the nervous system. The role of glucocorticoids in neuropathology is suggested by the observation that pathological signs attenuate with treatment with glucocorticoid receptor (GR) antagonists/modulators. In the present study, we demonstrated in 5-month-old clinically afflicted Wobbler mice that the selective GR modulator CORT125329 decreased motoneuron degeneration, astro- and microgliosis, and levels of pro-inflammatory factors (HMGB1, toll-like receptor 4, tumor necrosis factor α, and its receptor). In addition, CORT125329 increased the acetylcholine-producing enzyme choline acetyltransferase, the neurotrophin brain-derived neurotrophic factor, and their cellular colocalization. Furthermore, the increased oligodendrocyte number and a healthier myelin ultrastructure are consistent with the enhanced axonal myelination after CORT125329 treatment. Finally, the high expression of immunoreactive protein and mRNA levels of aquaporin4 in Wobblers was decreased by CORT125329 treatment, implying this water channel is a glucocorticoid target involved in neuropathology. The beneficial effects of CORT125329 correlated with enhanced motor behavioral performance and trophic changes of the forelimbs. In conclusion, our results support further preclinical and clinical studies on GR modulators in sporadic amyotrophic lateral sclerosis.}, }
@article {pmid40379483, year = {2025}, author = {Lester, DG and Thompson, AG and Talbot, K and Turner, MR}, title = {Progression and life expectancy in primary lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2025-336037}, pmid = {40379483}, issn = {1468-330X}, abstract = {OBJECTIVES: To characterise the clinical characteristics and longitudinal outcomes in primary lateral sclerosis (PLS), including median survival from symptom onset and age at death.<br><br>METHODS: The authors retrospectively reviewed electronic health records of patients diagnosed with PLS referred to a specialised motor neuron disorders clinic from 2002 to 2024, analysed longitudinal Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) assessments using joint models and used Kaplan-Meier methods and life tables to calculate median survival and age at death compared with population-based values.<br><br>RESULTS: Of 52 patients, 34 (65%) were male, 41 (79%) first noted symptoms in the lower limbs and 10 (19%) in corticobulbar function. Median age of symptom onset was 53 years. The mean annual rate of functional decline was -1.92 ALSFRS-R points (95%&#x2009;CI -3.03 to -0.78), with equal highest rates of decline in fine and gross motor subscores. Five patients (10%) received gastrostomy and three (6%) non-invasive ventilation. Median survival from symptom onset was 23.1 years (22.7 to not reached), and median age at death was 79.5 years (77.8 to not reached) compared with a population-based reference mean of 81.9 years (81.1 to 82.8).<br><br>DISCUSSION: PLS may be commensurate with near-normal life expectancy. Significant disability arises from limb motor dysfunction, with a minority of patients requiring nutritional or respiratory support. This has important implications for counselling and trial design.}, }
@article {pmid40379219, year = {2025}, author = {Konopka, A and Jamali, MS and Fowler, M and Mehta, P and Parakh, S and Takalloo, Z and Farzana, F and Mumtaz, N and Hunter, J and Shadfar, S and Rogers, ML and Atkin, JD}, title = {Pathological forms of TDP-43 in amyotrophic lateral sclerosis (ALS) promote aberrant telomere elongation.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {}, number = {}, pages = {167906}, doi = {10.1016/j.bbadis.2025.167906}, pmid = {40379219}, issn = {1879-260X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. TAR DNA-binding protein 43 (TDP-43) mis-localisation from the nucleus to the cytoplasm is the major pathological characteristic of ALS. Telomeres are repetitive DNA sequences found in complex with proteins at chromosomal ends. The shelterin protein complex protects telomeres from DNA damage by producing characteristic t-loop structures, and telomere repeat binding factor 2 (TRF2) has an essential role in this process. Telomere dysregulation is reported in ALS, but conflicting findings have been obtained. Here we examined if telomere dysregulation is present in cortical neurons in a mouse model with pathological mis-localisation of TDP-43 to the cytoplasm - TDP-43 rNLS - compared to controls, and in cortical primary neurons expressing TDP-43 ALS associated mutations (A315T, A90V). We demonstrate that telomeres are significantly longer and of more variable in length in this model compared to controls. This was proceeded by downregulation of TRF2 in early disease stages with subsequent upregulation of TRF2 at advanced disease in TDP43 rNLS mice. A trend towards TRF2 upregulation was also present in human ALS. We detected dysregulation of catalytic subunit of telomerase, TERT and trend towards upregulation of telomere interacting protein, Rif 1 in these mice and human ALS spinal cord lysates. The longer telomeres were independent of the alternative lengthening of telomeres (ALT). Similarly, no DNA damage at telomere sites was detected. Our findings imply that telomere protection is compromised, leading to longer telomeres in cortical neurons in ALS associated with TDP-43 pathology.}, }
@article {pmid40378897, year = {2025}, author = {Fontanelli, L and Nisini, N and Pirola, S and Recchia, FA}, title = {Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing.}, journal = {Pharmacology &amp; therapeutics}, volume = {}, number = {}, pages = {108876}, doi = {10.1016/j.pharmthera.2025.108876}, pmid = {40378897}, issn = {1879-016X}, abstract = {The inherent technical difficulties, ethical/regulatory issues and costs of experimental studies in animal models is prompting investigators to replace as much as possible living organisms with in vitro physiological models named organoids and assembloids. Generated from induced pluripotent stem cells, these three-dimensional structures approximate the complexity of tissues and their interactions, enabling personalized disease modelling and drug testing. The integration of multiple components in assembloids further enhances their predictive value for multi-system interactions and toxicities. This review describes how neuromuscular organoids, incorporating functional neuromuscular junctions and contractile muscle tissue, have been used to replicate, in vitro, complex neuromuscular morpho-functional structures, offering very valuable platforms to study molecular mechanisms and drug effects in models of incurable diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. In the cardiological field, cardiac organoids and assembloids are proving reliable models for testing drug effects at molecular, morphological, electrophysiological and mechanical level. Recently, the integration of neuronal components into cardiac organoids has provided a potential approach to investigate autonomic function, a fundamental aspect of many neurological, neuromuscular and cardiac diseases. Challenges and limitations still remain, including the non-uniform differentiation protocols across studies, the incomplete maturation of cell phenotypes, and the lack of integrated pharmacokinetic modelling. We discussed some future developments aimed at overcoming such hurdles. Despite their current limitations, organoids and assembloids clearly hold great promises and will help advancing many fields of biomedicine.}, }
@article {pmid40378485, year = {2025}, author = {Keating, ME and Byrne, HJ}, title = {Seeding multivariate algorithms for spectral analysis, a data augmentation approach to enhance analytical performance.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {340}, number = {}, pages = {126369}, doi = {10.1016/j.saa.2025.126369}, pmid = {40378485}, issn = {1873-3557}, abstract = {Seeding spectral datasets by augmenting the data matrix with either the full spectrum or selected spectral features in order to bias multivariate analysis towards the solution of interest is explored. It is demonstrated that such seeding can have a profound effect on the endpoint of the analysis. Using Raman spectroscopic data of human lung adenocarcinoma cells (A549) in vitro, systematic perturbations to the spectra are introduced to simulate dose dependent exposure to a drug (cisplatin), and/or cellular response, representing reduced viability. Taking Principal Components Analysis (PCA) as the first example, seeding with the known spectral profiles of the drug exposure is demonstrated to greatly increase the ability of the algorithm to differentiate two distinct data subsets, representing control and exposed. The improved differentiation is quantified by further Linear Discriminant Analysis of the PCA data. Other examples of where seeding may be applied include, simulated datasets consisting of simultaneous changes in the spectral markers of exposure dose and cellular response, which are used for Multivariate Curve Resolution - Alternating Least Squares analysis (MCR-ALS). In the example presented, adding pure components to the dataset improves the ability of the algorithm to both model the systematic variation of concentration dependent data and extract the component spectra more accurately than the unseeded dataset. The seeded approach thus provides improved performance for differential analysis of datasets, as well as spectral unmixing analyses, to monitor, for example, the kinetic evolution of a reaction mixture, or metabolic pathway.}, }
@article {pmid40378471, year = {2025}, author = {Birylo, M and Błaszczak-Bąk, W and Suchocki, C}, title = {Application of GLDAS models and ALS point clouds in assessing the impact of modified evapotranspiration on the water budget.}, journal = {Water research}, volume = {283}, number = {}, pages = {123746}, doi = {10.1016/j.watres.2025.123746}, pmid = {40378471}, issn = {1879-2448}, abstract = {Monitoring and assessing the water budget is crucial, especially in the context of climate change and increasing occurrences of extreme weather events. The water budget is influenced by precipitation, evapotranspiration, and surface runoff, which are shaped by meteorological conditions. Additionally, terrain topography and land cover structure play a significant role, although they are often overlooked in water budget calculations. This study presents the integration of data from the Global Land Data Assimilation System (GLDAS) and airborne laser scanning (ALS) point clouds, enabling a comprehensive analysis of hydrological processes. The results highlight that modified evapotranspiration significantly affects water availability, particularly in regions with diverse topography, where terrain features influence local hydrological conditions. The findings confirm that precipitation remains the dominant factor in the water budget, but terrain-driven variations in evapotranspiration contribute to seasonal and spatial differences. The study demonstrates that incorporating ALS-derived vegetation and terrain data into hydrological modeling improves the accuracy of water budget assessments, which is crucial for sustainable water resource management.}, }
@article {pmid40375549, year = {2025}, author = {Kuiper, MM and Kruithof, WJ and Broekman-Peters, N and Schröder-van den Nieuwendijk, DL and Visser-Meily, JMA and Beelen, A}, title = {Nutritional care practices in ALS: perspectives of healthcare professionals and people with ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/21678421.2025.2501681}, pmid = {40375549}, issn = {2167-9223}, abstract = {Objective: To map nutritional care provided to people with ALS, PMA and PLS (pwALS) and identify barriers encountered by healthcare professionals and pwALS. Methods: Two online questionnaires, addressing current nutritional management of ALS in the Netherlands, were sent to healthcare professionals of the 36 certified ALS care teams and pwALS drawn from a population-based registry. Topics were: 1) contact between pwALS and their ALS care team, 2) monitoring nutritional status, 3) nutritional advice provided or received, and 4) satisfaction with current nutritional care and barriers encountered. Results: In total, 100 healthcare professionals and 372 pwALS completed the questionnaires. Dietitian responses (n = 36/100) showed that 28% utilized malnutrition screening tools and 17% measured body composition. Dietitians used different predictive equations to estimate energy and protein requirements. Patient responses showed that 50% had contact with a dietitian, 7% indicated body composition had been measured and 25% reported never being weighed or weighing themselves. Healthcare professionals and pwALS highlighted the need for comprehensive, up-to-date information on nutrition and ALS, national consensus on nutritional advice and monitoring methods, patient information material, training for healthcare professionals and personalized nutritional advice for pwALS. Conclusions: Practice variation was observed in the assessment and monitoring of nutritional status and the provision of nutritional advice. Suboptimal monitoring of nutritional status and estimation of nutritional requirements may result in delayed detection of malnutrition and inaccurate dietary recommendations. Further research and national consensus on monitoring methods and nutritional advice is required.}, }
@article {pmid40375307, year = {2025}, author = {Trautwig, AN and Fox, EJ and Dammer, EB and Shantaraman, A and Ping, L and Duong, DM and Watson, CM and Wu, F and Asress, S and Guo, Q and Levey, AI and Lah, JJ and Verde, F and Doretti, A and Ratti, A and Ticozzi, N and Ly, CV and Miller, TM and Garret, MA and Berry, JD and Thomas, EV and Fournier, CN and McEachin, ZT and Seyfried, NT and Glass, JD}, title = {Network analysis of the cerebrospinal fluid proteome reveals shared and unique differences between sporadic and familial forms of amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {58}, pmid = {40375307}, issn = {1750-1326}, support = {P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P01NS084974/NS/NINDS NIH HHS/United States ; P30AG066511//National Institute of Aging/ ; P30AG066511//National Institute of Aging/ ; P30AG066511//National Institute of Aging/ ; P30AG066511//National Institute of Aging/ ; AG070937/NH/NIH HHS/United States ; AG070937/NH/NIH HHS/United States ; R01 NS138499./NH/NIH HHS/United States ; NS097816/NH/NIH HHS/United States ; 1RO1NS137434/NH/NIH HHS/United States ; RF-2021-12374238//Italian Ministry of Health/ ; No Grant ID//Italian Ministry of Education and Research/ ; No Grant ID//Biogen, Inc/ ; No Grant ID//Biogen, Inc/ ; No Grant ID//Biogen, Inc/ ; No grant ID//Muscular Dystrophy Association/ ; No grant ID//Muscular Dystrophy Association/ ; No grant ID//Association of Frototemporal Dementia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; Male ; Female ; Middle Aged ; *Proteome ; C9orf72 Protein/genetics ; Proteomics/methods ; Biomarkers/cerebrospinal fluid ; Aged ; Superoxide Dismutase-1/genetics ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3-5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups.<br><br>METHODS: We employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, and controls (N&#x2009;=&#x2009;101). To verify trends in our Emory University cohort we used data-independent acquisition (DIA-MS) on an expanded, four center cohort. This expanded cohort of 259 individuals included 50 sporadic ALS (sALS), 43 C9orf72 ALS, 22 SOD1 ALS, 72 asymptomatic gene carriers (59 C9orf72 and 13 SOD1) and 72 age-matched controls. We identified 2330 proteins and used differential protein abundance and network analyses to determine how protein profiles vary across disease subtypes in ALS CSF.<br><br>RESULTS: Differential abundance and co-expression network analysis identified proteomic differences between ALS and control, as well as differentially abundant proteins between sporadic, C9orf72 and SOD1 ALS. A panel of proteins differentiated forms of ALS that are indistinguishable in a clinical setting. An additional panel differentiated asymptomatic from symptomatic C9orf72 and SOD1 mutation carriers, marking a pre-symptomatic proteomic signature of genetic forms of ALS. Leveraging this large, multicenter cohort, we validated our ALS CSF network and identified ALS-specific proteins and network modules.<br><br>CONCLUSIONS: This study represents a comprehensive analysis of the CSF proteome across sporadic and genetic causes of ALS that resolves differences among these ALS subgroups and also identifies proteins that distinguish symptomatic from asymptomatic gene carriers. These new data point to varying pathogenic pathways that result in an otherwise clinically indistinguishable disease.}, }
@article {pmid40374790, year = {2025}, author = {Verma, KK and Gaur, PK and Gupta, SL and Lata, K and Kaushik, R and Sharma, V}, title = {Metabolomics: a new frontier in neurodegenerative disease biomarker discovery.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {21}, number = {3}, pages = {67}, pmid = {40374790}, issn = {1573-3890}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Biomarkers/metabolism/analysis ; *Metabolomics/methods ; Animals ; }, abstract = {BACKGROUND: Neurodegenerative disorders are a group of debilitating diseases affecting the central nervous system, and are characterized by the progressive loss of neurons, leading to declines in cognitive function, movement, and overall quality of life. While the exact causes remain elusive, it's believed that a combination of genetic, environmental, and lifestyle factors contribute to their development. Metabolites, the end products of cellular processes, reflect the physiological state of an organism. By analysing these molecules, researchers can gain a deeper understanding of the underlying metabolic changes associated with neurodegenerative disorders.<br><br>AIM OF REVIEW: This review aims to explore the possibilities between metabolites and their association with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS) and Huntington's disease (HD).<br><br>Metabolomic studies could potentially illuminate altered biochemical pathways, facilitating earlier detection and treatment of these conditions. Metabolomic investigations have revealed the role of oxidative stress, alterations in glucose and fat metabolism, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and alterations in myelin composition in neurodegenerative disorders. The common metabolic biomarkers identified includes glutamate, taurine, uric acid, branched chain amino acids, acylcarnitine, creatinine, choline, with some more amino acids and lipids. Metabolomics offers valuable insights into disease mechanisms and potential therapeutic targets by identifying biochemical and metabolic alterations, but still there are several aspects to be explored for accurate mapping of metabolites with specific pathway involved in the disease.}, }
@article {pmid40374755, year = {2025}, author = {Krishnan, D and Talbot, DL and Ashhurst, JF and Park, SB and Vucic, S and Timmins, HC and Kiernan, MC}, title = {Longitudinal assessment of cortical motor function in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {16978}, pmid = {40374755}, issn = {2045-2322}, support = {1156093//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Motor Cortex/physiopathology ; Male ; Female ; Middle Aged ; Transcranial Magnetic Stimulation ; Longitudinal Studies ; Evoked Potentials, Motor/physiology ; Aged ; Adult ; Disease Progression ; Prospective Studies ; }, abstract = {Background Short interval intracortical inhibition (SICI) remains the most sensitive parameter to assess motor cortical function in amyotrophic lateral sclerosis (ALS). While an initial value of SICI has been utilised to support a diagnosis of ALS, less is known about progression of change. Methods Motor cortex function was prospectively assessed in ALS patients, through serial threshold tracking transcranial magnetic stimulation (TMS) assessment over more than 12 months. Motor cortical potentials were recorded from the abductor pollicis brevis (APB). Demographic information and clinical variables were analysed. Results A cohort of 52 ALS patients (69.2% limb-onset disease; 47.2% right-side) were assigned to undergo longitudinal assessment of cortical motor function. Mean ALSFRS-R score at baseline was 39.5 ± 1.0 denoting relatively milder clinical deficits at study commencement. Cortical motor dysfunction was evident at baseline, with reduction in averaged SICI (p = 0.004) when compared to healthy controls. In terms of disease trajectory, ALS patients experienced a significant decline in averaged SICI overtime. When compared to initial assessment, averaged SICI was significantly reduced after 12 months (p = 0.004). There was no significant main effect of site of onset on averaged SICI (p = 0.78). The progressive change in averaged SICI was more robust in the dominant hemisphere, with the proportion of ALS patients who demonstrated a clinically abnormal averaged SICI value (< 5.5%) increasing by 50%, compared to 15.4% for the non-dominant hemisphere. Conclusion ALS patients demonstrate progressive cortical motor abnormalities, evident through longitudinal assessment. While SICI represents a diagnostic biomarker, the rate of decline in the present series is consistent with disease progression, suggesting a potential role to monitor the efficacy of therapeutic intervention.}, }
@article {pmid40374720, year = {2025}, author = {Usategui-Martín, R and Esteban-López, V and Chantre-Fortes, E and Sánchez-Martín, M and Riancho, JA and López, DE and González-Sarmiento, R}, title = {The p.R321C mutation in the p62 protein is associated with abnormalities in the central nervous system.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {16929}, pmid = {40374720}, issn = {2045-2322}, mesh = {Animals ; *Sequestosome-1 Protein/genetics/metabolism ; Mice ; Humans ; Autophagy/genetics ; *Mutation ; *Central Nervous System/metabolism/pathology/abnormalities ; Disease Models, Animal ; NF-kappa B/metabolism ; Male ; Seizures/genetics/pathology ; }, abstract = {SQSTM1/p62 has an essential role in autophagy, a catabolic pathway that is vital for maintaining cell homeostasis. p62 alterations have been observed in multiple pathological conditions, including neurodegenerative diseases and bone metabolism alterations. The p.R321C p62 protein mutation has been described in patients with amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Paget's disease of bone. In vitro studies associated the p62-321C variant with a blockade of autophagy and with the activation of the NF-kB pathway. We aimed to provide a deeper understating of the pathophysiological consequences of the p.R321C p62 mutation using a humanized mouse model. Micro-computed tomography, immunohistochemistry, and western blot analysis studied the functional consequences of the p. R321C p62 mutation. Statistical analyses were performed using SPSS software. The results showed that the p62-321C mice developed seizures after tactile-vestibular stimulation, probably associated with a blockage of the autophagy and NF-kB activation. Changes in expression of cFos and p62 were found in the amygdala, hypothalamic nuclei, and hippocampi nuclei. In addition, numerous degenerating motor neurons were observed in the spinal cord of the p62-321C mice. We report that the blockage of the autophagy, caused by p.R321C p62 mutation, is associated with abnormalities in the central nervous system, mainly seizures after tactile-vestibular stimulation and degeneration of the motor neurons of the spinal cord but not with bone abnormalities in a humanized mouse model.}, }
@article {pmid40373763, year = {2025}, author = {Wu, J and Song, H and Arkin, M and Zhang, S and Huang, X and Fan, D and Xu, Y}, title = {Characteristics of Neuromuscular Ultrasound in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000546425}, pmid = {40373763}, issn = {1660-2862}, abstract = {INTRODUCTION: Neuromuscular ultrasound has been increasingly used in the detection and diagnosis of amyotrophic lateral sclerosis (ALS), commonly characterized by peripheral nerve atrophy, degeneration, and muscle fasciculations. The aim of this study was to assess the ultrasound characteristics of ALS patients.<br><br>METHODS: A total of 67 consecutive patients with sporadic ALS and 19 with ALS mimics (63.16% peripheral neuropathy) were recruited. Ultrasound and electrophysiological examinations were performed; the peripheral nerve cross-sectional area (CSA) and fasciculation grades were compared between the groups, and correlations between ultrasound and electrophysiological data in ALS patients were determined.<br><br>RESULTS: ALS patients had smaller proximal median and ulnar nerve CSAs than those of ALS mimics, who exhibited asymmetric changes. Fasciculation differences in the trapezius, triceps brachii, extensor digitorum communis, thenar, and first dorsal interosseous muscles were observed. In ALS patients, the CSA and fasciculation relative scores were correlated with electrophysiological indicators.<br><br>CONCLUSION: Ultrasound is a valuable tool for monitoring peripheral nerve CSA and muscle fasciculations, both of which correlate with electrophysiological indices, in ALS patients.}, }
@article {pmid40373575, year = {2025}, author = {de Carvalho, M}, title = {The F-wave fingerprint of amyotrophic lateral sclerosis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {55}, number = {4}, pages = {103080}, doi = {10.1016/j.neucli.2025.103080}, pmid = {40373575}, issn = {1769-7131}, }
@article {pmid40373480, year = {2025}, author = {Jih, KY and Fang, SY and Tsai, YS and Sytwu, HP and Liao, YC and Lee, YC}, title = {TARDBP variants in Taiwanese ALS patients: Genetic spectrum, clinical features, and founder effects.}, journal = {Journal of the neurological sciences}, volume = {474}, number = {}, pages = {123531}, doi = {10.1016/j.jns.2025.123531}, pmid = {40373480}, issn = {1878-5883}, abstract = {BACKGROUND: TARDBP is one of the most commonly implicated genes in amyotrophic lateral sclerosis (ALS). It encodes TAR DNA-binding protein 43 (TDP-43), a protein critical to ALS pathology, whose pathogenic variants disrupt its nuclear-cytoplasmic translocation, leading to aggregation. This study aimed to investigate the role of TARDBP variants in a Taiwanese ALS cohort.<br><br>METHODS: We analyzed the coding regions of TARDBP using Sanger sequencing in 650 unrelated ALS patients recruited between 2000 and 2024. The cohort included 388 men and 262 women, with an average age of onset of 56&#xa0;&#xb1;&#xa0;13&#xa0;years. Approximately 20&#xa0;% presented with bulbar-onset ALS. Haplotype analysis was conducted using single nucleotide polymorphism and short tandem repeat markers flanking TARDBP.<br><br>RESULTS: Pathogenic TARDBP variants were identified in 17 probands and 11 of their relatives, with an average age of onset of 49.1&#xa0;&#xb1;&#xa0;10.3&#xa0;years, 32&#xa0;% of whom had bulbar-onset disease. Six probands carried the p.M337V variant, five had p.S375G, two had p.N378D, and one each carried p.G348C, p.G348V, p.G376D, or p.I383V. Haplotype analysis suggested a common founder for the p.S375G variant and most families with p.M337V. Asymptomatic carriers were also identified, suggesting incomplete penetrance.<br><br>CONCLUSIONS: Our study revealed that pathogenic TARDBP variants are a significant genetic contributor to ALS in Taiwan, associated with earlier disease onset but reduced penetrance. The recurrent M337V and p.S375G variants likely reflect a founder effect.}, }
@article {pmid40370030, year = {2025}, author = {Fusaro, L and Bangari, DS and Pasterkamp, RJ and Fernández-Ruiz, J and Youssef, SA and Sharma, AK}, title = {Neurodegenerative Diseases: Pathogenesis and Preclinical Models for Translational Drug Discovery.}, journal = {Toxicologic pathology}, volume = {}, number = {}, pages = {1926233251339105}, doi = {10.1177/01926233251339105}, pmid = {40370030}, issn = {1533-1601}, abstract = {The fourth session of the 2024 European Society of Toxicologic Pathology (ESTP) Congress brought together lectures focused on the use of in vitro and in vivo models to investigate neurodegenerative diseases. Four presentations highlighted various aspects of neurodegenerative diseases including dementia, immune-mediated conditions, and neuromuscular disorders. The session began with an overview of animal models of dementia underscoring their critical role in understanding disease pathogenesis and supporting the development of effective therapeutic drugs. Subsequent presentations investigated immunological self-tolerance in autoimmune neurodegenerative diseases, such as multiple sclerosis and Guillain-Barré syndrome, and the application of in vitro models to study neuromuscular diseases such as amyotrophic lateral sclerosis. The final presentation examined cannabinoid-based therapeutic options for treating neurodegenerative diseases, highlighting their potential in neuroprotection and neurorepair. This session provided valuable insights into the latest research and advancements in neurodegenerative disease modeling and therapy, offering promising directions for improved modeling and therapeutic strategies.}, }
@article {pmid40369342, year = {2025}, author = {Uechi, H and Sridharan, S and Nijssen, J and Bilstein, J and Iglesias-Artola, JM and Kishigami, S and Casablancas-Antras, V and Poser, I and Martinez, EJ and Boczek, E and Wagner, M and Tomschke, N and de Jesus Domingues, AM and Pal, A and Doeleman, T and Kour, S and Anderson, EN and Stein, F and Lee, HO and Zhang, X and Fritsch, AW and Jahnel, M and Fürsch, J and Murthy, AC and Alberti, S and Bickle, M and Fawzi, NL and Nadler, A and David, DC and Pandey, UB and Hermann, A and Stengel, F and Davis, BG and Baldwin, AJ and Savitski, MM and Hyman, AA and Wheeler, RJ}, title = {Small-molecule dissolution of stress granules by redox modulation benefits ALS models.}, journal = {Nature chemical biology}, volume = {}, number = {}, pages = {}, pmid = {40369342}, issn = {1552-4469}, support = {103261/Z/13/Z//Wellcome Trust (Wellcome)/ ; 390729961//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; STE 2517/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; STE 2517/5-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; R01GM147677//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; EP/V011359/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; EP/V011359/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; }, abstract = {Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.}, }
@article {pmid40366870, year = {2025}, author = {Arguedas, A and Schneck, D and Cui, E and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Walk, D and Fiecas, M}, title = {Risk prediction for ALS using semi-competing risk models with applications to the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2500359}, pmid = {40366870}, issn = {2167-9223}, abstract = {Background and objectives: Important landmarks in progression of amyotrophic lateral sclerosis (ALS) can occur prior to death. Predictive models for the risk of these events can assist in clinical trial design and personal planning. We propose a predictive model, using a semi-competing risks modeling approach, for five important disease progression landmarks in ALS. Methods: Data on 1508 participants from the ALS Natural History Consortium (ALS NHC) were used, including baseline characteristics and the ALS Functional Rating Scale-Revised (ALSFRS-R) score collected at clinic visits. A semi-competing risks modeling approach was used to study the time to disease progression landmarks, accounting for the possibility of death. Specifically, time to gastrostomy, use of noninvasive ventilation (NIV), continuous use of NIV, loss of speech, and loss of ambulation were chosen and modeled individually. To measure the predictive capabilities of the model, the integrated Brier score was computed for each model using cross-validation for the NHC data. Data from Emory University were used for external validation of the models. Results: We present model results using gastrostomy as the intermediate outcome. Similar trends in disease progression groups were found across all model pathways. Diagnostic delay, age, and site of onset were the most important covariates. Predictive metrics in both internal and external validation are presented across all models and for different pathways. Conclusion: Semi-competing risks modeling is a flexible approach to studying disease progression. The models have good predictive capabilities across different outcomes and pathways. These are replicated in the external validation dataset.}, }
@article {pmid40366590, year = {2025}, author = {Wu, H and He, Q and Wang, Q}, title = {Histochemical Assays for Analyzing Abscission Layer Development and Function in Rice.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2916}, number = {}, pages = {99-107}, pmid = {40366590}, issn = {1940-6029}, mesh = {*Oryza/growth &amp; development/physiology/metabolism/genetics ; *Histocytochemistry/methods ; Gene Expression Regulation, Plant ; }, abstract = {This chapter outlines detailed methods and protocols for studying the structure and mechanisms of abscission layers (ALs) in rice. Utilizing rice spikelets as a primary example, these protocols provide comprehensive techniques for analyzing AL development, including tissue preparation, microscopy, and histochemical assays. The AL is a specialized tissue where cell separation takes place, and it is crucial for processes such as organ shedding and fruit drop. By examining the AL, researchers can uncover the physiological and genetic factors governing plant organ separation. These insights are pertinent for advancing agricultural practices and crop improvement, as understanding the dynamics of the AL can lead to the development of rice varieties with enhanced traits related to abscission and grain retention. These improvements can result in better yield stability and reduced post-harvest losses, which are essential for meeting the food demands of a growing global population. By focusing on the genetic and physiological mechanisms governing the AL, researchers can develop innovative strategies to optimize rice production and contribute to food security.}, }
@article {pmid40288540, year = {2025}, author = {He, M and Jia, H}, title = {Enhancing access to scalp cooling therapy: How can we move forward? A response to Novice et al's "the financial burden of scalp cooling therapy: A nonprofit organization data analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.093}, pmid = {40288540}, issn = {1097-6787}, }
@article {pmid40365999, year = {2025}, author = {Gao, Z and Qiu, R and Dave, DR and Chandravanshi, P and Soares, GP and Smith, CS and Ortega, JA and Palmer, LC and Álvarez, Z and Stupp, SI}, title = {Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.5c00105}, pmid = {40365999}, issn = {1520-5126}, abstract = {Neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.}, }
@article {pmid40365763, year = {2025}, author = {Cheng, F and Chapman, T and Venturato, J and Davidson, JM and Polido, SA and Rosa-Fernandes, L and San Gil, R and Suddull, HJ and Zhang, S and Macaslam, CY and Szwaja, P and Chung, R and Walker, AK and Rayner, SL and Morsch, M and Lee, A}, title = {Proteomics Analysis of the TDP-43 Interactome in Cellular Models of ALS Pathogenesis.}, journal = {Journal of neurochemistry}, volume = {169}, number = {5}, pages = {e70079}, doi = {10.1111/jnc.70079}, pmid = {40365763}, issn = {1471-4159}, support = {IG2308//Motor Neurone Disease Research Australia/ ; //FightMND/ ; AL230125//U.S. Department of Defense/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Proteomics/methods ; Animals ; Oxidative Stress/physiology ; }, abstract = {Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) is a hallmark pathology of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, the protein interactome of TDP-43 remains incompletely defined. In this study, we aimed to identify putative TDP-43 protein partners within the nucleus and the cytoplasm and with different disease models of TDP-43 by comparing TDP-43 interaction partners in three different cell lines. We verified the levels of interaction of protein partners under stress conditions as well as after introducing TDP-43 variants containing ALS missense mutations (G294V and A315T). Overall, we identified 58 putative wild-type TDP-43 interactors, including novel binding partners responsible for RNA metabolism and splicing. Oxidative stress exposure broadly led to changes in TDP-43[WT] interactions with proteins involved in mRNA metabolism, suggesting a dysregulation of the transcriptional machinery early in disease. Conversely, although G294V and A315T mutations are both located in the C-terminal domain of TDP-43, both mutants presented different interactome profiles with most interaction partners involved in translational and transcriptional machinery. Overall, by correlating different cell lines and disease-simulating interventions, we provide a list of high-confidence TDP-43 interaction partners, including novel and previously reported proteins. Understanding pathological changes to TDP-43 and its specific interaction partners in different models of stress is critical to better understand TDP-43 proteinopathies and provide novel potential therapeutic targets and biomarkers.}, }
@article {pmid40365751, year = {2025}, author = {Connaghan, KP and Eshghi, M and Haenssler, AE and Green, JR and Wang, J and Scheier, Z and Keegan, M and Clark, A and Onnela, JP and Burke, KM and Berry, JD}, title = {A Preliminary Investigation of Acoustic Features for Remote Monitoring of Respiration in ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28435}, pmid = {40365751}, issn = {1097-4598}, support = {K24DC06312/NH/NIH HHS/United States ; K23DC019179/NH/NIH HHS/United States ; R15DC018944/NH/NIH HHS/United States ; F32DC020896/NH/NIH HHS/United States ; //ALS Association/ ; }, abstract = {INTRODUCTION/AIMS: There is a substantial need to establish reliable approaches for low-burden at-home monitoring of respiratory function for people with amyotrophic lateral sclerosis (PALS). This preliminary study assessed the potential of acoustic features extracted from a smartphone passage reading task to serve as clinically meaningful outcome measures reflecting instrumental and self-reported respiratory function measures.<br><br>METHODS: Thirty-six PALS completed an in-clinic slow vital capacity (SVC) task, followed by at-home completion of surveys and audio recording of a reading passage using a smartphone application. Speaking rate and pause features were extracted offline. Correlation analysis evaluated the relationship between the acoustic features and both instrumental (SVC) and self-reported (respiratory subscale of the self-entry version of the ALS Functional Rating Scale-Revised; ALSFRS-RSE) measures of respiratory function. Receiver operator characteristic (ROC) with area under the curve (AUC) analysis evaluated the utility of acoustic features for classifying participants with and without respiratory involvement.<br><br>RESULTS: SVC and respiratory self-ratings were significantly correlated with pause, but not rate, measures. Percent pause time was the most strongly correlated acoustic feature with both SVC (r&#x2009;=&#x2009;-0.62) and ALSFRS-RSE respiratory subscale ratings (r&#x2009;=&#x2009;-0.43). ROC analysis revealed that percent pause time classified participants presenting with respiratory involvement based on instrumentation (SVC <&#x2009;70% predicted [AUC&#x2009;=&#x2009;0.70]; SVC <&#x2009;50% predicted [AUC&#x2009;=&#x2009;0.88]) and self-ratings when using the respiratory ALSFRS-RSE score cut-off of <&#x2009;11 (AUC&#x2009;=&#x2009;0.78), but not <&#x2009;12 (AUC&#x2009;=&#x2009;0.61).<br><br>DISCUSSION: Percent pause time, extracted from a smartphone-recorded passage reading, offers a promising index for remote assessment and monitoring of respiratory function in PALS.}, }
@article {pmid40364652, year = {2025}, author = {Gonçalves Netto, A and Ribeiro, VHV and Nicolai, M and Lopez Ovejero, RF and Silva, VFV and Junior, GJP and Brunharo, C}, title = {Genetic diversity and population structure of ALS-resistant Amaranthus hybridus across Brazil's primary soybean-growing regions.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8893}, pmid = {40364652}, issn = {1526-4998}, abstract = {BACKGROUND: Resistance to acetolactate synthase (ALS)-inhibiting herbicides has emerged in Amaranthus hybridus populations across Brazil's soybean-growing regions. To gain insights into the evolutionary origins and spread of resistance, this study (1) investigated the ALS inhibitor resistance mechanisms in nine A. hybridus populations and (2) assessed their genetic diversity, structure, and relatedness.<br><br>RESULTS: Resistance to the ALS inhibitor chlorimuron in A. hybridus was associated with two distinct target-site mutations: Trp-574-Leu and Asp-376-Glu. Population genetics revealed low levels of genetic diversity (HE&#x2009;=&#x2009;0.00117 to 0.16019; &#x3c0;&#x2009;=&#x2009;0.00126 to 0.17421) and inbreeding (FIS&#x2009;=&#x2009;0.0015 to 0.13157). Principal component analysis differentiated A. hybridus by geographical region, while ADMIXTURE analysis revealed population structure with evidence of admixture between genetic clusters in three groups of populations.<br><br>CONCLUSION: The results suggest multiple local and independent evolutionary origins of resistance. The spread of resistance is primarily driven by local herbicide selection pressure and gene flow through seed dispersal. &#xa9; 2025 The Author(s). Pest Management Science published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.}, }
@article {pmid40364643, year = {2025}, author = {Wen, X and Lan, T and Su, W and Cao, B and Wang, Y and Chen, Y}, title = {Latest progress and challenges in drug development for degenerative motor neuron diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01266}, pmid = {40364643}, issn = {1673-5374}, abstract = {Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions. They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage. The main types include amyotrophic lateral sclerosis, progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy, the pathological processes of which are largely identical, with the main disparity lying in the location of the lesions. Amyotrophic lateral sclerosis is the representative condition in this group of diseases, while other types are its variants. Hence, this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases. Although the precise pathogenesis remains elusive, recent advancements have shed light on various theories, including gene mutation, excitatory amino acid toxicity, autoimmunology, and neurotrophic factors. The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis: riluzole, edaravone, AMX0035, and tofersen, with the latter being the most recent to receive approval. However, following several phase III trials that failed to yield favorable outcomes, AMX0035 has been voluntarily withdrawn from both the US and Canadian markets. This article presents a comprehensive summary of drug trials primarily completed between January 1, 2023, and June 30, 2024, based on data sourced from clinicaltrials.gov. Among these trials, five are currently in phase I, seventeen are in phase II, and eleven are undergoing phase III evaluation. Notably, 24 clinical trials are now investigating potential disease-modifying therapy drugs, accounting for the majority of the drugs included in this review. Some promising drugs being investigated in preclinical studies, such as ATH-1105, are included in our analysis, and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases. This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs, with the aim of highlighting the latest potentialities for clinical therapy.}, }
@article {pmid40364629, year = {2025}, author = {Sepehrimanesh, M and Xu, W and Ding, B}, title = {Comparative analysis of chemical and lentiviral approaches in the generation of human induced pluripotent stem cell-derived motor neurons.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-00435}, pmid = {40364629}, issn = {1673-5374}, abstract = {The generation of human induced pluripotent stem cell-derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotrophic lateral sclerosis. Motor neurons generated through different strategies may exhibit substantial differences in purity, maturation, characterization, and even neuronal identity, leading to variable outcomes in disease modeling and drug screening. However, very few comparative studies have been conducted to determine the similarities and differences among motor neurons prepared via different protocols. In this study, we prepared human induced pluripotent stem cell-motor neurons via lentiviral delivery of transcription factors and chemical induction and performed a systematic comparative analysis. We found that motor neurons generated by both approaches showed typical motor neuron morphology and robustly expressed motor neuron-specific markers, such as nuclear homeobox transcription factor 9 and choline acetyltransferase. The chemical induction protocol utilizes a combination of small molecules to induce motor neuron differentiation, offering a significantly faster maturation time of 35 days compared to 46 days with lentiviral delivery of transcription factors. Additionally, while lentiviral delivery of transcription factors are suitable for downstream biochemical analysis, chemical induction are more applicable for therapeutic approaches as they avoid the use of lentiviruses. Both approaches produce motor neurons with high purity (> 95%) and yield. No significant differences were found between chemical induction and lentiviral delivery of transcription factors in terms of motor neuron markers and maturation markers. These robust methodologies offer researchers powerful tools for investigating motor neuron diseases and potential therapeutic strategies.}, }
@article {pmid40364088, year = {2025}, author = {Plotti, F and Martinelli, A and Terranova, C and De Cicco Nardone, C and Montera, R and Luvero, D and Guzzo, F and Di Donato, V and Cundari, GB and Manco, S and Angioli, R}, title = {Laparoscopic Lateral Suspension (LLS) for Pelvic Organ Prolapse (POP): Update and Systematic Review of Prospective and Randomised Trials.}, journal = {Journal of clinical medicine}, volume = {14}, number = {9}, pages = {}, doi = {10.3390/jcm14093056}, pmid = {40364088}, issn = {2077-0383}, abstract = {Background: Pelvic organ prolapse (POP) significantly impacts women's quality of life, especially in postmenopausal patients. Although laparoscopic sacrocolpopexy (LSC) is the gold standard for advanced apical prolapse, its complexity and risk of complications have led to alternative approaches like laparoscopic lateral suspension (LLS), a minimally invasive technique with promising results. Methods: A comprehensive search using PubMed databases was performed. The search was conducted from June 2024 to September 2024. The search string used was as follows: (pelvic organ prolapse) AND (lateral suspension) OR (laparoscopic lateral suspension). We included randomized controlled trials, prospective cohort studies, prospective observational studies, and case studies. We excluded retrospective studies, small case series, case reports, and articles not published in English. All selected articles were screened based on the titles and abstracts. Relevant data were extracted and tabulated. Results: An overall number of 12 studies were included in our analysis. LLS demonstrated high anatomical success rates: 91.15% for the anterior, 94.95% for the central, and 86.55% for the posterior compartments. The randomized controlled studies exhibit comparable effectiveness between both methods (LLS vs. LSC) and LLS appears to be the best option for anterior repair or anterior-apical repair. Patient satisfaction rates exceeded 90%, with reduced operative times (123 ± 33 min and 193 ± 55.6 min for ALS and ASC, respectively). According to the Claiven-Dindo scale, 0.17% of postoperative complications were graded more than III. The rate of mesh erosion was 0% to 10%. The technique showed particular benefit for uterine preservation and in obese patients but was less effective for severe posterior prolapse. Conclusions: Laparoscopic lateral suspension offers a safe, effective alternative for POP management, with significant anatomical and functional benefits. Its minimally invasive nature, shorter surgery time, and high satisfaction rates make it suitable for tailored patient care. Further studies should standardize evaluation metrics and assess long-term outcomes. The review was not registered. No funding was received. The authors declare no competing interests.}, }
@article {pmid40363964, year = {2025}, author = {Niemann, BR and Murthy, J and Breinholt, C and Swords, J and Stevens, A and Garland-Kledzik, M and Mayers, K and Groves, E and Train, K and Murken, D}, title = {Postoperative C-Reactive Protein Trend Is a More Accurate Predictor of Anastomotic Leak than Absolute Values Alone.}, journal = {Journal of clinical medicine}, volume = {14}, number = {9}, pages = {}, doi = {10.3390/jcm14092931}, pmid = {40363964}, issn = {2077-0383}, abstract = {Background/Objectives: An anastomotic leak (AL) following colorectal surgery is one of the most feared complications due to its associated morbidity and mortality. Early detection of ALs remains difficult, as the development of clinical signs of deterioration can be a late finding. This is particularly problematic in patients with poor access to care after discharge. C-reactive protein (CRP) is a systemic marker of inflammation that has been proposed as an early AL screening. However, absolute cut-off values have been shown to have limited sensitivity and specificity. We propose the use of CRP trends for early AL detection. Methods: A retrospective chart review of patients undergoing surgery requiring at least one anastomosis at a single tertiary care center was performed. Patients with two or fewer postoperative CRP values were excluded. Postoperative CRP trends were compared between control and AL patients using a mixed model with a Geisser-Greenhouse correction. Results: CRP trends differed significantly between AL and control patients, with a 10% CRP increase after postoperative day two showing 100% sensitivity and 84% specificity for an AL as well as a 100% negative predictive value. Accepted CRP cut-off values on postoperative days three and four had sensitivities of only 71.4% and 80% and specificities of 70.0% and 76.5%, respectively. CRP trends differed in AL versus control patients despite the surgical approach or presence of additional procedures. Conclusions: Daily monitoring of CRP trends (versus absolute cut-offs) may enhance early anastomotic leak detection and aid in discharge decision-making, particularly important in rural settings with limited healthcare access.}, }
@article {pmid40362907, year = {2025}, author = {Christopher, CJ and Morgan, KH and Tolleson, CM and Trudell, R and Fernandez-Romero, R and Rice, L and Abiodun, BA and Vickery, Z and Jones, KA and Woodall, BM and Nagy, C and Mieczkowski, PA and Bowen, G and Campagna, SR and Ellis, JC}, title = {Specific Bacterial Taxa and Their Metabolite, DHPS, May Be Linked to Gut Dyshomeostasis in Patients with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {17}, number = {9}, pages = {}, doi = {10.3390/nu17091597}, pmid = {40362907}, issn = {2072-6643}, support = {N/A//The Cole Family who support Parkinson's care and research at the Cole Center for Parkinson's Disease and Movement Disorders/ ; N/A//University of Tennessee at Knoxville's Human Health &amp; Wellness Program/ ; N/A//Laboratory Directed Research and Development Program at Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the U.S. Department of Energy/ ; N/A//A philanthropic donor to ALS research at the University of Tennessee Medical Center/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Parkinson Disease/microbiology/metabolism ; *Alzheimer Disease/microbiology/metabolism ; *Dysbiosis/microbiology ; Male ; Female ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; Aged ; Middle Aged ; Feces/microbiology ; *Bacteria/metabolism/classification ; Homeostasis ; Metabolomics ; Case-Control Studies ; }, abstract = {Background: Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. Methods: Using untargeted mass spectrometry-based metabolomics and 16S sequencing of human stool, we investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs-amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD)-and healthy controls (HC). Results: We discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and gut dysbiosis in NDDs. DHPS was downregulated in AD, ALS, and PD, while bacteria involved in DHPS metabolism, Eubacterium and Desulfovibrio, were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS, suggesting a potential role in DHPS metabolism. A catabolic product of DHPS is hydrogen sulfide, and when in excess, it is known to promote inflammation, oxidative stress, mitochondrial damage, and gut dysbiosis, known hallmarks of NDDs. Conclusions: These findings suggest that cryptic sulfur metabolism via DHPS is a potential missing link in our current understanding of gut dysbiosis associated with NDD onset and progression. As this was a hypothesis generating study, more work is needed to elucidate the role of DHPS in gut dysbiosis and neurodegenerative diseases.}, }
@article {pmid40362746, year = {2025}, author = {Moțățăianu, A and Mănescu, IB and Șerban, G and Ion, V and Bălașa, R and Andone, S}, title = {The Effects of a Mediterranean Diet on Metabolic Hormones and Cytokines in Amyotrophic Lateral Sclerosis Patients: A Prospective Interventional Study.}, journal = {Nutrients}, volume = {17}, number = {9}, pages = {}, doi = {10.3390/nu17091437}, pmid = {40362746}, issn = {2072-6643}, support = {PN-III-P1-1.1-TE-2021-0960//Ministry of Research, Innovation and Digitization, CNCS - UEFISCDI/ ; }, mesh = {Humans ; *Diet, Mediterranean ; *Amyotrophic Lateral Sclerosis/diet therapy/blood ; Male ; Female ; Prospective Studies ; Middle Aged ; *Cytokines/blood ; Aged ; Leptin/blood ; Glucagon-Like Peptide 1/blood ; Insulin/blood ; Disease Progression ; *Gastrointestinal Hormones/blood ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a prevalent neurodegenerative disease but lacks effective treatments. Dietary interventions, notably the Mediterranean diet, promise to modulate disease pathways. This study aimed to investigate the impact of the Mediterranean diet on gut hormones and cytokines in patients with amyotrophic lateral sclerosis (ALS). Methods: We conducted a 12-month, single-center prospective study on a total of 44 ALS patients. After a 6-month observation period, the patients were placed on a dairy-free Mediterranean diet for the next 6 months. We evaluated the patients at baseline (T0), 6 months (T1), and 12 months (T2). We measured the ALS Functional Rating Scale-Revised (ALSFRS-R) scores and a panel of metabolic hormones and cytokines. Results: The ALSFRS-R scores declined over 12 months (37.59 ± 6.32 at T0 vs. 30.23 ± 8.91 at T2, p < 0.001), indicating expected disease progression with no significant difference in the rate of decline before and after the dietary intervention. The leptin levels significantly decreased from T0 to T1 (T0: 4956 ± 3994 pg/mL vs. T1: 3196 ± 2807 pg/mL, p = 0.038). The insulin and GLP-1 levels showed significant drops at T2 (insulin T0: 480 ± 369 vs. T2: 214 ± 213 pmol/L, p < 0.01; GLP-1 T0: 118 ± 76 vs. T2: 60 ± 57 pg/mL, p < 0.01). C-peptide increased at T2 (T0: 3814 ± 1967 vs. T2: 9532 ± 4000 pg/mL, p < 0.001). Among the cytokines, the levels of IL-12P70, IL-13, IL-9, and IL-2 significantly decreased from T0 to T2 (all p < 0.05), while IL-17A and TNFα significantly increased between T1 and T2 (p < 0.01). Conclusions: The Mediterranean diet intervention in ALS patients modulated several metabolic hormones and cytokines but with no evidence of impacting the disease's evolution or of a slowed clinical progression. These findings suggest a potential role for dietary intervention, particularly the Mediterranean diet, in modulating gut hormones and cytokines in ALS patients, but its impact on disease course is unclear. Future randomized studies are needed to confirm these changes and to determine whether dietary intervention can have any benefit in ALS.}, }
@article {pmid40362586, year = {2025}, author = {Zhang, R and Azhir, A and McGrath, MS}, title = {Respiratory Function Improvement and Lifespan Extension Following Immunotherapy with NP001 Support the Concept That Amyotrophic Lateral Sclerosis (ALS) Is an Immuno-Neurologic Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, doi = {10.3390/ijms26094349}, pmid = {40362586}, issn = {1422-0067}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy/physiopathology/mortality/therapy ; Middle Aged ; Male ; Female ; Aged ; *Immunotherapy/methods ; Body Mass Index ; Adult ; Vital Capacity/drug effects ; Immunity, Innate/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease that involves progressive loss of voluntary muscle and ultimately, respiratory function, which is the primary cause of death in ALS patients. Respiratory vital capacity (VC) measurements are objective, reproducible, and directly related to survival. Respiratory function is known to be negatively affected in individuals with excess abdominal fat contributing to a chronic innate immune inflammatory state. To test whether ALS patients might have a body mass index (BMI) related VC response to the innate immune system regulator NP001, clinical results from two NP001 phase 2 trials were evaluated in an intent-to-treat manner, stratified by BMI measurements. Slowing of progressive VC loss and extension of overall survival (OS) occurred primarily in ALS patients who were overweight with a BMI ≥ 25 (70% of patients in the phase 2 trials). Innate immune dysfunction is a characteristic of ALS patients ≤ 65 years of age, and in this group both VC and OS changes in response to NP001 were most significant. This study represents a novel approach to ALS, wherein VC and OS were both significantly improved through immunologic, not neurologic modulation with NP001, a precursor to the dominant regulator of inflammation, taurine chloramine.}, }
@article {pmid40362582, year = {2025}, author = {Kitaoka, Y and Uchihashi, T and Kawata, S and Nishiura, A and Yamamoto, T and Hiraoka, SI and Yokota, Y and Isomura, ET and Kogo, M and Tanaka, S and Spigelman, I and Seki, S}, title = {Role and Potential of Artificial Intelligence in Biomarker Discovery and Development of Treatment Strategies for Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, doi = {10.3390/ijms26094346}, pmid = {40362582}, issn = {1422-0067}, support = {24K13154//Japan Society for the Promotion of Science/ ; 21K10091//Japan Society for the Promotion of Science/ ; 24K13113//Japan Society for the Promotion of Science/ ; 23K09351//Japan Society for the Promotion of Science/ ; 24K13112//Japan Society for the Promotion of Science/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; *Artificial Intelligence ; Proteomics/methods ; Neuroimaging/methods ; Deep Learning ; }, abstract = {Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), present significant challenges owing to their complex pathologies and a lack of curative treatments. Early detection and reliable biomarkers are critical but remain elusive. Artificial intelligence (AI) has emerged as a transformative tool, enabling advancements in biomarker discovery, diagnostic accuracy, and therapeutic development. From optimizing clinical-trial designs to leveraging omics and neuroimaging data, AI facilitates understanding of disease and treatment innovation. Notably, technologies such as AlphaFold and deep learning models have revolutionized proteomics and neuroimaging, offering unprecedented insights into ALS pathophysiology. This review highlights the intersection of AI and ALS, exploring the current state of progress and future therapeutic prospects.}, }
@article {pmid40362512, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Targeting Gene C9orf72 Pathogenesis for Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, doi = {10.3390/ijms26094276}, pmid = {40362512}, issn = {1422-0067}, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/therapy ; Humans ; DNA Repeat Expansion ; Animals ; Mutation ; Autophagy ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most common genetic pathogenesis of ALS. The literature review indicates that the C9orf72 HRE causes both the gain-of-function toxicity and loss of function of C9ORF72. The formation of RNA foci and dipeptide repeats (DPRs) resulting from HRE is responsible for toxic function gain. The RNA foci can interfere with RNA processing, while DPRs directly bind to and sequester associated proteins to disrupt processes of rRNA synthesis, mRNA translation, autophagy, and nucleocytoplasmic transport. The mutations of C9orf72 and HRE result in the loss of functional C9ORF72. Under physiological conditions, C9ORF72 binds to Smith-Magenis chromosome region 8 and WD repeat-containing protein and forms a protein complex. Loss of C9ORF72 leads to autophagic impairment, increased oxidative stress, nucleocytoplasmic transport impairment, and inflammatory response. The attempted treatments for ALS have been tried by targeting C9orf72 HRE; however, the outcomes are far from satisfactory yet. More studies should be performed on pharmacological and molecular modulators against C9orf72 HRE to evaluate their efficacy by targeting HRE.}, }
@article {pmid40362464, year = {2025}, author = {Yapici, I and Tokur, AG and Sever, B and Ciftci, H and Basak, AN and DeMirci, H}, title = {Structural Insights into the Dynamics of Water in SOD1 Catalysis and Drug Interactions.}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, doi = {10.3390/ijms26094228}, pmid = {40362464}, issn = {1422-0067}, support = {122Z429//Scientific and Technological Research Council of Turkey (T&#xdc;B&#x130;TAK)/ ; 101061939//European Union's Horizon Europe research and innovation programme under the Marie Sktodowska-Curie grant agreement/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/antagonists &amp; inhibitors/genetics ; *Water/chemistry/metabolism ; Humans ; Molecular Docking Simulation ; Catalytic Domain ; Hydrogen Bonding ; Catalysis ; Molecular Dynamics Simulation ; Amyotrophic Lateral Sclerosis/drug therapy ; Crystallography, X-Ray ; Protein Conformation ; }, abstract = {Superoxide dismutase 1 (SOD1) is a crucial enzyme that protects cells from oxidative damage by converting superoxide radicals into H2O2 and O2. This detoxification process, essential for cellular homeostasis, relies on a precisely orchestrated catalytic mechanism involving the copper cation, while the zinc cation contributes to the structural integrity of the enzyme. This study presents the 2.3 Å crystal structure of human SOD1 (PDB ID: 9IYK), revealing an assembly of six homodimers and twelve distinct active sites. The water molecules form a complex hydrogen-bonding network that drives proton transfer and sustains active site dynamics. Our structure also uncovers subtle conformational changes that highlight the intrinsic flexibility of SOD1, which is essential for its function. Additionally, we observe how these dynamic structural features may be linked to pathological mutations associated with amyotrophic lateral sclerosis (ALS). By advancing our understanding of hSOD1's mechanistic intricacies and the influence of water coordination, this study offers valuable insights for developing therapeutic strategies targeting ALS. Our structure's unique conformations and active site interactions illuminate new facets of hSOD1 function, underscoring the critical role of structural dynamics in enzyme catalysis. Moreover, we conducted a molecular docking analysis using SOD1 for potential radical scavengers and Abelson non-receptor tyrosine kinase (c-Abl, Abl1) inhibitors targeting misfolded SOD1 aggregation along with oxidative stress and apoptosis, respectively. The results showed that CHEMBL1075867, a free radical scavenger derivative, showed the most promising docking results and interactions at the binding site of hSOD1, highlighting its promising role for further studies against SOD1-mediated ALS.}, }
@article {pmid40362304, year = {2025}, author = {Shiryaeva, O and Tolochko, C and Alekseeva, T and Dyachuk, V}, title = {Targets and Gene Therapy of ALS (Part 1).}, journal = {International journal of molecular sciences}, volume = {26}, number = {9}, pages = {}, doi = {10.3390/ijms26094063}, pmid = {40362304}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/pathology ; *Genetic Therapy/methods ; Animals ; Superoxide Dismutase-1/genetics ; C9orf72 Protein/genetics ; Mutation ; Gene Editing ; RNA-Binding Protein FUS/genetics ; Oligonucleotides, Antisense/therapeutic use ; CRISPR-Cas Systems ; DNA-Binding Proteins/genetics ; RNA Interference ; MicroRNAs/genetics ; Disease Models, Animal ; RNA, Small Interfering/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as SOD1, C9orf72, FUS, and TARDBP has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials.}, }
@article {pmid40360341, year = {2025}, author = {Lin, W and Huang, C and Tan, Z and Xu, H and Wei, W and Wang, L}, title = {Cu[II]-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases.}, journal = {Seminars in nuclear medicine}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.semnuclmed.2025.03.008}, pmid = {40360341}, issn = {1558-4623}, abstract = {Neurodegenerative diseases, characterized by progressive neuronal degeneration and associated with neuroinflammation and oxidative stress, present significant challenges in diagnosis and treatment. This review explores the potential of copper(II)-bis(thiosemicarbazone) complexes, particularly Cu-ATSM, as a dual-purpose radiopharmaceutical for imaging and therapeutic interventions. Cu-ATSM exhibits unique redox-dependent retention in pathological microenvironments, driven by mitochondrial dysfunction and hyper-reductive states, which enables the noninvasive detection of oxidative stress via positron emission tomography (PET). Preclinical studies demonstrate its efficacy in mitigating neuroinflammation by suppressing glial activation, reducing the secretion of pro-inflammatory cytokines (e.g., TNF-α, MCP-1), and increasing the expression of neuroprotective metallothionein-1 (MT1). Some Clinical research reveals elevated [64]Cu-ATSM uptake in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients, correlating with disease severity and regional oxidative stress markers. Furthermore, Cu-ATSM derivatives show promise in modulating blood-brain barrier (BBB) permeability, enhancing amyloid-β clearance, and restoring copper homeostasis in ALS models. Despite these advances, limitations such as small cohort sizes and heterogeneity in clinical studies underscore the need for larger-scale validation. Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders.}, }
@article {pmid40360159, year = {2025}, author = {Li, Z and Li, Y and Zhao, J and Zhang, F and Dang, W and Jia, Y and Guo, F and Guo, L}, title = {Association among blood pressure, antihypertensive drugs, and amyotrophic lateral sclerosis.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {5}, pages = {1-8}, doi = {10.1055/s-0045-1804922}, pmid = {40360159}, issn = {1678-4227}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/prevention &amp; control ; *Antihypertensive Agents/therapeutic use ; *Blood Pressure/drug effects/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Hypertension/drug therapy/genetics/complications ; Risk Factors ; Male ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease. The impacts of antihypertensive drugs and blood pressure (BP) on ALS are currently debatable.<br><br>OBJECTIVE: &#x2003;To evaluate the causal relationship involving antihypertensive drugs, BP, and ALS through a Mendelian randomization (MR) analysis.<br><br>METHODS: &#x2003;The causal relationship between BP and ALS was evaluated by a bidirectional two-sample MR analysis. Then, a sensitivity analysis was performed using a secondary BP genome-wide association study. The drug-target MR was employed to evaluate the impact of antihypertensive drugs on ALS. Furthermore, we used cis-expression quantitative trait loci (cis-eQTLs) data from brain tissue and blood to validate the positive results by a summary-based MR method.<br><br>RESULTS: &#x2003;We found that an increment in systolic BP (SBP) could elevate the risk of ALS (inverse-variance weighted [IVW] odds ratio [OR]&#x2009;=&#x2009;1.003; 95% confidence interval [95%CI]: 1.001-1.006; per 10-mmHg increment) and ALS might be protected by angiotensin-converting enzyme inhibitors (ACEIs; OR&#x2009;=&#x2009;0.970; 95%CI: 0.956-0.984; p&#x2009;=&#x2009;1.96&#x2009;&#xd7;&#x2009;10[-5]; per 10-mmHg decrement). A causal relationship was not observed between diastolic BP and other antihypertensive drugs in ALS.<br><br>CONCLUSION: &#x2003;In the present study, genetic support for elevated SBP serves as a risk factor for ALS. Besides, ACEIs hold promise as a candidate for ALS.}, }
@article {pmid40358451, year = {2025}, author = {Rahsepar, AA and Bedayat, A}, title = {Beyond Spirometry: AI-Driven Chest CT Analysis, a New Frontier in Monitoring Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {315}, number = {2}, pages = {e250988}, doi = {10.1148/radiol.250988}, pmid = {40358451}, issn = {1527-1315}, }
@article {pmid40358443, year = {2025}, author = {Choi, SJ and Kim, JS and Jeong, SY and Son, H and Sung, JJ and Park, CM and Choi, KS}, title = {Association of Deep Learning-based Chest CT-derived Respiratory Parameters with Disease Progression in Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {315}, number = {2}, pages = {e243463}, doi = {10.1148/radiol.243463}, pmid = {40358443}, issn = {1527-1315}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/mortality ; Male ; Female ; Retrospective Studies ; Aged ; *Deep Learning ; Disease Progression ; *Tomography, X-Ray Computed/methods ; Middle Aged ; Vital Capacity ; Lung/diagnostic imaging/physiopathology ; Respiratory Muscles/diagnostic imaging/physiopathology ; }, abstract = {Background Forced vital capacity (FVC) is a standard measure of respiratory function in patients with amyotrophic lateral sclerosis (ALS) but has limitations, particularly for patients with bulbar impairment. Purpose To determine the value of deep learning-based chest CT-derived respiratory parameters in predicting ALS progression and survival. Materials and Methods This retrospective study included patients with ALS diagnosed between January 2010 and July 2023 who underwent chest CT at a tertiary hospital. Deep learning-based software was used to measure lung and respiratory muscle volume, normalized for height as the lung volume index (LVI) and respiratory muscle index (RMI). Differences in these parameters across King clinical stages were assessed using ordinal logistic regression. Tracheostomy-free survival was evaluated using Cox regression and time-dependent receiver operating characteristic analysis. Subgroup analysis was conducted for patients with bulbar impairment. In addition, a Gaussian process regressor model was developed to estimate FVC based on lung volume, respiratory muscle volume, age, and sex. Results A total of 261 patients were included in the study (mean age, 65.2 years ± 11.9 [SD]; 156 male patients). LVI and RMI decreased with increasing King stage (both P < .001). The high LVI and high RMI groups had better survival (both P < .001). After adjustment, LVI (hazard ratio [HR] = 0.998 [95% CI: 0.996, 1.000]; P = .021) and RMI (HR = 0.992 [95% CI: 0.988, 0.996]; P < .001) remained independent prognostic factors. In patients with bulbar impairment, LVI (HR = 0.998 [95% CI: 0.996, 1.000]; P = .029) and RMI (HR = 0.991 [95% CI: 0.987, 0.996]; P < .001) were independent prognostic factors. Time-dependent receiver operating characteristic curve analysis revealed no significant differences in survival prediction performance among LVI, RMI, and FVC. The Gaussian process regressor model estimated FVC with approximately 8% error. Conclusion The deep learning-derived CT metrics LVI and RMI reflected ALS stage, enabled FVC prediction, and supported assessment in patients with limited respiratory function. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Rahsepar and Bedayat in this issue.}, }
@article {pmid40356623, year = {2025}, author = {Mori, S and Zhou, H and Omura, T and Tsumoto, H and Miura, Y and Shigemoto, K}, title = {Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1556120}, pmid = {40356623}, issn = {1664-2295}, abstract = {Neuromuscular junction (NMJ) denervation is an early event preceding motor neuron loss in amyotrophic lateral sclerosis (ALS). Progressive loss of the NMJ leads to irreversible muscle weakness and atrophy. Muscle-specific kinase (MuSK), locally expressed at the postsynaptic membrane of the NMJ, is activated by agrin released from motor nerve terminals and is essential for NMJ maintenance and regeneration. Here, we found that the progression of NMJ denervation prior to the onset of muscle weakness in SOD1-93A mouse model of ALS correlated with increased serum MuSK immunoreactivity and elevated MuSK expression throughout the skeletal muscle. Our results suggest that neuromuscular failure associated with the onset of muscle weakness increases MuSK expression throughout the muscle, which is subsequently cleaved by proteolytic enzymes to increase MuSK immunoreactivity in the blood. These results demonstrate that the level of serum MuSK immunoreactivity may indicate the early phase of NMJ denervation and serve as a biomarker for assessing the progression of other types of ALS and therapeutic benefits in preclinical studies.}, }
@article {pmid40355776, year = {2025}, author = {Hirose, S and Kobatake, Y and Tada, N and Kandeel, M and Itoh, A and Oh-Hashi, K}, title = {NanoBiT-based Analysis of Canine SOD1 Protein Dynamics: Understanding the Role of CCS and Ebselen Derivatives as Potential Therapeutics for Canine Degenerative Myelopathy.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {40355776}, issn = {1559-0283}, support = {KFU241899//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University/ ; }, abstract = {Canine degenerative myelopathy (DM) is a progressive neurodegenerative disorder that shares common pathological features with amyotrophic lateral sclerosis (ALS) in humans. Both diseases are linked to mutations in the superoxide dismutase 1 (SOD1) gene. Understanding the molecular differences between wild-type (WT) and mutant SOD1 proteins is critical for developing therapeutic strategies. In this study, we employed the NanoLuc complementation (NanoBiT) reporter system to investigate the expression and functional differences between WT and E40K mutant canine SOD1 to assess the therapeutic potential of copper chaperone for SOD1 (CCS) and ebselen derivatives. E40K cSOD1 displayed significantly reduced luciferase activity compared to WT cSOD1 in all NanoBiT-tagged combinations, indicating altered homodimerization and protein stability. Co-transfection with CCS increased both WT and mutant cSOD1 protein levels and reporter activities, with a more pronounced effect on the E40K mutant. Ebselen treatment enhanced luciferase activity, particularly in E40K cSOD1-expressing cells. Two compounds (compounds 2 and 5) were stronger than the parent compound in improving mutant cSOD1-derived NanoBiT activities. Additionally, molecular docking simulations revealed stronger binding affinities of ebselen and its derivatives to E40K cSOD1, suggesting potential therapeutic benefits. In conclusion, the NanoLuc reporter system offers a valuable tool for screening potential therapeutics for SOD1-linked neurodegenerative diseases. CCS and ebselen derivatives exhibited promising effects on SOD1 activity, providing a basis for future therapeutic strategies targeting both DM and ALS.}, }
@article {pmid40355001, year = {2025}, author = {Ognard, J and El Hajj, G and Verma, O and Ghozy, S and Kadirvel, R and Kallmes, DF and Brinjikji, W}, title = {Advances in endovascular brain computer interface: Systematic review and future implications.}, journal = {Journal of neuroscience methods}, volume = {420}, number = {}, pages = {110471}, doi = {10.1016/j.jneumeth.2025.110471}, pmid = {40355001}, issn = {1872-678X}, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) translate neural activity into real-world commands. While traditional invasive BCIs necessitate craniotomy, endovascular BCIs offer a minimally invasive alternative using the venous system for electrode placement.<br><br>NEW METHOD: This systematic review evaluates the technical feasibility, safety, and clinical outcomes of endovascular BCIs, discussing their future implications. A systematic review was conducted per PRISMA guidelines. The search spanned PubMed, Web of Science, and Scopus databases using keywords related to neural interfaces and endovascular approaches. Studies were included if they reported on endovascular BCIs in preclinical or clinical settings. Dual independent screening and extraction focused on electrode material, recording capabilities, safety parameters, and clinical efficacy.<br><br>RESULTS: From 1385 initial publications, 26 met the inclusion criteria. Seventeen studies investigated the Stentrode device. Among the 24 preclinical studies, 16 used ovine or rodent models, and 9 addressed engineering or simulation aspects. Two clinical studies reported six ALS patients successfully using an endovascular BCI for digital communication. Preclinical data established the endovascular ovine model, demonstrating stable neural recordings and vascular changes with long-term implantation. Key challenges include thrombosis risk, long-term electrode stability, and anatomical variability.<br><br>Endovascular BCI reduced invasiveness, improved safety profiles, with comparable neural recording fidelity to invasive methods, and promising preliminary clinical outcomes in severely paralyzed patients.<br><br>CONCLUSIONS: Early results are promising, but clinical data remain scarce. Further research is needed to optimize signal processing, enhance electrode biocompatibility, and refine endovascular procedures for broader clinical applications.}, }
@article {pmid40354800, year = {2025}, author = {Benatar, M and McDermott, MP}, title = {Examining the evidence for IL-2 in amyotrophic lateral sclerosis.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)00901-8}, pmid = {40354800}, issn = {1474-547X}, }
@article {pmid40280333, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Shapiro, J and Lacouture, ME and Lo Sicco, KI}, title = {Response to Venkatesh et al's "Analysis of breast health outcomes in women on oral 5-alpha reductase inhibitors: A single-center retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.091}, pmid = {40280333}, issn = {1097-6787}, }
@article {pmid40354799, year = {2025}, author = {Bensimon, G and Leigh, PN and Tree, T and Malaspina, A and Payan, CA and Pham, HP and Klaassen, P and Shaw, PJ and Al Khleifat, A and Amador, MDM and Attarian, S and Bell, SM and Beltran, S and Bernard, E and Camu, W and Corcia, P and Corvol, JC and Couratier, P and Danel, V and Debs, R and Desnuelle, C and Dimitriou, A and Ealing, J and Esselin, F and Fleury, MC and Gorrie, GH and Grapperon, AM and Hesters, A and Juntas-Morales, R and Kolev, I and Lautrette, G and Le Forestier, N and McDermott, CJ and Pageot, N and Salachas, F and Sharma, N and Soriani, MH and Sreedharan, J and Svahn, J and Verber, N and Verschueren, A and Yildiz, O and Suehs, CM and Saker-Delye, S and Muller, C and Masseguin, C and Hajduchova, H and Kirby, J and Garlanda, C and Locati, M and Zetterberg, H and Asselain, B and Al-Chalabi, A and , }, title = {Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(25)00262-4}, pmid = {40354799}, issn = {1474-547X}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS.<br><br>METHODS: In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18-76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12-18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete.<br><br>FINDINGS: From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2LD (hazard ratio 0&#xb7;81 [95% CI 0&#xb7;54-1&#xb7;22], p=0&#xb7;33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2LD (0&#xb7;32 [0&#xb7;14-0&#xb7;73], p=0&#xb7;007), with a significant treatment by CSF-pNFH interaction (1&#xb7;0003 [1&#xb7;0001-1&#xb7;0005], p=0&#xb7;001). IL-2LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2LD was associated with a significant 48% decrease in risk of death (0&#xb7;52 [0&#xb7;30-0&#xb7;89], p=0&#xb7;016) in the 70% of the population with low (750-3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1&#xb7;37 [0&#xb7;68-2&#xb7;75], p=0&#xb7;38).<br><br>INTERPRETATION: With this treatment schedule, IL-2LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS.<br><br>FUNDING: European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association.}, }
@article {pmid40354780, year = {2025}, author = {Delivoria, DC and Konia, E and Matis, I and Skretas, G}, title = {Optimization of a High-Throughput Screen for Monitoring Disease-Associated Protein Misfolding and Aggregation in Bacteria.}, journal = {ACS synthetic biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acssynbio.5c00166}, pmid = {40354780}, issn = {2161-5063}, abstract = {Protein misfolding and aggregation are central features of a wide range of diseases, including neurodegenerative disorders, systemic amyloidoses, and cancer. The identification of compounds that can modulate protein folding and aggregation is a key step toward developing effective therapies. High-throughput screening methods are essential for efficiently identifying such compounds. In this study, we optimized a previously developed high-throughput genetic screen for monitoring protein misfolding and aggregation in bacteria. This system is based on monitoring the fluorescence of Escherichia coli cells expressing fusions of human misfolding-prone and disease-related proteins (MisPs) with the green fluorescent protein. We systematically tested a variety of experimental conditions, such as overexpression conditions and MisP-GFP fusion formats, to identify key parameters that affect the sensitivity and dynamic range of the assay. Using misfolding-prone, cancer-associated variants of human p53 as a model system, we found that strong overexpression conditions, such as high copy number vectors, strong promoters, high inducer concentrations, and high overexpression temperatures, can yield optimal assay performance. These optimized assay conditions were also validated with additional MisPs, such as the Alzheimer's disease-associated amyloid-β peptide and variants of superoxide dismutase 1 associated with amyotrophic lateral sclerosis. At the same time, we observed that certain conditions, such as inducer concentrations and overexpression temperature, may need to be precisely fine-tuned for each new MisP target to yield optimal assay performance. Our findings provide a framework for standardizing MisP-GFP screening assays, facilitating their broad application in the discovery of therapeutic agents targeting protein misfolding and aggregation.}, }
@article {pmid40353906, year = {2025}, author = {Kleinerova, J and Querin, G and Pradat, PF and Siah, WF and Bede, P}, title = {New developments in imaging in ALS.}, journal = {Journal of neurology}, volume = {272}, number = {6}, pages = {392}, pmid = {40353906}, issn = {1432-1459}, support = {JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; *Neuroimaging/methods/trends ; *Brain/diagnostic imaging ; Magnetic Resonance Imaging ; }, abstract = {Neuroimaging in ALS has contributed considerable academic insights in recent years demonstrating genotype-specific topological changes decades before phenoconversion and characterising longitudinal propagation patterns in specific phenotypes. It has elucidated the radiological underpinnings of specific clinical phenomena such as pseudobulbar affect, apathy, behavioural change, spasticity, and language deficits. Academic concepts such as sexual dimorphism, motor reserve, cognitive reserve, adaptive changes, connectivity-based propagation, pathological stages, and compensatory mechanisms have also been evaluated by imaging. The underpinnings of extra-motor manifestations such as cerebellar, sensory, extrapyramidal and cognitive symptoms have been studied by purpose-designed imaging protocols. Clustering approaches have been implemented to uncover radiologically distinct disease subtypes and machine-learning models have been piloted to accurately classify individual patients into relevant diagnostic, phenotypic, and prognostic categories. Prediction models have been developed for survival in symptomatic patients and phenoconversion in asymptomatic mutation carriers. A range of novel imaging modalities have been implemented and 7 Tesla MRI platforms are increasingly being used in ALS studies. Non-ALS MND conditions, such as PLS, SBMA, and SMA, are now also being increasingly studied by quantitative neuroimaging approaches. A unifying theme of recent imaging papers is the departure from describing focal brain changes to focusing on dynamic structural and functional connectivity alterations. Progressive cortico-cortical, cortico-basal, cortico-cerebellar, cortico-bulbar, and cortico-spinal disconnection has been consistently demonstrated by recent studies and recognised as the primary driver of clinical decline. These studies have led the reconceptualisation of ALS as a "network" or "circuitry disease".}, }
@article {pmid40353466, year = {2025}, author = {Dhasmana, S and Dhasmana, A and Khan, S and Narula, AS and Haque, S and Yallapu, MM and Chauhan, SC}, title = {Excessive Urinary p75ecd is a Potential Indicator of Amyotrophic Lateral Sclerosis: An American Cohort Study.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X352364250212035802}, pmid = {40353466}, issn = {1875-6190}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and rapidly progressive neurodegenerative disease. At present, neurofilament light (NFL) and phosphorylated neurofilament heavy (pNfH) proteins in biological fluids are commonly known prognostic biomarkers, but their levels stabilize over time. Thus, there is a critical gap in the field to identify unique biomarkers that can aid disease diagnosis, progression and monitoring the therapy response.<br><br>AIM: To evaluate the presence of extracellular domain of p75 (p75ecd) in urine of ALS patients and healthy control volunteers in the North American cohort.<br><br>METHOD: An enzyme-linked immunoassay (ELISA) and creatinine assay was used to determine the levels of p75ecd and creatinine in the urine of ALS patients and healthy control volunteers respectively. This assay demonstrated clear discrimination in the levels of the p75ecd in the urine samples of ALS patients as compared to healthy individuals.<br><br>RESULTS: It was found that the concentration of p75ecd in ALS samples was significantly higher than that of healthy controls group. Additionally, high p75ecd levels were segregated with respect to age, sex, family history, occupation and drug treatment, medication status. Moreover, we observed differential expression patterns among the different stages of the disease. Our results followed the pattern that was observed in the Chinese, and Australian cohort.<br><br>CONCLUSION: Altogether, our results indicate that the development of an efficient system for the detection of elevated levels of p75ecd in the urine could serve as a useful modality for early ALS diagnosis, disease progression, and monitoring the effectiveness of therapeutic interventions.}, }
@article {pmid40353188, year = {2025}, author = {Liu, Y and Topsakal, M and Zheng, K and Betancourt, LE and Woods, M and Roy, S and Patra, N and Leshchev, D and Halstenberg, P and Maltsev, DS and Dai, S and Ivanov, AS and Bryantsev, VS and Wishart, JF and Gakhar, R and Frenkel, AI and Gill, SK}, title = {Correlative analysis of Ni(ii) coordination states in molten salts using a combination of X-ray and optical spectroscopies and simulations.}, journal = {Chemical science}, volume = {}, number = {}, pages = {}, doi = {10.1039/d5sc01059d}, pmid = {40353188}, issn = {2041-6520}, abstract = {Understanding the factors that control the speciation of metal ions in molten salts is crucial for the successful deployment of molten salts in both concentrated solar power and nuclear energy applications. The speciation of the Ni(ii) ion is of interest because it is a common corrosion product, and the distribution of coordination states it occupies is highly sensitive to the molten salt matrix. We employ in situ X-ray absorption spectroscopy (XAS), optical spectroscopy, and ab initio molecular dynamics (AIMD) simulations to investigate and understand the heterogeneities of Ni(ii) coordination in LiCl-KCl, NaCl-MgCl2, and LiCl-ZnCl2 molten salt systems. The main challenge lies in identifying the population distribution of Ni(ii) coordination states as a function of temperature and melt composition. We combined the multivariate curve resolution - alternating least squares (MCR-ALS) analysis of the XAS data and principal component analysis (PCA) of the optical spectra to determine the number of unique coordination states coexisting in the molten state, extract X-ray spectra for each state, and obtain their mixing fractions at different temperatures and for different salt mixtures. AIMD simulations were essential in identifying the coordination states corresponding to the deconvoluted spectra. The differences in the coordination states of Ni(ii) in different salt systems are discussed in terms of the effects of the varying polarizing powers of the cations in the host salt matrix on chloride ion coordination to Ni(ii). Such elucidation of the local structure adopted by metal ions enables a better understanding of the factors controlling the speciation of ions and their effect on molten salt properties.}, }
@article {pmid40352904, year = {2025}, author = {Quizhpilema, JC and Legarda, A and Hidalgo, JM and Lecumberri, P and Jerico, I and Cabada, T}, title = {Asymmetric white matter degeneration in amyotrophic lateral sclerosis: a diffusion kurtosis imaging study of motor and extra-motor pathways.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1581719}, doi = {10.3389/fnins.2025.1581719}, pmid = {40352904}, issn = {1662-4548}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that lacks effective early biomarkers. This study investigated the potential of diffusion kurtosis imaging (DKI) as a non-invasive biomarker for detecting and monitoring ALS progression through a comprehensive analysis of white matter alterations.<br><br>METHODS: We performed a cross-sectional analysis of magnetic resonance images with advanced diffusion imaging techniques in ALS patients recruited from a neurodegenerative consultation service over a 3-year period and healthy controls. Our methodology employed multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD) for tract reconstruction and diffusion kurtosis imaging for microstructural analysis. The study focused particularly on the corticospinal tract and associated pathways, utilizing both tract-specific Bundle Analytics (BUAN) and whole-brain Tract-Based Spatial Statistics (TBSS) approaches.<br><br>RESULTS: The study included 33 ALS patients and 37 controls with no significant differences in age or gender. ALS patients predominantly presented with spinal onset and exhibited moderate functional impairment (ALSFRS-R: 39.09 &#xb1; 5). Whole-brain TBSS revealed widespread white matter alterations, with increased MD, RD, and AD, and decreased FA notably in the corona radiata, internal capsule, and corticospinal tracts. Detailed fiber tracking of the corticospinal tracts showed significant microstructural changes, with the left CST displaying pronounced increases in MD and AD alongside reduced FA, while the right CST exhibited distinctive regional variations. Additionally, analyses of the frontopontine and parietopontine tracts uncovered further alterations in diffusion metrics. Despite imaging findings, clinical-radiological correlations with functional scores and disease progression were not statistically significant.<br><br>CONCLUSIONS: This study explores DKI as a potential biomarker for ALS pathology, revealing microstructural changes in both motor and extra-motor pathways. Using whole-brain TBSS analysis and tractography with DIPY, we identified an asymmetric pattern of degeneration and involvement of integrative neural networks, providing new insights into ALS pathophysiology. These findings contribute to our understanding of the complex structural alterations in ALS and suggest that DKI-derived metrics may have utility in characterizing the disease process.}, }
@article {pmid40351442, year = {2025}, author = {Khanal, P and Chikhale, R and Machhi, J}, title = {Editorial: Targeting neuroinflammation for novel therapeutics in neurodegenerative diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1602495}, doi = {10.3389/fphar.2025.1602495}, pmid = {40351442}, issn = {1663-9812}, }
@article {pmid40350993, year = {2025}, author = {Vedeler, A and Tartaglia, GG and Pastore, A}, title = {Annexin, a Protein for All Seasons: From Calcium Dependent Membrane Metabolism to RNA Recognition.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {}, number = {}, pages = {e70019}, doi = {10.1002/bies.70019}, pmid = {40350993}, issn = {1521-1878}, support = {ASTRA_855923//ERC&#xa0;/ ; PNRRCN00000041andEPNRRCN3//Piano Nazionale di Ripresa e Resilienza of Italian MUR/ ; IVBM4PAP_101098989//EIC Pathfinder/ ; ARUK_PG2019B-020//ARUK&#xa0;/ ; }, abstract = {Annexins are a protein family well known to bind to phospholipids in a calcium-dependent way. They are involved in several different crucial cellular processes such as cell division, calcium signaling, membrane repair, vesicle trafficking, and apoptosis. Although RNA binding for some members of the family was reported long ago, it was only recently that it was shown that a common feature of the family is also the ability to bind RNA, a discovery that has added significantly to our perception of the cellular role of these proteins. In the present review, we discuss the properties of annexins under an updated light and the current knowledge on the RNA binding properties of annexins. We then focus specifically on annexin A11, because this is a less characterized member of the family but, at the same time, a potentially important component of the mRNA transport machinery in neurons. We hope to offer to the reader a more complete picture of the annexins' binding properties and new tools to evaluate the multifaceted functions of this important protein family.}, }
@article {pmid40350723, year = {2025}, author = {Kuznetsova, DR and Kutlubaev, MA and Pervushina, EV}, title = {[Oculomotor disorders in patients with amyotrophic lateral sclerosis].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {4}, pages = {7-12}, doi = {10.17116/jnevro20251250417}, pmid = {40350723}, issn = {1997-7298}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Ocular Motility Disorders/etiology/physiopathology/diagnosis ; Saccades ; Eye Movements ; }, abstract = {Oculomotor disorders are not typical manifestations of amyotrophic lateral sclerosis (ALS). Occasionally, this disease is associated with vertical gaze paresis, presenting a distinct type as «ALS+progressive supranuclear palsy». Studies using eye-tracking methods have revealed a variety of subclinical oculomotor disorders in this disease. These disorders can manifest as changes in reflex and voluntary saccades, antisaccades, smooth tracking eye movements, and fixations. A significant association between oculomotor disorders and clinical manifestations of ALS was reported. The occurrence of oculomotor disorders indicates the involvement of broader neuroanatomical structures, including the prefrontal cortex and basal ganglia. The lack of consistency in the data from different studies and their limited number emphasize the need for further research in this area.}, }
@article {pmid40350633, year = {2025}, author = {Ishiura, H}, title = {[Genetics of Motor Neuron Diseases and Hereditary Spastic Paraplegia].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {5}, pages = {481-491}, doi = {10.11477/mf.188160960770050481}, pmid = {40350633}, issn = {1881-6096}, mesh = {Humans ; *Spastic Paraplegia, Hereditary/genetics/diagnosis/therapy ; *Motor Neuron Disease/genetics/diagnosis ; }, abstract = {Motor neuron diseases encompass a range of phenotypes, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and spinal muscular atrophy (SMA). Related conditions include spinal and bulbar muscular atrophy (SBMA) and hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). Hereditary spastic paraplegia (HSP)-a group of disorders primarily affecting the corticospinal tract-also exhibits diverse clinical manifestations. This review summarizes the genetic basis of these diseases, along with their clinical characteristics, diagnostic approaches, and disease-specific therapies.}, }
@article {pmid40350531, year = {2025}, author = {Woo, TG and Han, J and Kim, Y and Hwang, YJ and Lee, M and Kang, SM and Park, S and Ji, Y and Chung, YH and Baek, S and Shin, E and Minju-Kim,  and Jang, H and Shin, YJ and Kwon, Y and Kim, BH and Park, BJ}, title = {Inhibition of SOD1 trimerization is a novel drug target for ALS disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {21}, pmid = {40350531}, issn = {2047-9158}, support = {RS-2024-00399681//Ministry of Science and ICT, South Korea/ ; RS-2024-00339289//Ministry of Science and ICT, South Korea/ ; RS-2023-00258714//Korea Drug Development Fund/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics/antagonists &amp; inhibitors ; Animals ; Humans ; Mice ; Mice, Transgenic ; *Protein Multimerization/drug effects ; Disease Models, Animal ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that begins with motor neuron death in the spinal cord and cerebral cortex, ultimately resulting in death from respiratory distress (breathing failure). About 90% of ALS cases are sporadic, and 10% of ALS cases are of the inherited type with a genetic cause. About 150 different gene mutations have been reported so far. SOD1 is a well-identified gene associated with ALS. Indeed, SOD1 aggregation has been reported in ALS patients, but the mechanism of SOD1 aggregation remains unclear. Our previous work showed that inhibiting SOD1 aggregation with a hit compound (PRG-A-01) could reduce the SOD1-induced cytotoxicity and extend the lifespan of ALS mouse model (SOD1[G93A-Tg]). However, the low bioavailability and rapid degradation of the compound in vivo necessitates the development of a more effective candidate. We generated different derivatives and finally obtained the most potential drug candidate, PRG-A-04.<br><br>METHODS: Neuronal cell lines were transfected with the mutant SOD1 expression vector and incubated with PRG-A-04. SOD1 aggregation was examined by SOD1 oligomerization assay, immunofluorescence and dot blot assay. The interaction between GST-conjugated SOD1 recombinant proteins and PRG-A-04 was identified using LC-MS/MS and GST pull-down assay. To check the in vivo therapeutic effect of PRG-A-04, SOD1[G93A-Tg] mice were injected with PRG-A-04; then behavioral test, histological analysis and microarray were performed.<br><br>RESULTS: PRG-A-04 demonstrated favorable pharmacokinetics including high bioavailability and significant blood-brain barrier penetration. Indeed, oral administration of PRG-A-04 in ALS mouse model inhibited the aggregation of SOD1 in the spinal cord, protected against neuronal loss, and extended the lifespan of ALS mice by up to 3&#xa0;weeks. In vitro, PRG-A-04 selectively bound to the mutant form of SOD1, but not the wild type, and efficiently inhibited the aggregation caused by SOD1-G147P (a SOD1 trimer stabilizer).<br><br>CONCLUSIONS: Our findings underscore the potential of targeting trimeric SOD1 in ALS treatment, positioning PRG-A-04 as a strong drug candidate for both familial and sporadic ALS.}, }
@article {pmid40350485, year = {2025}, author = {Rofail, D and Chladek, M and Williams, B and Patel, N and Nowell, WB and Karantzoulis, S and Levy, O}, title = {Advancing Future Amyotrophic Lateral Sclerosis Medicines by Incorporating The Patient Voice Into Patient-Centered Holistic Measurement Strategies for Clinical and Real-World Studies: Results from Targeted Literature Reviews.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {40350485}, issn = {2193-8253}, abstract = {INTRODUCTION: This analysis sought to understand the patient experience in amyotrophic lateral sclerosis (ALS) and to assess whether commonly used clinical outcome assessments (COAs) reliably and validly capture that experience.<br><br>METHODS: Two targeted literature reviews were conducted to identify and describe key concepts potentially important to patients (signs, symptoms, impacts), and identify commonly used COAs in ALS. Insights gained were used to map target COAs to concepts identified as potentially relevant to patients and their caregivers. COAs of interest were further examined to evaluate evidence of their validity and reliability within ALS.<br><br>RESULTS: Forty-three articles were identified for concept extraction. Signs and symptoms were identified across multiple themes: motor; non-motor; respiratory; cognitive; and behavioral. Patient impacts were identified across multiple themes: physical; functional; emotional; social; and other aspects of well-being. Caregiver impacts were identified across four themes: general; emotional; social; and physical. Of 236 unique COAs identified, 6 were found to provide the greatest coverage of potentially important concepts. Closer examination of these showed some evidence gaps supporting content validity and/or psychometric properties.<br><br>CONCLUSIONS: Several concepts related to ALS were identified that are relevant to patients in their daily lives. We identified and reviewed COAs commonly used in assessing these concepts, and found gaps in their content validity and/or psychometric properties. These findings suggest the need for further testing/refinement of existing tools, and the opportunity to use other instruments alongside those most frequently used (e.g., ALSFRS-R) to comprehensively capture the patient experience of ALS in future clinical trial and real-world studies.}, }
@article {pmid40350140, year = {2025}, author = {Amin, MA and Zehravi, M and Sweilam, SH and Shatu, MM and Durgawale, TP and Qureshi, MS and Durgapal, S and Haque, MA and Vodeti, R and Panigrahy, UP and Ahmad, I and Khan, S and Emran, TB}, title = {Neuroprotective potential of epigallocatechin gallate in Neurodegenerative Diseases: Insights into molecular mechanisms and clinical Relevance.}, journal = {Brain research}, volume = {}, number = {}, pages = {149693}, doi = {10.1016/j.brainres.2025.149693}, pmid = {40350140}, issn = {1872-6240}, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis pose significant challenges due to their complex pathophysiology and lack of effective treatments. Green tea, rich in the epigallocatechin gallate (EGCG) polyphenolic component, has demonstrated potential as a neuroprotective agent with numerous medicinal applications. EGCG effectively reduces tau and Aβ aggregation in ND models, promotes autophagy, and targets key signaling pathways like Nrf2-ARE, NF-κB, and MAPK. This review explores the molecular processes that underlie EGCG's neuroprotective properties, including its ability to regulate mitochondrial dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Clinical research indicates that EGCG may enhance cognitive and motor abilities, potentially inhibiting disease progression despite absorption and dose optimization limitations. The substance has been proven to slow the amyloidogenic process, prevent protein aggregation, decrease amyloid cytotoxicity, inhibit fibrillogenesis, and restructure fibrils for synergistic therapeutic effects. The review highlights the potential of EGCG as a natural, multi-targeted strategy for NDs but emphasizes the need for further clinical trials to enhance its therapeutic efficacy.}, }
@article {pmid40349639, year = {2025}, author = {Maiocchi, A and Pedrini, M and Ferrari, V and Assunçao Carreira, AS and D'Amore, VM and Santoro, F and Di Porzio, A and Bosetti, M and Cristofani, R and Silvani, A and Brancaccio, D and Marinelli, L and Di Leva, FS and Provenzani, A and Poletti, A and Seneci, P}, title = {Design, synthesis and characterization of aryl bis-guanyl hydrazones as RNA binders of C9orf72 G4C2 extended repeats.}, journal = {European journal of medicinal chemistry}, volume = {293}, number = {}, pages = {117736}, doi = {10.1016/j.ejmech.2025.117736}, pmid = {40349639}, issn = {1768-3254}, abstract = {Expanded G4C2 repeats derived from mutations of the C9orf72 gene are causative factors in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, leading to multiple pathological events. Bis thiophene para dinicotinimidamide 2a was reported to preferentially stabilize G-quadruplex G4C2 RNA structures at sub-micromolar concentrations. We replaced its amidine groups with BBB-compliant guanyl hydrazones, and carried out scaffold variations to improve water solubility. An eight-membered array was built around bis-thiophene- (4b-6a), bis-oxazole- (7b), diphenylurea diamide- (8b) and phenyldioxy ditriazolephenyl scaffolds (9a,b). Biological profiling of the array identified 4b as a promising, drug-like hit, active in cellular assays on ALS patient-derived cells.}, }
@article {pmid40349338, year = {2025}, author = {Hölbling, BV and Gupta, Y and Marchi, PM and Atilano, ML and Flower, M and Ureña, E and Goulden, RA and Dobbs, HK and Katona, E and Mikheenko, A and Giblin, A and Awan, AR and Fisher-Ward, CL and O'Brien, N and Vaizoglu, D and Kempthorne, L and Wilson, KM and Gittings, LM and Carcolé, M and Ruepp, MD and Mizielinska, S and Partridge, L and Fratta, P and Tabrizi, SJ and Selvaraj, BT and Chandran, S and Armstrong, E and Whiting, P and Isaacs, AM}, title = {A multimodal screening platform for endogenous dipeptide repeat proteins in C9orf72 patient iPSC neurons.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115695}, doi = {10.1016/j.celrep.2025.115695}, pmid = {40349338}, issn = {2211-1247}, abstract = {Repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-associated non-AUG (RAN) translation generates neurotoxic dipeptide repeat proteins (DPRs). To study endogenous DPRs, we inserted the minimal HiBiT luciferase reporter downstream of sense repeat derived DPRs polyGA or polyGP in C9orf72 patient iPSCs. We show these "DPReporter" lines sensitively and rapidly report DPR levels in lysed and live cells and optimize screening in iPSC neurons. Small-molecule screening showed the ERK1/2 activator periplocin dose dependently increases DPR levels. Consistent with this, ERK1/2 inhibition reduced DPR levels and prolonged survival in C9orf72 repeat expansion flies. CRISPR knockout screening of all human helicases revealed telomere-associated helicases modulate DPR expression, suggesting common regulation of telomeric and C9orf72 repeats. These DPReporter lines allow investigation of DPRs in their endogenous context and provide a template for studying endogenous RAN-translated proteins, at scale, in other repeat expansion disorders.}, }
@article {pmid40349108, year = {2025}, author = {Weiss, A and Gilbert, JW and Rivera Flores, IV and Belgrad, J and Ferguson, C and Dogan, EO and Wightman, N and Mocarski, K and Echeverria, D and Harkins, AL and Summers, A and Bramoto, B and McHugh, N and Furgal, R and Yamada, N and Cooper, D and Monopoli, K and Godinho, BMDC and Hassler, MR and Yamada, K and Greer, P and Henninger, N and Brown, RH and Khvorova, A}, title = {RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2025.05.010}, pmid = {40349108}, issn = {1525-0024}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNA[SOD1] extended survival in SOD1-G93A ALS mice, increasing survival beyond that previously seen in these mice by ASO modalities, slowed disease progression according to the standard ALS preclinical endpoints, and attenuated ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.}, }
@article {pmid40348172, year = {2025}, author = {Xin, Z and Xin, C and Huo, J and Liu, Q and Dong, H and Li, X and Liu, Y and Li, R}, title = {Stage-dependent efficacy of short-chain fatty acids in amyotrophic lateral sclerosis: Insights into autophagy and neuroprotection.}, journal = {Life sciences}, volume = {}, number = {}, pages = {123686}, doi = {10.1016/j.lfs.2025.123686}, pmid = {40348172}, issn = {1879-0631}, abstract = {AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options. Previously, we have shown that a combination of multiple probiotic strains can regulate intestinal flora, increase serum short-chain fatty acids (SCFAs), reduce abnormal protein accumulation in the spinal cord, and protect neurons. It is necessary to explore the mechanism to provide therapeutic targets for ALS.<br><br>MATERIALS AND METHODS: This study utilizes live cell imaging, mouse behavioral research, immunofluorescence, Electron microscopy, Western Blot, and polymerase chain reaction to explore the impact of various SCFAs on ALS animal and cell models, as well as their underlying mechanisms.<br><br>KEY FINDINGS: We found SCFAs, including butyrate and propionate can increase the levels of acetylated histones, enhance the expression of autophagy-related genes and regulate autophagy, leading to a decrease in abnormal SOD1 aggregation, reduction of cell damage, and enhancement of cell proliferation in NSC34-SOD1[G93A] cells. Furthermore, systemic administration of butyrate and propionate can regulate autophagy, reduce SOD1 aggregation, and protect spinal cord neurons in SOD1[G93A] mice. However, these favorable effects of butyrate and propionate are greatly decreased at later stages of the disease process in SOD1[G93A] mice.<br><br>SIGNIFICANCE: Our study revealed that the positive impact of SCFAs in autophagy could be a promising focus for ALS therapy. However, this effect might have different impacts in different stages of ALS.}, }
@article {pmid40347374, year = {2025}, author = {Varshney, V and Gabble, BC and Bishoyi, AK and Varma, P and Qahtan, SA and Kashyap, A and Panigrahi, R and Nathiya, D and Chauhan, AS}, title = {Exploring Exosome-Based Approaches for Early Diagnosis and Treatment of Neurodegenerative Diseases.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40347374}, issn = {1559-1182}, abstract = {Neurodegenerative diseases (NDs), like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), present an increasingly significant global health burden, primarily due to the lack of effective early diagnostic tools and treatments. Exosomes-nano-sized extracellular vesicles secreted by nearly all cell types-have emerged as promising candidates for both biomarkers and therapeutic agents in NDs. This review examines the biogenesis, molecular composition, and diverse functions of exosomes in NDs. Exosomes play a crucial role in mediating intercellular communication. They are capable of reflecting the biochemical state of their parent cells and have the ability to cross the blood-brain barrier (BBB). In doing so, they facilitate the propagation of pathological proteins, such as amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn), while also enabling the targeted delivery of neuroprotective compounds. Recent advancements in exosome isolation and engineering have opened up new possibilities for diagnostic and therapeutic strategies. These range from the discovery of non-invasive biomarkers to innovative approaches in gene therapy and drug delivery systems. However, challenges related to standardization, safety, and long-term effects must be addressed before exosomes can be translated into clinical applications. This review highlights both the promising potential and the obstacles that must be overcome to leverage exosomes in the treatment of NDs and the transformation of personalized medicine.}, }
@article {pmid40346952, year = {2025}, author = {Çelik, F}, title = {Xenon in ALS Treatment: What Are We Waiting for?.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {31}, number = {5}, pages = {e70435}, pmid = {40346952}, issn = {1755-5949}, }
@article {pmid40346939, year = {2025}, author = {Santibanez, RCG and Fournier, CN}, title = {The Necessity of Overcoming Racial Disparities in Amyotrophic Lateral Sclerosis Care and Research.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28433}, pmid = {40346939}, issn = {1097-4598}, }
@article {pmid40348049, year = {2025}, author = {Reda, A and Khalil, H and Bahgat, EA and Fawzy, MG}, title = {Univariate versus multivariate approaches for resolving the overlapped spectra of azelastine hydrochloride and mometasone furoate.}, journal = {Analytical biochemistry}, volume = {}, number = {}, pages = {115902}, doi = {10.1016/j.ab.2025.115902}, pmid = {40348049}, issn = {1096-0309}, abstract = {Azelastine hydrochloride (AZE) and Mometasone furoate (MOM) combination is used to treat allergic rhinitis' symptoms. The aim of this work is to qualitatively and quantitatively analyze both medications using univariate and multivariate spectrophotometric techniques in a comparative study. Regarding univariate approaches; AZE was quantified by direct measurement at 291 nm within (5 - 60 μg/mL) concentration range. While, MOM was assayed by absorption correction (AC) approach at 250 nm within the range of (2 - 18 μg/mL). The LOD values for AZE and MOM were (0.79 μg/mL) and (0.21 μg/mL), respectively. Classical least squares (CLS), partial least squares (PLS), principal component regression (PCR), multivariate curve resolution-alternating least squares (MCR-ALS) and artificial neural networks (ANN) were the applied multivariate chemometric models. The proposed methods were utilized for analyzing the binary mixture in laboratory-prepared mixtures and pharmaceutical preparation with correlation coefficients values ≥ 0.9996. No statistically significant variation was found between the applied methods and the reported HPLC one. The methods' sustainability was assessed using blue applicability grade index (BAGI) and Red-Green-Blue 12 (RGB12) metrics. The obtained findings revealed that the suggested methodologies are safer option than the published HPLC technique for the conventional pharmaceutical analysis of the studied medications.}, }
@article {pmid40347946, year = {2025}, author = {Blazev, R and Zee, BM and Peckham, H and Ng, YK and Lewis, CTA and Zhang, C and McNamara, JW and Goodman, CA and Gregorevic, P and Ochala, J and Steyn, FJ and Ngo, ST and Stokes, MP and Parker, BL}, title = {Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS.}, journal = {Cell reports methods}, volume = {}, number = {}, pages = {101048}, doi = {10.1016/j.crmeth.2025.101048}, pmid = {40347946}, issn = {2667-2375}, abstract = {UFMylation is a ubiquitin-like protein modification of Ubiquitin Fold Modifier 1 (UFM1) applied to substrate proteins and regulates several cellular processes such as protein quality control. Here, we describe the development of an antibody-based enrichment approach to immunoprecipitate remnant UFMylated peptides and identification by mass spectrometry. We used this approach to identify >200 UFMylation sites from various mouse tissues, revealing extensive modification in skeletal muscle. In vivo knockdown of the E2 ligase, UFC1, followed by enrichment and analysis of remnant UFMylated peptides quantified concomitant down-regulation and validation of a subset of modification sites, particularly myosin UFMylation. Furthermore, we show that UFMylation is increased in skeletal muscle biopsies from people living with amyotrophic lateral sclerosis (plwALS). Quantification of UFMylation sites in these biopsies with multiplexed isotopic labeling reveal prominent increases in myosin UFMylation. Our data suggest that in vivo UFMylation is more complex than previously thought.}, }
@article {pmid40346885, year = {2025}, author = {Tahedl, M and Kleinerova, J and Doherty, MA and Hengeveld, JC and McLaughlin, RL and Hardiman, O and Tan, EL and Bede, P}, title = {Progressive Thalamo-Cortical Disconnection in Amyotrophic Lateral Sclerosis Genotypes: Structural Degeneration and Network Dysfunction of Thalamus-Relayed Circuits.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70146}, doi = {10.1111/ene.70146}, pmid = {40346885}, issn = {1468-1331}, support = {17/CDA/4737/SFI_/Science Foundation Ireland/Ireland ; SFI SP20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; HRB EIA-2017-019 &amp; JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/diagnostic imaging/physiopathology ; *Thalamus/pathology/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Neural Pathways/pathology/diagnostic imaging/physiopathology ; Magnetic Resonance Imaging ; *Cerebral Cortex/pathology/diagnostic imaging/physiopathology ; Genotype ; Adult ; Prospective Studies ; *Nerve Net/pathology/diagnostic imaging/physiopathology ; Longitudinal Studies ; }, abstract = {BACKGROUND: The thalamus is a key subcortical hub of numerous corticobasal and corticocortical circuits mediating a wealth of cognitive, behavioural, sensory and motor processes. While thalamic pathology is increasingly recognised in amyotrophic lateral sclerosis, its degeneration is often assessed in isolation instead of adopting a network-wise perspective and assessing the integrity of its rich cortical projections.<br><br>METHODS: A prospective imaging study was conducted in a cohort of genetically stratified patients to assess the structural and functional integrity of thalamo-cortical circuits and volumetric alterations longitudinally.<br><br>RESULTS: The white matter integrity of thalamic projections to the anterior cingulate cortex, cerebellum, dorsolateral prefrontal cortex (DLPFC), Heschl's gyrus, medial frontal gyrus (MFG), orbitofrontal cortex, parietal cortex, postcentral gyrus and precentral gyrus (PreCG) is affected at baseline in ALS, which is more marked in C9orf72 hexanucleotide repeat carriers. Precentral gyrus and cerebellar grey matter volumes are also reduced, particularly in C9orf72. Longitudinal analyses capture progressive disconnection between the thalamus and frontal regions (DLPFC and MFG) in both C9orf72 positive and sporadic patients and progressive thalamo-PreCG disconnection in the sporadic C9orf72 negative cohort. Functional connectivity analyses revealed increasing thalamo-cerebellar connectivity in sporadic ALS and increasing thalamo-DLPFC connectivity in intermediate-length CAG repeat expansion carriers in ATXN2 over time.<br><br>DISCUSSION: Our data provide evidence of extensive thalamo-cortical connectivity alterations in ALS. Corticobasal circuits mediating extrapyramidal, somatosensory, cognitive and behavioural functions are increasingly affected as the disease progresses. The degeneration of thalamic projections support the conceptualisation of ALS as a 'network disease' and the notion of 'what wires together degenerates together'.}, }
@article {pmid40346540, year = {2025}, author = {Lombardi, I and Ferrero, C and Vulcano, E and Rasà, DM and Gelati, M and Pastor, D and Carletti, RM and de la Morena, S and Profico, DC and Longobardi, S and Lazzarino, E and Perciballi, E and Rosati, JD and Martinez, S and Vercelli, A and Vescovi, AL and Boido, M and Ferrari, D}, title = {Safety and efficacy evaluation of intracerebroventricular human neural stem cell transplantation in SOD1 mice as a novel approach for ALS.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {529}, pmid = {40346540}, issn = {1479-5876}, support = {Fondazione Revert Onlus//Fondazione Revert Onlus/ ; 2019-ATESP-0028//Universit&#xe0; degli Studi di Milano-Bicocca/ ; Dipartimenti di Eccellenza 2023-2027 to Department of Neuroscience "Rita Levi Montalcini"//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; R24-5x1000 to Fondazione IRCCS Casa Sollievo della Sofferenza//Ministero della Salute/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/pathology/physiopathology ; *Neural Stem Cells/transplantation/cytology ; Humans ; *Superoxide Dismutase-1/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Injections, Intraventricular ; *Stem Cell Transplantation ; Treatment Outcome ; Spinal Cord/pathology ; }, abstract = {BACKGROUND: Neural stem cell (NSC) transplantation holds promising therapeutic potential for neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). However, pre-clinical studies and early-phase clinical trials have faced challenges hindering the effective clinical translation of this approach. Crucial hurdles include the side-effects of prolonged immunosuppression, concerns regarding cell origin and transplantation dosage, identification of the most appropriate therapeutic window, and invasiveness of surgical procedures. Here, we assessed the safety and efficacy of intracerebroventricular (ICV) hNSC transplantation as a novel and possibly more effective experimental approach for ALS.<br><br>METHODS: We evaluated the safety of administering up to 1&#x2009;&#xd7;&#x2009;10[6] hNSCs in immunodeficient mice and assessed their potential efficacy in reducing ALS hallmarks employing the SOD1[G93A] mouse model. Both transient (15 days) and prolonged immunosuppression regimens, at low (15&#xa0;mg/kg) and high (30&#xa0;mg/kg) doses, were tested along with two different cell dosages (3&#x2009;&#xd7;&#x2009;10[5] and 1&#x2009;&#xd7;&#x2009;10[6]).<br><br>RESULTS: Our study suggests that: (i) a bilateral ICV transplantation of 1&#x2009;&#xd7;&#x2009;10[6] hNSCs is safe and non-tumorigenic in immunodeficient hosts; (ii) sustained and high-dose immunosuppression is essential for ensuring cell survival in immunocompetent SOD1[G93A] mice; and (iii) hNSCs may delay motor symptom progression and reduce spinal cord microgliosis in SOD1[G93A] mice when administered in the lateral ventricles under prolonged high-dose (30&#xa0;mg/kg) immunosuppression.<br><br>CONCLUSIONS: ICV transplantation of hNSCs emerges as a safe and promising strategy for ALS, demonstrating potential to delay motor decline and reduce spinal cord microgliosis. However, sustained high-dose immunosuppression is crucial for therapeutic efficacy, emphasizing the need for further optimization to overcome translational challenges and achieve durable clinical benefits.}, }
@article {pmid40346135, year = {2025}, author = {Abril, SP and Rincón-Díaz, N and Puyana, M and Castellanos, L and Ramos, FA}, title = {Photoprotective activity from Colombian Caribbean brown algae using HPLC-DAD metabolic profiling by MCR-ALS data analysis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {16204}, pmid = {40346135}, issn = {2045-2322}, support = {1101-852-69964//Ministerio de Ciencia, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; 1101-852-69964//Ministerio de Ciencia, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; 1101-852-69964//Ministerio de Ciencia, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; 1101-852-69964//Ministerio de Ciencia, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; 1101-852-69964//Ministerio de Ciencia, Tecnolog&#xed;a e Innovaci&#xf3;n/ ; }, mesh = {Chromatography, High Pressure Liquid/methods ; *Phaeophyceae/metabolism/chemistry ; Antioxidants/pharmacology/chemistry ; *Metabolomics/methods ; Ultraviolet Rays/adverse effects ; Caribbean Region ; *Sunscreening Agents/pharmacology/chemistry ; *Metabolome ; }, abstract = {Although synthetic UV filters are widely used for skin photoprotection, growing concerns about their environmental and health impacts underscore the need for new, effective photoprotective products. This study aimed to develop a screening methodology for selecting brown macroalgae extracts with potential photoprotective activity. The approach integrates in vitro photoprotection assays, antioxidant TLC-DPPH assays, and HPLC-DAD metabolic profiling of 17 algal samples from the Dictyota, Canistrocarpus, Stypopodium, Sargassum, Lobophora, Padina, and Turbinaria genera. The results revealed concentration-dependent sun protection factor (SPF) values ranging from 0.403 to 2.915, UVA ratios (UVAr) ranging from 0.167 to 3.623, critical wavelengths (λc) ranging from 335 to 393 nm, and antioxidant DPPH-TLC activity in 10 of the evaluated extracts. These findings were correlated with the HPLC-DAD metabolic profile using the Multivariate Curve Resolution- Alternating Least Squares (MCR-ALS) algorithm and multivariate data analysis tools. Extracts from Canistrocarpus cervicornis (CCe) and Stypopodium zonale (SS) presented the most promising photoprotective activity. Through NMR and MS analysis, 2,5,7-trihydroxy-2-pentadecylchroman-4-one (1), fucoxanthin, pheophytin a, and pheophorbide a were identified as the main contributors to this activity. This methodology was successfully implemented and could be further used to screen for photoprotective activity in algal species.}, }
@article {pmid40345258, year = {2025}, author = {Sepulveda, M and Martinez-Traub, F and Ojeda, P and Perez, V and Ojeda, J and Mella, J and Diaz, R and Rozas, P and Mansilla-Jaramillo, M and Zuleta, A and Diaz, G and Kerr, B and Woehlbier, U and Henríquez, JP and Medinas, DB and Hetz, C}, title = {Expression of a protein disulfide isomerase A3 variant associated with amyotrophic lateral sclerosis triggers disease features in mice.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106947}, doi = {10.1016/j.nbd.2025.106947}, pmid = {40345258}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated with motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving biochemical and genetic perturbations. In ALS cases, we previously identified variants in the gene encoding PDIA3 (also known as Grp58 or ERp57), which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here, we report the generation of transgenic mice expressing the ALS-associated PDIA3[Q481K] variant. Moderate PDIA3[Q481K] overexpression resulted in altered motor capacity accompanied by decreased motoneuron number. The adverse effects of PDIA3[Q481K] were associated with induction of ER stress in the spinal cord and subtle morphological changes in neuromuscular junctions. Our results suggest that the PDIA3[Q481K] variant is likely pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction may predispose an individual to develop the disease.}, }
@article {pmid40345169, year = {2025}, author = {Meng, Y and Li, W and Zhang, Y and Li, Y and He, Y and Zhang, N}, title = {ANXA11 Mutations in the FTD Spectrum: A Novel Finding in a Patient With Semantic Variant Primary Progressive Aphasia.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70187}, doi = {10.1111/ene.70187}, pmid = {40345169}, issn = {1468-1331}, support = {24JCYBJC00650//Natural Science Foundation of Tianjin Municipality/ ; 2022ZD0211605//Science and Technology Innovation 2030 Major Projects/ ; }, abstract = {BACKGROUND: Semantic variant primary progressive aphasia (svPPA) is typically a sporadic disorder, and few cases have been linked to ANXA11 mutations. Comprehensive analyses of genetic mutations in svPPA are limited. Furthermore, the clinical and genetic distinctions between typical svPPA and right temporal variant frontotemporal dementia (rtvFTD) are poorly understood.<br><br>METHODS: A 68-year-old patient with svPPA carrying a heterozygous ANXA11 c.119A>G (p.D40G) mutation underwent comprehensive neuropsychological, neuroimaging, and genetic assessments at baseline and at the one-year follow-up timepoint. Additionally, systematic reviews were conducted to identify reported cases of ANXA11 mutations in the FTD spectrum and the genetic mutations associated with svPPA. Clinical-genetic profiles of typical svPPA and rtvFTD were compared based on data from the literature.<br><br>RESULTS: Thirty-two patients with ANXA11 mutations were identified, including 11 with pure FTD phenotypes and the majority exhibiting FTD-amyotrophic lateral sclerosis (ALS). Among 167 svPPA-related cases, MAPT, GRN, and C9ORF72 mutations were most frequently implicated; ANXA11 mutations were primarily identified in East Asian patients. Comparative analysis revealed overlapping age at onset, disease duration, sex distribution, and APOE &#x3b5;4 allele frequencies between typical svPPA and rtvFTD but differing clinical presentations.<br><br>CONCLUSIONS: This study reports a case of typical svPPA in China associated with the ANXA11 p.D40G mutation without ALS-related features. Our findings highlight the importance of ANXA11 mutations in FTD pathogenesis.}, }
@article {pmid40345155, year = {2025}, author = {Liu, X and Liu, X and Zhan, J and Yuan, W and Zhu, Y and Huang, W and Li, H and Liu, T and Amine, K and Li, H and Yu, G}, title = {High-Performance Al-S Batteries by Spin Polarization Modulation via Catalytic Ni-MoS2 Nanosheets.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {}, number = {}, pages = {e202503835}, doi = {10.1002/anie.202503835}, pmid = {40345155}, issn = {1521-3773}, abstract = {Aluminum-sulfur (Al-S) batteries catalysts with adsorption and catalytic capabilities can effectively improve the slow redox kinetics, but the current research often ignores the effect of optimizing the electronic structure of the catalyst on improving charge transfer and adsorption. Here, Ni-doped monolayer MoS2 nanosheets are synthesized and used as a catalytic additive for the sulfur cathode. The addition of Ni promotes spin splitting of 4d orbital of Mo, thereby affecting polarization degree of the basal plane sulfur, and making it changed from a low spin state to a high spin one. This high spin configuration raises the electron energy level and provides an active electron state to react with aluminum polysulfides (AlPSs), which optimizes the adsorption energy. At the same time, it accelerates electron transfer and lowers the energy barrier for the overall conversion of the polysulfides. Benefiting from these features, Al-S batteries based on rationally designed S@Ni-MoS2/C cathodes exhibit a high initial capacity (1603.0 mAh g-1 at 0.5 A g-1) and extraordinary cycling stability (0.035% capacity decay rate during 2000 cycles). This study showcases a spin-polarized electronic structure control strategy to enhance catalytic activity, providing a viable approach for developing efficient catalysts for practical Al-S batteries.}, }
@article {pmid40344943, year = {2025}, author = {Zhou, ZD and Yi, L and Popławska-Domaszewicz, K and Chaudhuri, KR and Jankovic, J and Tan, EK}, title = {Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges.}, journal = {Pharmacological research}, volume = {216}, number = {}, pages = {107770}, doi = {10.1016/j.phrs.2025.107770}, pmid = {40344943}, issn = {1096-1186}, abstract = {Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.}, }
@article {pmid40344633, year = {2025}, author = {Tang, S and Shi, J and Li, X and Yang, M and Li, C and Zhang, D and Yang, S and Mei, C and Luo, Z and Zhang, L and Zhang, W and Zhang, C and Zhu, C and Ma, X and Xia, R and Chen, Y and Zhang, J and Chen, Q and Chen, S and Xie, Q and Yu, F}, title = {Development and Breeding of Herbicide-Resistant Sorghum for Effective Cereal-Legume Intercropping.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2503083}, doi = {10.1002/advs.202503083}, pmid = {40344633}, issn = {2198-3844}, support = {YZGG-04//Sorghum Seed Industry Innovation and Improved Joint Research Project of Shanxi Province/ ; 2023YFD1200700//National Key R&amp;D Program of China/ ; 2023YFF1001400//National Key R&amp;D Program of China/ ; 32222010//National Natural Science Foundation of China/ ; 32430077//National Natural Science Foundation of China/ ; }, abstract = {Weeds bring a serious challenge to crop production, and herbicides is the most effective and economic way to manage it in field. Sorghum is a critical crop for staple food, fodder, and biofuel. However, the lack of herbicide-resistant sorghum germplasm severely impedes its production. Here, we conducted a large-scale screening and identified 13 sorghum mutant lines resistant to imidazolinone (IMI) herbicides. Two unique mutation sites in SbALS (acetolactate synthase), thus namely Sbals-1 (A93T) and Sbals-2 (S624N) are discovered, both enhance sorghum tolerance to imazamox. Notably, under high concentrations of imazamox, sbals-1 presented a superior growth phenotype and elevated SbALS activity than sbals-2, a difference that can be attributed to the predicted protein structures. Breeding with Sbals, both grain- and grass-type sorghum, shows great weed control and field performance. The herbicide imazamox resistance is further evaluated in a soybean population for sorghum-soybean strip intercropping, identifying 123 highly resistant soybean varieties. Field intercropping tests indicated health growth of both soybean and sorghum lines post-imazamox treatment, which enhance field clearance of weed. This study, therefore, provides valuable insights not only for herbicide-resistant sorghum breeding but also for the successful implementation of efficient and sustainable cereal-legume intercropping systems.}, }
@article {pmid40344624, year = {2025}, author = {Temme, N and Haehre, T and Boyher, C and Hoppe, L and Davenport, C and Stumo, Z and Prenzler, K and Maeser, A and Pflugmacher, M and Koch, K and Stahl, DJ}, title = {Host-induced gene silencing of the amino acid biosynthesis gene acetolactate synthase of Phytophthora infestans caused strong enhanced late blight resistance of potato in the field.}, journal = {Plant biotechnology journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/pbi.70133}, pmid = {40344624}, issn = {1467-7652}, support = {Forschungsvorhaben 0315701C//Bundesministerium f&#xfc;r Bildung und Forschung/ ; GABI-PLANT-KBBE II//Bundesministerium f&#xfc;r Bildung und Forschung/ ; }, abstract = {Late blight caused by Phytophthora infestans is the most serious disease of potatoes. Here we present the effectiveness of the host-induced gene silencing (HIGS) technology against an amino acid biosynthesis gene of the pathogen to increase the resistance against the plant-infecting oomycete in the field. A RNAi hairpin construct directed against the acetolactate synthase (ALS) gene of Phytophthora infestans was transferred into potato. HIGS-ALS potato lines displayed efficient target gene silencing revealed by a luciferase reporter gene assay. Plant-derived siRNAs targeting the oomycete's ALS gene were detected by small RNA sequencing. ALS gene expression of P. infestans was reduced during the early infection stages of HIGS-ALS potatoes, as shown by qRT-PCR. HIGS-ALS plants revealed an enhanced late blight resistance in detached leaf assays. ALS gene silencing also conferred strong enhanced late blight resistance to the HIGS lines in trials under near-field conditions in Europe and in field trials in the USA against European and US P. infestans isolates, respectively. These results demonstrated the value of the HIGS technology for the development of a new quantitative resistance source for potato against Phytophthora infestans.}, }
@article {pmid40342184, year = {2025}, author = {Ribeiro, VHV and Gallagher, J and Mallory-Smith, C and Barroso, J and Brunharo, CACG}, title = {Multiple Origins or Widespread Gene Flow in Agricultural Fields? Regional Population Genomics of Herbicide Resistance in Bromus tectorum.}, journal = {Molecular ecology}, volume = {}, number = {}, pages = {e17791}, doi = {10.1111/mec.17791}, pmid = {40342184}, issn = {1365-294X}, support = {//Oregon Wheat Commission/ ; //College of Agricultural Sciences, Pennsylvania State University/ ; Project#PEN04859,Accession#7005632//USDA National Institute of Food and Agriculture/ ; }, abstract = {The repeated evolution of herbicide resistance in agriculture provides an unprecedented opportunity to understand how organisms rapidly respond to strong anthropogenic-driven selection pressure. We recently identified agricultural populations of the grass species Bromus tectorum L. with resistance to multiple herbicides. To understand the evolutionary origins and spread of resistance, we investigated the resistance mechanisms to acetolactate synthase (ALS) inhibitors and photosystem II inhibitors, two widely used herbicide modes of action, in 49 B. tectorum populations. We assessed the genetic diversity, structure and relatedness in a subset of 21 populations. Resistance to ALS inhibitors was associated with multiple nonsynonymous mutations in ALS, the target site gene, despite the relatively small geographic region where populations originated, suggesting ALS inhibitor resistance evolution occurred multiple times in the region. We also found evidence that mechanisms not related to the target site evolved and were common in the populations studied. Resistance to photosystem II inhibitors was confirmed in two populations and was conferred by nonsynonymous mutations in the plastid gene psbA. Population genomics analyses suggested that ALS resistance in most populations, at the nucleotide level, spread via gene flow, except for one population where we found evidence that Pro-197-His mutations may have evolved in three separate events. Our results suggest that both gene flow via pollen and/or seed dispersal and multiple local evolutionary events were involved in the spread of herbicide-resistant B. tectorum. Our results provide an empirical example of the rapid repeated evolution of a trait under strong anthropogenic selection and elucidate the evolutionary origins of herbicide resistance in a plant species of agricultural importance.}, }
@article {pmid40341849, year = {2025}, author = {Neuhaus, D and Wendebourg, MJ and Deigendesch, N and Berger, C and Bauer, M and Haas, T and Scheurer, E and Schlaeger, R and Lenz, C}, title = {Exploring Potential Biomarkers for Amyotrophic Lateral Sclerosis Using Postmortem In Situ Magnetic Resonance Imaging.}, journal = {NMR in biomedicine}, volume = {38}, number = {6}, pages = {e70059}, doi = {10.1002/nbm.70059}, pmid = {40341849}, issn = {1099-1492}, support = {//Neuromuscular Research Association Basel/ ; //Stiftung zur Foerderung der gastroenterologischen und der allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Biomarkers/metabolism ; Male ; *Magnetic Resonance Imaging ; Female ; Middle Aged ; Aged ; Brain/diagnostic imaging/pathology ; Autopsy ; }, abstract = {There is an urgent need for reliable magnetic resonance imaging (MRI) biomarkers for the diagnosis, prognosis or therapy management of amyotrophic lateral sclerosis (ALS). The aim of this study was to explore potential biomarkers for ALS by conducting postmortem (PM) in situ MRI, allowing for a non-invasive evaluation of the disease's end-stage without the effects of formalin fixation. PM in situ MRI whole-brain scans of five deceased patients with clinically definite ALS and seven deceased healthy controls (HC) without known neurological disorders were performed at 3 Tesla. Fractional anisotropy, mean diffusivity, T1, T2 and T2* were assessed for cortex, deep grey matter, white matter, whole brain and hippocampus. For the validation of the MRI DTI data, the focus was placed on the hippocampus, where the myelin density was evaluated by analysing histological samples from the dentate gyrus. A custom python script was developed for the quantification of the myelin density in histological data. Comparing ALS to HC values suggested potential reductions of mean diffusivity, T1 (after outlier removal) and T2* in white matter and of T2 in deep grey matter in the ALS group. Furthermore, mean diffusivity was potentially reduced in the hippocampus of patients with ALS (after outlier removal), whereas no difference in myelin density was found by histopathological assessment. The results of this exploratory study suggest potential differences in diffusivity and relaxometry between PM in situ brains of patients with ALS and HC. Understanding these variations at the end-stage of ALS might contribute to the development of novel MRI prognostic and diagnostic biomarkers for ALS. However, larger sample sizes and complementary histological examinations are needed to confirm these results and to clarify the underlying mechanisms.}, }
@article {pmid40341287, year = {2025}, author = {Merler, M and Agurto, C and Peller, J and Roitberg, E and Taitz, A and Trevisan, MA and Navar, I and Berry, JD and Fraenkel, E and Ostrow, LW and Cecchi, GA and Norel, R}, title = {Clinical assessment and interpretation of dysarthria in ALS using attention based deep learning AI models.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {260}, pmid = {40341287}, issn = {2398-6352}, abstract = {Speech dysarthria is a key symptom of neurological conditions like ALS, yet existing AI models designed to analyze it from audio signal rely on handcrafted features with limited inference performance. Deep learning approaches improve accuracy but lack interpretability. We propose an attention-based deep learning AI model to assess dysarthria severity based on listener effort ratings. Using 2,102 recordings from 125 participants, rated by three speech-language pathologists on a 100-point scale, we trained models directly from recordings collected remotely. Our best model achieved R[2] of 0.92 and RMSE of 6.78. Attention-based interpretability identified key phonemes, such as vowel sounds influenced by 'r' (e.g., "car," "more"), and isolated inspiration sounds as markers of speech deterioration. This model enhances precision in dysarthria assessment while maintaining clinical interpretability. By improving sensitivity to subtle speech changes, it offers a valuable tool for research and patient care in ALS and other neurological disorders.}, }
@article {pmid40340943, year = {2025}, author = {Kellett, EA and Bademosi, AT and Walker, AK}, title = {Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {53}, pmid = {40340943}, issn = {1750-1326}, mesh = {Humans ; *DNA-Binding Proteins/metabolism ; Phosphorylation/physiology ; Animals ; *Neurodegenerative Diseases/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid-liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid-liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration.}, }
@article {pmid40340620, year = {2025}, author = {Shen, D and Liu, A and Yang, X and Liu, Q and Liu, M and Cui, L}, title = {Exploring oculomotor challenges in amyotrophic lateral sclerosis: a comprehensive review.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2025.2501690}, pmid = {40340620}, issn = {2167-9223}, abstract = {Traditionally understood as a motor neuron disease, amyotrophic lateral sclerosis (ALS) is now recognized to involve broader neurodegenerative processes, including the oculomotor system. This narrative review summarizes current evidence on oculomotor dysfunction in ALS, with a focus on its relationship to disease-related motor and cognitive impairments. Specifically, the review examines key eye-tracking (ET) metrics, including saccades, smooth pursuit, and fixation, highlighting their potential to reflect both motor and extramotor degeneration. Notably, patients with bulbar-onset ALS exhibit more pronounced oculomotor impairments. By synthesizing findings on the connection between oculomotor dysfunction and cognitive decline, this review underscores the potential of ET as a noninvasive tool for assessing ALS progression. Oculomotor metrics, as part of a broader understanding of ALS's impact on multiple neural networks, may offer valuable insights to refine patient assessment and care strategies, particularly in advanced disease stages.}, }
@article {pmid40340591, year = {2025}, author = {Ward, AL and Nooijen, C and Bernstein, J}, title = {Power wheelchair users with ALS: Impact of an alerting system on complications with prolonged sitting and power feature utilization.}, journal = {Assistive technology : the official journal of RESNA}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10400435.2025.2497865}, pmid = {40340591}, issn = {1949-3614}, abstract = {An interventional technology called Virtual Seating Coach (VSC) provided alerts via an app to perform pressure redistribution using power wheelchair seat functions. The objective was whether alerts can contribute to more function utilization and thereby reduce pressure injuries and pain. Thirty-nine individuals with Amyotrophic Lateral Sclerosis (ALS) participated, 14 consented to use VSC, and 25 controls. The duration of the study was 27 months, with follow-up at 1 month or 3 months. Due to multiple technological and disease-related difficulties, three of those consented for the VSC received alerts once per hour to move into prescribed positions for one minute. These participants were able to use the VSC through the study end, and two of the three adhered to performing pressure redistribution after receiving alerts. The three using the VSC did not report pressure injuries; 12 of 21 controls reported development of a pressure injury. Furthermore, those using VSC noted a decrease in pain; most controls showed an increase during the same time period. The study thus highlighted the potential for such alerting technology while at the same time revealing many limitations due to disease progression and diminishing access to wheelchair controls.}, }
@article {pmid40339618, year = {2025}, author = {Zhou, C and Hardin, EJ and Zimmer, TS and Jackvony, S and Barnett, D and Khobrekar, N and Giacomelli, E and Studer, L and Orr, AL and Orr, AG}, title = {Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106939}, doi = {10.1016/j.nbd.2025.106939}, pmid = {40339618}, issn = {1095-953X}, abstract = {Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions.}, }
@article {pmid40339566, year = {2025}, author = {Parameswaran, J and McEachin, ZT}, title = {PI3P: Rising to the (DPR) challenge in C9-ALS/FTD.}, journal = {Neuron}, volume = {113}, number = {9}, pages = {1301-1303}, doi = {10.1016/j.neuron.2025.04.007}, pmid = {40339566}, issn = {1097-4199}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; C9orf72 Protein ; *Phosphatidylinositol Phosphates/metabolism ; *DNA Repeat Expansion/genetics ; *Proteins/genetics ; Animals ; *Dipeptides/genetics/metabolism ; }, abstract = {A hexanucleotide G4C2 repeat expansion in C9orf72 causes accumulation of dipeptide repeat (DPR) proteins and is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a recent issue of Neuron, Zhang et al.[1] report that elevating PI3P levels mitigates endolysosomal deficits and DPR-associated neurotoxicity.}, }
@article {pmid40338888, year = {2025}, author = {Faisal, M and Khosa, I and Waris, A and Gilani, SO and Khan, MJ and Hazzazi, F and Ijaz, MA}, title = {Optimizing the impact of time domain segmentation techniques on upper limb EMG decoding using multimodal features.}, journal = {PloS one}, volume = {20}, number = {5}, pages = {e0322580}, doi = {10.1371/journal.pone.0322580}, pmid = {40338888}, issn = {1932-6203}, mesh = {Humans ; *Electromyography/methods ; *Upper Extremity/physiology ; Male ; Adult ; Female ; Movement/physiology ; Signal Processing, Computer-Assisted ; Support Vector Machine ; Young Adult ; }, abstract = {Neurological disorders, such as stroke, spinal cord injury, and amyotrophic lateral sclerosis, result in significant motor function impairments, affecting millions of individuals worldwide. To address the need for innovative and effective interventions, this study investigates the efficacy of electromyography (EMG) decoding in improving motor function outcomes. While existing literature has extensively explored classifier selection and feature set optimization, the choice of preprocessing technique, particularly time-domain windowing techniques, remains understudied posing a significant knowledge gap. This study presents upper limb movement classification by providing a comprehensive comparison of eight time-domain windowing techniques. For this purpose, the EMG data from volunteers is recorded involving fifteen distinct movements of fingers. The rectangular window technique among others emerged as the most effective, achieving a classification accuracy of 99.98% while employing 40 time-domain features and a L-SVM classifier, among other classifiers. This optimal combination has implications for the development of more accurate and reliable myoelectric control systems. The achieved high classification accuracy demonstrates the feasibility of using surface EMG signals for accurate upper limb movement classification. The study's results have the potential to improve the accuracy and reliability of prosthetic limbs and wearable sensors and inform the development of personalized rehabilitation programs. The findings can contribute to the advancement of human-computer interaction and brain-computer interface technologies.}, }
@article {pmid40338003, year = {2025}, author = {Chen, X and Chen, X and Lin, X and Zhou, W and Hu, H and Jiang, H}, title = {Unveiling ten novel SETX mutations: implications for ALS pathogenesis and clinical diversity.}, journal = {Somatosensory &amp; motor research}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/08990220.2025.2500940}, pmid = {40338003}, issn = {1369-1651}, abstract = {OBJECTIVE: To investigate the relationship between newly identified senataxin (SETX) gene mutations and the clinical manifestation of Amyotrophic Lateral Sclerosis (ALS), enhancing understanding of the genetic underpinnings associated with this disorder.<br><br>METHODS: A cohort study was conducted at Nanfang Hospital, involving comprehensive genetic sequencing of ALS patients to identify novel SETX mutations. Homology modelling and structural analysis were employed to predict the functional impacts of these mutations on the senataxin protein. Clinical assessments, including symptom evaluation, age of onset, and progression rate, were integrated with electrophysiological studies to establish correlations between genetic variants and clinical outcomes.<br><br>RESULTS: Ten novel SETX mutations were identified, expanding the genetic landscape of ALS. These mutations exhibited diverse impacts on clinical presentations, with patients showing variability in onset age, symptom severity, and progression rates. Computational modelling suggested that certain mutations cause significant structural changes in senataxin, potentially affecting its RNA/DNA helicase function. Electrophysiological findings consistently revealed nerve conduction abnormalities, indicating that these mutations may influence neuronal excitability and contribute to ALS pathogenesis.<br><br>CONCLUSION: The discovery of novel SETX mutations provides valuable insights into the genetic and clinical complexity of ALS. This study underscores the importance of genetic screening for SETX mutations and suggests potential personalised therapeutic approaches targeting senataxin dysfunction. By elucidating genotype-phenotype correlations, these findings contribute to the broader understanding of ALS and offer pathways for developing targeted interventions to address the challenges posed by this disabling disease.}, }
@article {pmid40280464, year = {2025}, author = {Gritsiuta, AI and Reep, G and Parupudi, S and Petrov, RV}, title = {Optimizing the management of anastomotic leaks after esophagectomy: a narrative review of salvage strategies and outcomes.}, journal = {Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract}, volume = {29}, number = {7}, pages = {102069}, doi = {10.1016/j.gassur.2025.102069}, pmid = {40280464}, issn = {1873-4626}, abstract = {BACKGROUND: Anastomotic leaks (ALs) after esophagectomy remain a major postoperative complication, leading to increased morbidity, prolonged hospital stays, and higher mortality. Despite advancements in surgical techniques and perioperative care, AL management lacks standardized protocols. This review aimed to evaluate current salvage strategies, including conservative, endoscopic, and surgical approaches, to optimize outcomes and reduce complications.<br><br>METHODS: A comprehensive literature search was conducted using PubMed, Scopus, Cochrane Library, and Google Scholar databases to identify studies published between 2000 and 2025 on AL management after esophagectomy. Peer-reviewed clinical trials, guidelines, and expert consensus reports were reviewed, focusing on minimally invasive and surgical interventions, patient outcomes, and emerging treatment strategies.<br><br>RESULTS: AL management strategies were classified into 3 primary approaches. Conservative management includes nutritional support, antibiotic therapy, and percutaneous drainage, particularly for contained leaks. Endoscopic interventions, such as self-expanding metal stents and endoscopic vacuum-assisted closure, have shown high success rates, with vacuum-assisted closure achieving superior closure outcomes. Hybrid techniques, including stent-over-sponge and vacuum-assisted closure-stent, are emerging as promising alternatives. Surgical interventions remain the gold standard for severe or refractory leaks with options, including primary repair, esophageal diversion, and delayed conduit reconstruction.<br><br>CONCLUSION: A multidisciplinary approach is crucial for optimizing AL management, incorporating enhanced recovery protocols, early risk assessment, and individualized treatment plans. Endoscopic techniques have reduced the need for surgical revisions, but surgical intervention remains necessary for severe cases. Future research should focus on refining treatment algorithms, integrating novel technologies, and establishing standardized guidelines to improve patient survival and quality of life.}, }
@article {pmid40335898, year = {2025}, author = {Kim, JH and Whitaker, VM and Lee, S}, title = {A haplotype-phased genome characterizes the genomic architecture and causal variants for RXf1 conferring resistance to Xanthomonas fragariae in strawberry (F. × ananassa).}, journal = {BMC genomics}, volume = {26}, number = {1}, pages = {453}, pmid = {40335898}, issn = {1471-2164}, support = {#2022-51181-38328//National Institute of Food and Agriculture/ ; #2022-51181-38328//National Institute of Food and Agriculture/ ; #2022-51181-38328//National Institute of Food and Agriculture/ ; }, mesh = {*Fragaria/genetics/microbiology ; *Disease Resistance/genetics ; *Haplotypes ; *Plant Diseases/microbiology/genetics ; *Xanthomonas/physiology ; *Genome, Plant ; Chromosome Mapping ; *Genomics ; Chromosomes, Plant/genetics ; }, abstract = {BACKGROUND: Cultivated octoploid strawberry (Fragaria × ananassa) is one of the most economically important fruits worldwide due to its flavor, texture, and health benefits. However, bacterial angular leaf spot (ALS) causes economic losses in fruit production and plant nurseries. All commercial strawberry varieties are susceptible to ALS. A major resistance locus, RXf1, has been reported, but the genomic structure and candidate genes underlying this resistance remain known.<br><br>RESULTS: Fine-mapping was performed using three segregating populations containing 663 individuals that were genotyped with subgenome specific seven high-resolution melting (HRM) markers to narrow the RXf1 region to a 486-kb interval on chromosome 6C. We assembled a haplotype-phased chromosome-scale genome of ALS-resistant breeding selection FL17.68-110 using highly accurate long-read sequencing and trio-binning with parental short reads. The 1.62 Gbp genome containing two haplotypes, 56 chromosomes and 193,072 annotated genes. Transcriptome analysis in response to the ALS pathogen identified a candidate gene, Resistance gene analogue 3 (RGA3), associated with the RXf1 resistance. The gene structure and sequence variations within FaRGA3 were identified between resistant and susceptible genotypes.<br><br>CONCLUSIONS: Our results narrowed the RXf1 region, identified structural variations within this locus and pointed to FaRGA3 as a promising candidate gene. This information will be useful for breeders toward developing ALS-resistant strawberry varieties, and the high-quality genome will be a valuable resource for further genomics research in octoploid strawberry.}, }
@article {pmid40334711, year = {2025}, author = {Sucker, C and Koscielny, J and Kappert, G}, title = {Ausgewählte Beiträge der BDDH-Veranstaltung im Rahmen der 69. Jahrestagung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) am 18.02.2025 in Lausanne.}, journal = {Hamostaseologie}, volume = {45}, number = {2}, pages = {209-211}, doi = {10.1055/a-2447-6517}, pmid = {40334711}, issn = {2567-5761}, abstract = {DHR -2025, WAS GIBT ES NEUES?: Die DHR-Webseite (www.pei.de/DE/regulation/melden/dhr/dhr-node.html) beinhaltet neben fünf Publikationen, die letzte von 2020, einen Jahresbericht 2022/2023. Die Daten aus 2023 sind als vorläufig gekennzeichnet. Veröffentlicht sind die Anzahlen gemeldeter Fälle (Hämophilie A/B nach Schweregrad, von Willebrand Syndrom Typ 3 und andere, seltene Faktoren und Hemmkörper bei Kindern und Erwachsenen), sowie der Verbrauch bis 2022. Klinisch relevante Daten, wie z.B. Blutungen, die Teil der Einzelmeldung sind, finden sich nicht.}, }
@article {pmid40333935, year = {2025}, author = {Vanderlinden, G and Carron, C and Van Weehaeghe, D and De Vocht, J and Ombelet, F and Masrori, P and De Weerdt, C and James, RE and Evans, LT and Schroeder, FA and Hooker, JM and Koole, M and Kranz, JE and Gilbert, TM and Van Damme, P and Van Laere, K}, title = {Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70067}, pmid = {40333935}, issn = {2328-9503}, support = {//Association for Frontotemporal Degeneration/ ; //Target ALS/ ; //Eikonizo Therapeutics/ ; }, abstract = {OBJECTIVE: [[18]F]EKZ-001 is a positron emission tomography (PET) tracer targeting histone deacetylase 6 (HDAC6), an enzyme responsible for intracellular transport and clearance of misfolded proteins. HDAC6 modulation is a promising treatment strategy in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Apart from motor symptoms, people with ALS (pwALS) can show a variable degree of cognitive impairment as part of the ALS-frontotemporal spectrum disorder (ALS-FTSD). This work assessed [[18]F]EKZ-001 binding in pwALS with variable involvement of FTSD.<br><br>METHODS: Twenty-four pwALS (13M/11F, 61&#x2009;&#xb1;&#x2009;10&#x2009;years) and 12 healthy controls (HC) (6M/6F, 58&#x2009;&#xb1;&#x2009;3&#x2009;years) were included. Thirteen pwALS were cognitively normal (ALS-CN), and eleven pwALS presented with FTSD (ALS-FTSD) ranging from mild cognitive or behavioral impairment to FTD, according to their performance on the Edinburgh cognitive and behavioral ALS screen (ECAS). All subjects underwent dynamic PET-MR imaging with arterial sampling, and regional distribution volumes (VT) were calculated using a Logan graphical analysis.<br><br>RESULTS: [[18]F]EKZ-001 VT was significantly lower in pwALS compared to HC. For ALS-CN, the largest reduction was found in the brainstem. For ALS-FTSD, reductions were more widespread in both gray and white matter. No differences in VT were found between pwALS with and without a C9orf72 mutation. [[18]F]EKZ-001 VT was not correlated with ECAS scores, age, or disease duration.<br><br>INTERPRETATION: [[18]F]EKZ-001 binding is lower throughout the brain in pwALS compared to HC. This may be related to a compensatory mechanism to repair intracellular transport defects in ALS or to reduced HDAC6 enzyme availability for [[18]F]EKZ-001 binding due to sequestration of HDAC6 within protein aggregates.}, }
@article {pmid40333317, year = {2025}, author = {Simula, ER and Jasemi, S and Cossu, D and Fais, M and Cossu, I and Chessa, V and Canu, M and Sechi, LA}, title = {Human Endogenous Retroviruses as Novel Therapeutic Targets in Neurodegenerative Disorders.}, journal = {Vaccines}, volume = {13}, number = {4}, pages = {}, doi = {10.3390/vaccines13040415}, pmid = {40333317}, issn = {2076-393X}, support = {PNRR-MCNT1-2023-12376993//Ministero della Salute/ ; 2022BP837R//MUR, PRIN 2022/ ; 22//Regione Autonoma Sardegna grant: legge regionale 12 22 December 2022/ ; e.INS Ecosystem of Innovation for Next Generation Sardinia spoke n 5//European Union/ ; }, abstract = {Human Endogenous Retroviruses comprise approximately 8% of the human genome, serving as fragments of ancient retroviral infections. Although they are generally maintained in a silenced state by robust epigenetic mechanisms, specific HERV groups, particularly HERV-W and HERV-K, can become derepressed under specific pathological conditions, thereby contributing to the initiation and progression of neuroinflammatory and neurodegenerative processes. Preclinical studies and clinical trials, such as those investigating monoclonal antibodies, indicate that directly targeting these elements may offer a novel therapeutic strategy. In this review, we provide an overview of HERVs' biology, examine their role in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease, and explore their therapeutic prospects, highlighting both the challenges and the potential future research directions needed to translate these approaches into clinical interventions.}, }
@article {pmid40332510, year = {2025}, author = {Stacchiotti, C and Mazzella di Regnella, S and Cinotti, M and Spalloni, A and Volpe, E}, title = {Neuroinflammation and Amyotrophic Lateral Sclerosis: Recent Advances in Anti-Inflammatory Cytokines as Therapeutic Strategies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {8}, pages = {}, doi = {10.3390/ijms26083854}, pmid = {40332510}, issn = {1422-0067}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/immunology ; *Cytokines/therapeutic use/metabolism ; Animals ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Blood-Brain Barrier/metabolism ; Inflammation ; }, abstract = {Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease.}, }
@article {pmid40332015, year = {2025}, author = {Duță, C and Dogaru, CB and Muscurel, C and Stoian, I}, title = {Nanozymes: Innovative Therapeutics in the Battle Against Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {8}, pages = {}, doi = {10.3390/ijms26083522}, pmid = {40332015}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Animals ; Antioxidants/therapeutic use/chemistry/pharmacology ; *Nanostructures/chemistry/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), represent a significant challenge to global health due to their progressive nature and the absence of curative treatments. These disorders are characterized by oxidative stress, protein misfolding, and neuroinflammation, which collectively contribute to neuronal damage and death. Recent advancements in nanotechnology have introduced nanozymes-engineered nanomaterials that mimic enzyme-like activities-as promising therapeutic agents. This review explores the multifaceted roles of nanozymes in combating oxidative stress and inflammation in neurodegenerative conditions. By harnessing their potent antioxidant properties, nanozymes can effectively scavenge reactive oxygen species (ROS) and restore redox balance, thereby protecting neuronal function. Their ability to modify surface properties enhances targeted delivery and biocompatibility, making them suitable for various biomedical applications. In this review, we highlight recent findings on the design, functionality, and therapeutic potential of nanozymes, emphasizing their dual role in addressing oxidative stress and pathological features such as protein aggregation. This synthesis of current research underscores the innovative potential of nanozymes as a proactive therapeutic strategy to halt disease progression and improve patient outcomes in neurodegenerative disorders.}, }
@article {pmid40331673, year = {2025}, author = {Ma, W and Dickie, A and Polgár, E and Yadav, M and Quillet, R and Gutierrez-Mecinas, M and Bell, AM and Todd, A}, title = {EXPRESS: Expression of Tacr1 and Gpr83 by spinal projection neurons.}, journal = {Molecular pain}, volume = {}, number = {}, pages = {17448069251342409}, doi = {10.1177/17448069251342409}, pmid = {40331673}, issn = {1744-8069}, abstract = {Anterolateral system (ALS) projection neurons underlie perception of pain, itch and skin temperature. These cells are heterogeneous, and there have therefore been many attempts to define functional populations. A recent study identified two classes of ALS neuron in mouse superficial dorsal horn (SDH) based on expression of the G protein-coupled receptors Tacr1 or Gpr83. It was reported that cells expressing these receptors formed largely non-overlapping populations, and that ~60% of ALS cells in SDH expressed Tacr1. An additional finding was that while Tacr1- and Gpr83-expressing ALS cells projected to several brain nuclei, their axons did not reach the ventral posterolateral (VPL) thalamic nucleus, which is reciprocally connected to the primary somatosensory cortex. These results were surprising, because we had reported that ~90% of SDH ALS neurons in the mouse possess the neurokinin 1 receptor (NK1r), which is encoded by Tacr1, and in addition the VPL is thought to receive input from lamina I ALS cells. Here we use retrograde and anterograde labelling in Tacr1CreERT2 and Gpr83CreERT2 mice to reinvestigate the expression of the receptors by ALS neurons and to reassess their projection patterns. We find that ~90% of ALS neurons in SDH express Tacr1, with 40-50% expressing Gpr83. We also show that axons of both Tacr1- and Gpr83-expressing ALS neurons reach the VPL. These results suggest that ALS neurons in the SDH that express these GPCRs show considerable overlap, and that they are likely to contribute to the sensory-discriminative dimension of pain through their projections to VPL.}, }
@article {pmid40331424, year = {2025}, author = {Santoro, F and D'Amico, E and Brunetti, ND}, title = {Amyotrophic lateral sclerosis and Takotsubo syndrome: a call for action!.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {26}, number = {5}, pages = {255-256}, doi = {10.2459/JCM.0000000000001724}, pmid = {40331424}, issn = {1558-2035}, }
@article {pmid40330963, year = {2025}, author = {Kayabaşi, M and Köksaldi, S and Demirel, N and Saatci, AO}, title = {The Effect of Axial Length on Macular Vascular Density in Eyes with High Myopia.}, journal = {Romanian journal of ophthalmology}, volume = {69}, number = {1}, pages = {88-100}, pmid = {40330963}, issn = {2501-2533}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Female ; Male ; *Retinal Vessels/pathology/diagnostic imaging ; *Axial Length, Eye/pathology/diagnostic imaging ; Middle Aged ; Fluorescein Angiography/methods ; Adult ; *Myopia, Degenerative/diagnosis/physiopathology ; *Macula Lutea/blood supply/pathology ; Retrospective Studies ; Visual Acuity ; Fundus Oculi ; Choroid/blood supply/pathology ; Microvascular Density ; Fovea Centralis ; Follow-Up Studies ; }, abstract = {OBJECTIVE: To evaluate the relationship between optical coherence tomography angiography (OCTA) findings and axial length (AL) in eyes with high myopia.<br><br>MATERIALS AND METHODS: A total of 122 eyes from 78 patients were included. Seventy-five eyes with an AL ranging between 26.00 and 27.49 mm comprised Group 1, and 47 with an AL of &#x2265; 27.50 mm comprised Group 2. Spectral-domain OCT was performed to measure the central macular thickness, subfoveal choroidal thickness (SCT) and swept-source OCTA was utilized to obtain the data on foveal avascular zone (FAZ) and vascular density (VD) values at the superficial and deep capillary plexuses (SCP and DCP), outer retina (OuR), and choriocapillaris (CC) segments.<br><br>RESULTS: While no significant differences were found in terms of the mean superficial-FAZ and deep-FAZ areas (p=0.284 and p=0.952, respectively), there were significant differences between the groups in terms of the mean foveal VD in the SCP (p=0.001), the mean total VD (p=0.045) and foveal VD in the DCP (p<0.001), the mean foveal VD (p=0.019) and superior parafoveal VD in the OuR (p=0.008), the mean total (p=0.005), temporal parafoveal (p=0.034), inferior parafoveal (p=0.029), and nasal parafoveal VDs in the CC segments (p=0.005).<br><br>DISCUSSION: The findings of the present study highlight the complex interplay between axial elongation and retinal microvasculature, suggesting that factors beyond mechanical stretching may contribute to these alterations. The variability in the existing literature on this topic arises from inconsistencies in the definition of high myopia, the use of different OCTA devices, and heterogeneous study populations. By including eyes with myopic maculopathy and employing axial length-based classification, this study provides a broad representation of high myopia. However, its retrospective design, single-center setting, and monoracial cohort represent limitations. Future large-scale, prospective studies involving diverse populations are needed to elucidate further the pathophysiology of high myopia and its impact on retinal and choroidal microcirculation.<br><br>CONCLUSIONS: Our study revealed that high-myopic eyes with longer ALs exhibited increased total VD in the DCP and increased foveal VD in the SCP, DCP, and OuR segments, while they showed decreased total VD and temporal, inferior, and nasal parafoveal VDs in the CC segment compared to high-myopic eyes with shorter ALs.}, }
@article {pmid40330290, year = {2025}, author = {Pérez-Holanda, S}, title = {Life-threatening bleeding caused by artery pseudoaneurysm after endoscopic procedure successfully treated by artery embolization.}, journal = {World journal of clinical cases}, volume = {13}, number = {13}, pages = {99278}, pmid = {40330290}, issn = {2307-8960}, abstract = {The Kakinuma et al's case report shows that non-pregnancy-related arterial pseudoaneurysm is a relatively rare, little known by some gynecologists, endoscopists, surgeons or radiologists, which can cause massive bleeding. Arterial pseudoaneurysm is a condition in which the wall of a blood vessel collapses due to some invasive event, and the resulting leaked blood is engulfed by soft tissues, forming a cavity that is in communication with the vessel. It is a potentially life-threatening complication that could occurs after some deliveries and some gynecological invasive procedures. Remarkably, an undetermined percentage of pseudoaneurysms are asymptomatic, and in an asymptomatic patient it is difficult to predict the risk of haemorrhage and the attitude to follow, which depends on several factors, such as, the size and location of the vessel involved, changes in the size of the pseudoaneurysm, or the available therapeutic resources to be offered to patients, among others circumstances. The management of abdominal arterial pseudoaneurysm does not have consistent scientific evidence, but it seems that, regardless of the associated circumstances, the pseudoaneurysm could be treated at least initially, and mainly, through endovascular procedures, as done by Kakinuma et al.}, }
@article {pmid40329780, year = {2025}, author = {Mohammadi, S and Ghaderi, S and Fatehi, F and Kalra, S and Batouli, SAH}, title = {Pathological Aging of Patients With Amyotrophic Lateral Sclerosis: A Preliminary Longitudinal Study.}, journal = {Brain and behavior}, volume = {15}, number = {5}, pages = {e70484}, doi = {10.1002/brb3.70484}, pmid = {40329780}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging/psychology ; Male ; Longitudinal Studies ; Female ; Middle Aged ; *Aging/pathology/physiology ; Aged ; Magnetic Resonance Imaging/methods ; *Brain/pathology/diagnostic imaging/physiopathology ; Neuropsychological Tests ; Cognition/physiology ; Cognitive Dysfunction/physiopathology ; Executive Function/physiology ; Disease Progression ; Adult ; }, abstract = {OBJECTIVE: This longitudinal study investigated pathological brain aging in amyotrophic lateral sclerosis (ALS) by evaluating disparities between chronological age and deep learning-derived brain structure age (BSA) and exploring associations with cognitive and functional decline.<br><br>METHODS: Ten limb-onset ALS patients (seven males) and 10 demographically matched healthy controls (HCs) underwent structural magnetic resonance imaging (sMRI) and cognitive assessments at baseline and follow-up. The BSA was estimated using the validated volBrain platform. Cognitive domains (language, verbal fluency, executive function, memory, and visuospatial skills) and global cognition (Persian adaptive Edinburgh Cognitive and Behavioral ALS Screen [ECAS] total score) were assessed along with functional status (ALSFRS-R).<br><br>RESULTS: ALS patients exhibited significant BSA-chronological age disparities at baseline (&#x394; = +7.31 years, p = 0.009) and follow-up (&#x394; = +8.39 years, p = 0.003), with accelerated BSA progression over time (p = 0.004). The HCs showed no such disparities (p = 0.931). Longitudinal BSA increases were correlated with executive function decline (r = -0.651, p = 0.042). Higher education predicted preserved language (r = 0.831, p = 0.003) and verbal fluency (r = 0.738, p = 0.015). ALSFRS-R decline paralleled visuospatial (r = 0.642, p = 0.045) and global cognitive deterioration (r = 0.667, p = 0.035).<br><br>CONCLUSIONS: ALS is characterized by accelerated structural brain aging that progresses independently of chronological age and is correlated with executive dysfunction. Education may mitigate cognitive decline, while motor functional deterioration aligns with visuospatial and global cognitive impairments. BSA has emerged as a potential biomarker for tracking pathological aging trajectories in ALS, warranting validation using larger cohorts.}, }
@article {pmid40328798, year = {2025}, author = {Wu, X and Yang, Z and Zou, J and Gao, H and Shao, Z and Li, C and Lei, P}, title = {Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {146}, pmid = {40328798}, issn = {2059-3635}, support = {32070961//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/enzymology/genetics/pathology ; *Drug Discovery ; *Protein Kinases/genetics/metabolism ; *Protein Kinase Inhibitors/therapeutic use ; Signal Transduction/drug effects/genetics ; Phosphorylation ; Animals ; }, abstract = {Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.}, }
@article {pmid40228660, year = {2025}, author = {Veenstra, J and Ozog, D and Stephens, A}, title = {Response to Barbieri, "Response to Veenstra et al's 'Benzoyl peroxide acne treatment shows no significant association with benzene-related cancers: A multicenter retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.090}, pmid = {40228660}, issn = {1097-6787}, }
@article {pmid40328546, year = {2025}, author = {Kleinerova, J and Tan, EL and Delaney, S and Smyth, M and Bede, P}, title = {Advances and research priorities in the respiratory management of ALS: Historical perspectives and new technologies.}, journal = {Revue neurologique}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurol.2025.04.008}, pmid = {40328546}, issn = {0035-3787}, abstract = {Respiratory involvement has been identified as a cardinal feature of amyotrophic lateral sclerosis (ALS) since its earliest descriptions in the 19th century. Since these initial reports, considerable research has been undertaken to clarify the pathophysiology and progression rates associated with respiratory compromise and effective management strategies have been developed. Clinical trials routinely incorporate respiratory measures as study end points, non-invasive ventilation is now widely used in the home setting, cough-assist techniques are commonly used, advanced neurophysiology techniques and wearable technologies have been integrated into respiratory monitoring protocols, and palliative guidelines have been developed to effectively manage respiratory distress. Despite the widespread implementation of these interventions, epidemiology studies are inconsistent and some studies suggest that survival in ALS has not improved significantly with the introduction of these measures. The outcomes of diaphragmatic pacing trials have been disappointing, advanced neurophysiology techniques are not routinely utilised, spinal and brainstem imaging are not commonly undertaken and significant geographical differences exist in proceeding to tracheostomy. The worldwide COVID pandemic has given impetus for remote monitoring, connected devices, video-consultations, and timely vaccinations in ALS; lessons that are invaluable long after the pandemic. Respiratory monitoring and management in ALS is a swiftly evolving facet of ALS care with considerable quality of life benefits.}, }
@article {pmid40328131, year = {2025}, author = {Amorim, RM and Gaudie-Ley, LW and Aguiar, M and Sant'Anna, PDS and Freitas, ADS and Caetano, LF and Póvoa, AA and Santos, CSG and Folly, E and Silva, EC and Neto, JAB}, title = {The role of bioremediation in mitigating urban expansion impacts on coastal lagoons: A comparative study of Araçatiba and Padre Lagoons, Rio de Janeiro.}, journal = {Marine pollution bulletin}, volume = {217}, number = {}, pages = {118048}, doi = {10.1016/j.marpolbul.2025.118048}, pmid = {40328131}, issn = {1879-3363}, abstract = {This study examines the impact of urban expansion on organic matter gradients in two coastal lagoons, Araçatiba (AL) and Padre (PL), in Rio de Janeiro, Brazil, using benthic macrofauna as ecological indicators. To mitigate the effects of organic enrichment, a microbial consortium (Lactobacillus casei, Lactobacillus acidophilus, and Saccharomyces cerevisiae) was applied in AL for nine months prior to sampling, while PL remained untreated. Sediment samples were collected from 43 stations and analyzed for Total Organic Carbon (TOC), Total Nitrogen (TN), and Total Phosphorus (TP), alongside water column parameters (e.g., dissolved oxygen, salinity, chlorophyll-a) and benthic macrofaunal composition. Results indicated higher macrofaunal abundance and diversity in AL compared to PL, where organic pollution and eutrophication were more severe. Canonical Correspondence Analysis (CCA) identified salinity and eutrophication as primary drivers of community structure, with taxa such as Capitella spp. and Streblospio sp. tolerating high organic loads and hypoxia. AL's benthic community was dominated by mollusks (Heleobia australis, Mytilopsis leucophaeata), while PL was dominated by annelids (oligochaetes, Alitta succinea), reflecting divergent environmental conditions. The AMBI index classified PL as moderately to severely disturbed and AL as slightly to moderately disturbed, aligning with geochemical data showing higher TOC and nutrient concentrations in PL sediments. Microbial bioremediation in AL correlated with improved water quality (higher WQI, lower BOD) and benthic health, underscoring its potential as a management tool. The study highlights the need for tailored strategies to address anthropogenic pressures and restore ecological balance in coastal lagoons.}, }
@article {pmid40328052, year = {2025}, author = {Mirveis, Z and Patil, N and Byrne, HJ}, title = {Exploring cellular metabolic kinetics through spectroscopic analysis of extracellular environments.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {340}, number = {}, pages = {126308}, doi = {10.1016/j.saa.2025.126308}, pmid = {40328052}, issn = {1873-3557}, abstract = {Studying the kinetics of metabolic pathways, such as glycolysis and glutaminolysis, is valuable due to their fundamental links to various diseases, including cancer. This study explores the potential of Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy for analysing low concentrations of metabolites in extracellular media. It also evaluates the use of the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to data mine the kinetic evolution of the spectroscopic signatures of the glycolysis metabolic pathway and to explore the impact of the presence of glutamine on it. By extracting samples at specific time intervals and drying them on the ATR crystal, ATR-FTIR could effectively measure individual metabolites of glucose, glutamine and lactate at low concentrations, providing clear spectra with strong correlations between peak absorbance and metabolite concentrations. In data mining, MCR-ALS successfully resolved two components, glucose and lactate, from time-series data of cellular glucose metabolism (glycolysis), showing approximately 28 % glucose consumption and 1 mM lactate production at a constant rate of 0.0016 min[-1]. However, when glutamine was introduced as a third component, the overlap of the peaks of glutamine and lactate limited the method's ability to deconvolute the data, highlighting constraints of MCR-ALS in complex mixtures.}, }
@article {pmid40327885, year = {2025}, author = {Malik, T and Sidisky, JM and Jones, S and Winters, A and Hocking, B and Rotay, J and Huhulea, EN and Moran, S and Connors, B and Babcock, DT}, title = {Synaptic defects in adult drosophila motor neurons in a model of amyotrophic lateral sclerosis.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf068}, pmid = {40327885}, issn = {1460-2083}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Like other neurodegenerative diseases, defects in synaptic integrity are among the earliest hallmarks of ALS. However, the specific impairments to synaptic integrity remain unclear. To better understand synaptic defects in ALS, we expressed either wild-type or mutant Fused in Sarcoma (FUS), an RNA binding protein that is often mis-localized in ALS, in adult motor neurons. Using optogenetic stimulation of the motor neurons innervating the Ventral Abdominal Muscles (VAMs), we found that expression of mutant FUS disrupted the functional integrity of these synapses. This functional deficit was followed by disruption of synaptic gross morphology, localization of pre- and post-synaptic proteins, and cytoskeleton integrity. We found similar synaptic defects using the motor neurons innervating the Dorsal Longitudinal Muscles (DLMs), where expression of mutant FUS resulted in a progressive loss of flight ability along with disruption of active zone distribution. Our findings uncover defects in synaptic function that precede changes in synaptic structure, suggesting that synaptic function is more sensitive to this ALS model. Highlighting the earliest synaptic defects in this disease model should help to identify strategies for preventing later stages of disease progression.}, }
@article {pmid40326917, year = {2025}, author = {van Eijk, RPA and Weemering, DN and Opie-Martin, S and van Unnik, JWJ and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, &#xc9; and McDonough, H and Manera, U and McDermott, CJ and McFarlane, R and Mouzouri, M and Ombelet, F and Povedano Panadés, M and Sennfält, S and Shaw, PJ and Terrafeta Pastor, C and Van Damme, P and Vasta, R and Veldink, JH and Al-Chalabi, A and van den Berg, LH}, title = {Natural history of the revised ALS functional rating scale and its association with survival: the PRECISION-ALS Extant Study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {30-40}, doi = {10.1080/21678421.2024.2443985}, pmid = {40326917}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; Disease Progression ; Aged ; Longitudinal Studies ; Cohort Studies ; Adult ; Severity of Illness Index ; Survival Rate/trends ; }, abstract = {OBJECTIVE: To characterize the natural history of the revised ALS functional rating scale (ALSFRS-R) over a 24-month period following initial assessment, and to assess its associations with survival.<br><br>METHODS: Longitudinal ALSFRS-R measurements and survival data were obtained from seven population-based, European cohorts. Different models for the ALSFRS-R trajectory were evaluated, including tests for linearity and between-cohort differences. We employed a joint modeling framework to factor in mortality, thereby aiming to derive a more precise estimate of the population's rate of decline, while simultaneously delineating its relationship with survival.<br><br>RESULTS: In total, 7,030 patients were included who produced 31,746 ALSFRS-R measurements during a follow-up period of 10,285 person-years. There was substantial evidence for a non-linear time trend within all cohorts (all p&#x2009;<&#x2009;0.001), with faster progression rates at the beginning of follow-up. The average rate over 24 months was 0.89 points per month; 95% of the patients had a rate between 0.04 and 1.96. Overall, two components of the ALSFRS-R trajectory were found to be associated with survival: (1) the actual value of the ALSFRS-R total score and (2) the rate of change at any given time (both p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Functional loss in ALS follows a decelerating trajectory, where the current functional status and the rate of change have a direct impact on the patient' s probability of survival. Given the pivotal role of the ALSFRS-R in drug development, these results help to separate treatment benefit from the disease's natural trajectory and to estimate the impact on survival.}, }
@article {pmid40326916, year = {2025}, author = {Sennfält, S and Al-Chalabi, A and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Lamaire, N and Mac Domhnaill, &#xc9; and McDonough, H and Manera, U and McDermott, CJ and McFarlane, R and Mouzouri, M and Ombelet, F and Opie-Martin, S and Povedano Panadés, M and Shaw, P and Terrafeta Pastor, C and Van Damme, P and van den Berg, L and van Eijk, RPA and Vasta, R and Veldink, JH and Weemering, DN and Ingre, C}, title = {Respiratory function, survival, and NIV prevalence over time in ALS - a PRECISION ALS study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {61-72}, doi = {10.1080/21678421.2025.2454923}, pmid = {40326916}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/physiopathology/genetics/epidemiology/complications ; Male ; Female ; Middle Aged ; *Noninvasive Ventilation/statistics &amp; numerical data/trends ; Aged ; Prevalence ; Prospective Studies ; *Respiratory Insufficiency/therapy/etiology ; Adult ; Disease Progression ; Cohort Studies ; C9orf72 Protein/genetics ; }, abstract = {INTRODUCTION: Respiratory function typically deteriorates as ALS progresses and is associated with shorter survival. This study aims to describe respiratory function and the prevalence of noninvasive ventilation (NIV) along the disease trajectory using prospective data from the PRECISION ALS project.<br><br>METHODS: We included 3449 ALS patients from six European population-based cohorts. All had comparable assessments of vital capacity, percent predicted (VC%) (58.1% had multiple assessments) and 56% had assessments of the revised ALS Functional Rating Scale (ALSFRS-R). The data were analyzed in relation to survival, NIV, and genetic status (C9orf72, SOD1, FUS, and TARDBP).<br><br>RESULTS: In those with a survival time of 1-4&#x2009;years from diagnosis, the median VC% declined from 91 to 97% at the first assessment to 47-50% at the last assessment 6&#x2009;months before death. In those with longitudinal assessments, the median VC% declined an average of 24 percentage points per year. Over time, there was an increase in respiratory symptoms relative to general functional impairment, as measured by the ALSFRS-R, and VC% was strongly associated with shorter survival. The confirmed prevalence of NIV was approximately 3%, 15%, and 25% in patients with a VC% of >80, 50-80, and <50, respectively.<br><br>CONCLUSION: There was a trend of worsening respiratory function over time and an increase in respiratory symptoms relative to general functional impairment. Survival was strongly associated with respiratory function. In those with impaired respiratory function, there was significant variation in the introduction of NIV.}, }
@article {pmid40326915, year = {2025}, author = {Caravaca Puchades, A and McDonough, HE and Al-Chalabi, A and Chiò, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, &#xc9; and Manera, U and McFarlane, R and Mouzouri, M and Ombelet, F and Opie-Martin, S and Sennfält, S and Terrafeta Pastor, C and Veldink, JH and Van Damme, P and van den Berg, L and van Eijk, RPA and Vasta, R and Weemering, DN and Shaw, P and McDermott, CJ and Povedano Panadés, M}, title = {Mapping the natural history of amyotrophic lateral sclerosis: time-to-event analysis of clinical milestones in the pan-European, population-based PRECISION-ALS cohort.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {8-19}, doi = {10.1080/21678421.2024.2448535}, pmid = {40326915}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/epidemiology/therapy/mortality ; Male ; Middle Aged ; Female ; Europe/epidemiology ; Aged ; Disease Progression ; Cohort Studies ; Age of Onset ; Prognosis ; Adult ; C9orf72 Protein/genetics ; Gastrostomy ; Noninvasive Ventilation ; Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: Map time to key clinical milestones in amyotrophic lateral sclerosis (ALS), highlighting underlying genotypic and phenotypic prognostic factors.<br><br>BACKGROUND: Understanding the ALS disease trajectory and factors influencing the heterogeneous disease course is important to guide clinical care and stratify individuals to effectively assess therapeutics in clinical trials.<br><br>METHODS: Population-based datasets from nine European ALS care centers were collated. Time-to-event analysis was conducted for key clinical milestones: symptom onset, diagnosis, gastrostomy insertion, noninvasive ventilation (NIV) initiation, and survival. Independent prognostic factors were determined.<br><br>RESULTS: 21,820 people with ALS from nine ALS centers were included. Median age of symptom onset was 63.9 years. Median diagnostic delay was 1.0 years, with median survival of 33.7 months from onset. Prognostic factors for survival included age at onset, baseline vital capacity, progression rate, diagnostic delay, site of onset, and C9orf72-positive status. SOD1 variants D91A and G94C had protective prognostic effects in the whole cohort. Median time from diagnosis to gastrostomy insertion in bulbar-onset disease was 2.34 years. Median time from diagnosis to NIV initiation in those diagnosed between 2010 and 2019 was 3.61 years. Significant differences between ALS clinical center cohorts were seen in time to gastrostomy insertion, time to NIV initiation, and in overall survival time.<br><br>CONCLUSION: Our analysis of a large, well-defined, population-based European cohort provides detailed insight into the natural history of ALS, highlighting phenotypic and genetic factors affecting time to key clinical milestones. Further study is needed to determine the drivers in observed differences between ALS clinical center cohorts in time to clinical interventions and overall survival.}, }
@article {pmid40326914, year = {2025}, author = {Vasta, R and Ombelet, F and Hobin, F and Manera, U and Ammar, AC and Caravaca Puchades, A and Corcia, P and Galvin, M and Hardiman, O and Heverin, M and Holmdahl, O and Ingre, C and Lamaire, N and McDermott, C and Mac Domhnaill, &#xc9; and McDonough, H and McFarlane, R and Mouzouri, M and Sarah, OM and Povedano Panadés, M and Sennfält, S and Shaw, P and Terrafeta Pastor, C and van den Berg, LH and van Eijk, RPA and Veldink, JH and Weemering, DN and Van Damme, P and Chiò, A}, title = {Real-world prognostic role of riluzole use in ALS: a multi-center study from PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {50-60}, doi = {10.1080/21678421.2025.2472889}, pmid = {40326914}, issn = {2167-9223}, mesh = {Humans ; *Riluzole/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/mortality/diagnosis ; Male ; Female ; Middle Aged ; *Neuroprotective Agents/therapeutic use ; Retrospective Studies ; Aged ; Prognosis ; Disease Progression ; Adult ; Kaplan-Meier Estimate ; Treatment Outcome ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) remains an incurable disease, with limited treatment options, and riluzole is the most widely available drug. We evaluated survival in a large cohort of patients with ALS, comparing those treated with riluzole to those who were not.<br><br>METHODS: Using data from the PRECISION-ALS database, we retrospectively analyzed patients with ALS who were treated with 100&#x2009;mg of riluzole daily at the time of diagnosis. ALSFRS-R slope from onset to diagnosis (&#x394;FRS) was calculated. Based on the &#x394;FRS distribution, we defined fast progressors as patients having a &#x394;FRS > 1.17, intermediate progressors as those with 1.17&#x2009;>&#x2009;&#x394;FRS > 0.31 and slow progressors as those with a &#x394;FRS < 0.31 points per month. We used Kaplan-Meier curves and Cox proportional hazards model to explore the association of riluzole use with patient survival since diagnosis.<br><br>RESULTS: Out of the 5842 patients with available riluzole data, 4847 (82.9%) received riluzole. The overall survival significantly differed between patients treated and not treated with riluzole (HR 0.70, 95%CI 0.69, 0.79), independently of sex, site of onset, age at onset and diagnostic delay. Patients treated with riluzole exhibited a 7&#x2009;month longer median survival than those who did not receive riluzole (17.6&#x2009;months, IQR 9.7, 29.9 vs 10.7&#x2009;months, IQR 4.3, 23.4; p&#x2009;=&#x2009;2&#x2009;&#xd7;&#x2009;10[-16]). The relationship between riluzole use and extended survival varied across &#x394;FRS strata, being only evident among fast progressors (HR = 0.50, 95% 0.40, 0.63).<br><br>CONCLUSIONS: Treatment with riluzole is an independent prognostic factor in ALS. The extended survival related to riluzole use was only evident among fast-progressing patients.}, }
@article {pmid40326913, year = {2025}, author = {McDonough, H and McFarlane, R and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, &#xc9; and Manera, U and Mouzouri, M and Ombelet, F and Opie-Martin, S and Povedano Panadés, M and Sennfält, S and Terrafeta Pastor, C and Veldink, JH and van Damme, P and van Den Berg, L and van Eijk, RPA and Vasta, R and Weemering, DN and Al-Chalabi, A and Shaw, P and McDermott, CJ and Hardiman, O}, title = {Examining changing working status and caregiver assistance in amyotrophic lateral sclerosis (ALS) using large-scale European databases as part of PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {20-29}, doi = {10.1080/21678421.2024.2448536}, pmid = {40326913}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/psychology/therapy/nursing ; *Caregivers/psychology/statistics &amp; numerical data ; Female ; Male ; Middle Aged ; Europe/epidemiology ; *Employment/statistics &amp; numerical data/trends ; Aged ; Adult ; Databases, Factual ; Cohort Studies ; Longitudinal Studies ; }, abstract = {OBJECTIVE: To examine the working status of people living with ALS (plwALS), the identity of their caregivers, the amount of informal care provided to them, and how these factors change over time.<br><br>METHODS: Data from nine specialist European ALS centers and previously funded projects, such as ALSCarE, were collated. The cohort was stratified into progression groups based on the calculated &#x394;FRS and compared longitudinally.<br><br>RESULTS: Twenty-one thousand eight hundred and twenty patients were identified at the time of data analysis. One thousand one hundred and eighty-four had working status data. Two hundred and thirty-seven patients in this group were followed in the form of semi-structured interviews. Within the 1184 patient group, 45% were identified as in "paid employment" prior to diagnosis, taking a median of 12 months to leave the workforce post-onset. Eighty-three percent of patients were no longer working 20 months post-diagnosis. Informal care hours increased over time, and were primarily provided by spouses and children. In those less than 12 months from symptom onset, the median number of care hours per week was 15.0 (IQR 63.8), rising to 60.0 (IQR 154.0) 48-96 months after onset. There was a significant relationship between ALSFRS-R total score and hours of care delivered (r&#xa0;=&#xa0;-0.47, p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: Up to 45% of plwALS are working prior to diagnosis and their working status changes rapidly, taking an average of 12 months to leave the workforce. Caregiver input increases over time, proportional to ALSFRS-R score. Caregivers are primarily spouses and children. Further work is needed to comprehensively capture this information and calculate its true socioeconomic impact.}, }
@article {pmid40326912, year = {2025}, author = {McFarlane, R and Opie-Martin, S and Caravaca Puchades, A and Chiò, A and Corcia, P and Galvin, M and Heverin, M and Hobin, F and Holmdahl, O and Ingre, C and Lamaire, N and Mac Domhnaill, &#xc9; and Manera, U and Mcdermott, CJ and McDonough, H and Mouzouri, M and Ombelet, F and Panadés, MP and Sennfält, S and Shaw, P and Terrafeta Pastor, C and Veldink, JH and Van Damme, P and van den Berg, L and Van Eijk, RPA and Vasta, R and Weemering, DN and Al-Chalabi, A and Hardiman, O}, title = {Clinical trajectories of genetic variants in ALS: a European observational study within PRECISION-ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {sup1}, pages = {41-49}, doi = {10.1080/21678421.2025.2450805}, pmid = {40326912}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Male ; Female ; *C9orf72 Protein/genetics ; Middle Aged ; *RNA-Binding Protein FUS/genetics ; Europe/epidemiology ; *Superoxide Dismutase-1/genetics ; Aged ; *DNA-Binding Proteins/genetics ; *Genetic Variation/genetics ; Adult ; Age of Onset ; Registries ; Genetic Testing ; }, abstract = {OBJECTIVE: To investigate the association between C9orf72, SOD1, FUS and TARDBP variants on the clinical trajectory of ALS patients in Europe.<br><br>METHODS: Nine ALS centers with population-based registries provided data on demographic and disease characteristics - at diagnosis and longitudinally - as part of PRECISION ALS. These data were harmonized and collated for analysis.<br><br>RESULTS: 21,820 ALS patients were identified, 9,887 underwent genetic testing for at least one of the 4 genes of interest. 9.8% of patients carried a hexanucleotide expansion in C9orf72; 2.9% carried a pathogenic variant in SOD1; 1.4% carried a pathogenic variant in TARDBP; and 0.8% carried a pathogenic variant in FUS. Only one p.A5V variant was identified in this dataset. The most frequently identified SOD1 variant was p.D91A, with evidence of other variant clusters in Belgium, Italy and the United Kingdom. TARDBP variants were clustered in the Netherlands and Italy. Earlier ages of onset were demonstrated compared to wild-type populations; C9orf72 59.58 (IQR 62.5, p&#x2009;<&#x2009;2.2e-16), SOD1 54.19 (IQR 19.4, p&#x2009;=&#x2009;6.304e-14), TARDBP 58.30 (IQR 16.23, p&#x2009;=&#x2009;0.00024) and FUS 51.16 (IQR 25.08, p&#x2009;=&#x2009;1.58e-06). C9orf72 was more bulbar (p&#x2009;<&#x2009;0.0001) in onset and SOD1 more spinal (p&#x2009;<&#x2009;0.0001). Those carrying variants spent distinctly different periods in each of the King's stages.<br><br>CONCLUSIONS: Genetic forms of ALS have an earlier age of onset, have distinct patterns in their sites of disease onset, and progress differently as compared to populations without such major-effect genes. There is also evidence of disease clusters across Europe suggestive of founder effects.}, }
@article {pmid40326218, year = {2025}, author = {Yan, G and Tang, H and Shen, Y and Han, L and Han, Q}, title = {AI-Generated Ammonium Ligands for High-Efficiency and Stable 2D/3D Heterojunction Perovskite Solar Cells.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e2503154}, doi = {10.1002/adma.202503154}, pmid = {40326218}, issn = {1521-4095}, support = {2020YFB1506400//National Key R&amp;D Program of China/ ; 2021YFB3800100//National Key R&amp;D Program of China/ ; U20A20245//National Natural Science Foundation of China/ ; U21A20171//National Natural Science Foundation of China/ ; 11834011//National Natural Science Foundation of China/ ; 12074245//National Natural Science Foundation of China/ ; }, abstract = {The 2D/3D heterojunction perovskite solar cells (PSCs) exhibit remarkable stability, but the quantum well in the 2D perovskite capping layer hinders the carrier transport, thereby lowering the power conversion efficiency (PCE). The relationship between the transport barrier and the complex structure of ammonium ligands (ALs) is currently poorly understood, thus leading to the one-sided approach and inefficient process in the development of 2D perovskite. Here, a machine learning procedure is established to comprehensively explore the relationship and combined it with an artificial intelligence (AI) model based on reinforcement learning algorithm to accelerate the generation of ALs. Finally, the AI-designed ALs improved the carrier transport performance of the 2D perovskite capping layer, and we achieved a certified PCE of 26.12% in inverted PSCs. The devices retained 96.79% of the initial PCE after 2000 h operation in maximum power point tracking under 1-sun illumination at 85°C.}, }
@article {pmid40325332, year = {2025}, author = {Liu, S and Feng, A and Li, Z}, title = {Neuron-Derived Extracellular Vesicles: Emerging Regulators in Central Nervous System Disease Progression.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40325332}, issn = {1559-1182}, abstract = {The diagnosis and exploration of central nervous system (CNS) diseases remain challenging due to the blood-brain barrier (BBB), complex signaling pathways, and heterogeneous clinical manifestations. Neurons, as the core functional units of the CNS, play a pivotal role in CNS disease progression. Extracellular vesicles (EVs), capable of crossing the BBB, facilitate intercellular and cell-extracellular matrix (ECM) communication, making neuron-derived extracellular vesicles (NDEVs) a focal point of research. Recent studies reveal that NDEVs, carrying various bioactive substances, can exert either pathogenic or protective effects in numerous CNS diseases. Additionally, NDEVs show significant potential as biomarkers for CNS diseases. This review summarizes the emerging roles of NDEVs in CNS diseases, including Alzheimer's disease, depression, traumatic brain injury, schizophrenia, ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It aims to provide a novel perspective on developing therapeutic and diagnostic strategies for CNS diseases through the study of NDEVs.}, }
@article {pmid40324968, year = {2025}, author = {Gomathy, SB and Macken, WL and Rani, N and Agarwal, A and Singh, R and Dhamne, M and Nair, SS and Reyaz, A and Ahmed, T and Dalal, A and Muthulakshmi, M and Wilson, L and Vijayaraghavan, A and ,  and Bhatia, R and Pitceathly, RD and Thangaraj, K and Reilly, MM and Srivastava, PM and Hanna, MG and Vishnu, VY}, title = {Kennedy's disease from India: An Indian Cohort with multisystemic manifestations.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251325795}, doi = {10.1177/22143602251325795}, pmid = {40324968}, issn = {2214-3602}, abstract = {BackgroundKennedy's disease (KD) is a rare, insidiously progressive lower motor neuron syndrome characterised by amyotrophy involving the appendicular or bulbar musculature of adult males in their fourth to fifth decade. There are no large series from the Indian subcontinent describing the clinical-genetic and laboratory spectrum of KD.AimTo describe the clinical, electrophysiologic, metabolic and genetic profile of patients with KD.MethodsWe conducted a retrospective review of ten genetically confirmed KD patients.ResultsThe mean age of the cohort was 47 years, with a mean age of onset of illness at 41.3 ± 9.9 years. The median duration of symptoms before presentation was 5 (3-12) years. The most common referral diagnosis was ALS. The majority presented with symmetric proximal limb weakness with bulbar symptoms and were found to have gynecomastia, lower motor neuron (LMN) facial weakness, and facial and lingual fasciculations. Electrophysiology revealed sensory neuropathy in five patients and chronic neurogenic changes consistent with anterior horn cell disease in all. Metabolic profile showed impaired glycemia, hyperlipidemia and evidence of non-alcoholic fatty liver disease in the majority. All had elevated serum creatine kinase. Genetic testing revealed a median of 46 CAG repeats. The phenotypes of our patients aligned with global data that is predominantly derived from participants of European ancestry.ConclusionWe describe a series of patients with KD from India with significant multisystemic involvement.}, }
@article {pmid40324960, year = {2025}, author = {Simkins Lead, T and Shefner, JM and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and van Eijk, RP}, title = {Application of the ENCALS predictive survival model in assessing the effect of the 24/44 inclusion criteria in FORTITUDE-ALS.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251336058}, doi = {10.1177/22143602251336058}, pmid = {40324960}, issn = {2214-3602}, abstract = {FORTITUDE-ALS was a study evaluating reldesemtiv in people living with ALS. Post-hoc analysis identified larger treatment effects in those with symptom onset ≤24 months and baseline ALSFRS-R ≤ 44 (24/44 criteria). Using the ENCALS risk score (RS), we analyzed how the 24/44 criteria changed the eligible population. Of the 272 participants meeting the 24/44 criteria, 73% had very short to intermediate RS compared to 18% not meeting the criteria. Though the 24/44 criteria enriched the FORTITUDE-ALS population with rapidly progressing patients, they did not completely exclude all patients with a very long predicted survival.}, }
@article {pmid40324158, year = {2025}, author = {Tabor Gray, L and Shune, S and Perry, S and Kosty, D and Namasivayam-MacDonald, A}, title = {Dysphagia Symptoms Contribute to Greater Care Partner Burden in Neurodegenerative Disease.}, journal = {American journal of speech-language pathology}, volume = {}, number = {}, pages = {1-9}, doi = {10.1044/2025_AJSLP-24-00529}, pmid = {40324158}, issn = {1558-9110}, abstract = {PURPOSE: Providing care for family members with neurodegenerative diseases entails significant physical and psychosocial costs, increasing caregiver burden. Limited research exists on the factors contributing to dysphagia-related burden, particularly across disease trajectories. This study aimed to (a) determine if dysphagia-related burden predicts general caregiver burden, (b) identify predictors of dysphagia-related burden, and (c) examine relationships between dysphagia severity, disease severity, and dysphagia-related burden.<br><br>METHOD: Care partners (N = 211; 80% female; Mage = 60 &#xb1; 14 years) from clinics in Canada, New Zealand, and the United States participated. Care recipients included those with amyotrophic lateral sclerosis (ALS; n = 48), dementia (n = 110), and Parkinson's disease (PD; n = 53). General burden was measured using the Zarit Burden Interview, while dysphagia-related burden was assessed via the Caregiver Assessment of Reported Experiences with Swallowing Difficulties. Multiple regression analyses examined predictors of general and dysphagia-related burden and their relationships to dysphagia and disease severity.<br><br>RESULTS: Higher general burden was associated with female caregivers (&#x3b2; = -.19, p = .05), higher education (&#x3b2; = .16, p = .03), caring for someone with dementia (&#x3b2; = .36, p = .01), and greater dysphagia-related burden (&#x3b2; = .33, p = .01). Predictors of dysphagia-related burden included working caregivers (&#x3b2; = .15, p = .01), increased dysphagia symptoms (&#x3b2; = .77, p < .01), and caring for individuals with ALS or dementia (vs. PD; &#x3b2; = -.16, p = .02). Dysphagia burden varied by disease severity and diet tolerance (p < .01).<br><br>CONCLUSIONS: Managing dysphagia independently contributes to caregiver burden, potentially increasing burnout and nonadherence to clinical recommendations. Early, proactive inquiry about dysphagia-related care partner burden and provision of support to minimize burden should be considered early in disease management.<br><br>SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.28843055.}, }
@article {pmid40323286, year = {2025}, author = {Zhao, N and Jiang, J and Zhu, T and Wang, Z and Hu, W and Yin, F and Cao, H and Liao, M}, title = {First Report on Resistance to ALS-Inhibiting Herbicides in the Broadleaved Weed Common Vetch (Vicia sativa L.) and Visual Detection of the Associated ALS Resistance Mutation.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.5c01785}, pmid = {40323286}, issn = {1520-5118}, abstract = {Common vetch (Vicia sativa L.), an economically significant crop, is also a detrimental weed in wheat fields in the middle and lower reaches of the Yangtze River, China. A population of V. sativa (AHLQ-1) exhibiting high resistance (>10-fold) to ALS inhibitors, tribenuron-methyl and florasulam, was identified. All resistant plants carried a Pro-197-Ser substitution in their ALS genes, rendering their ALS enzymes 16.89 times less sensitive. Molecular docking revealed that the binding energies between ALS active sites and tribenuron-methyl or florasulam were reduced by over 80% due to the mutation at codon position 197. A LAMP method was successfully developed to visually detect this mutation, and a dCAPS assay was established to distinguish specific resistance mutations between homozygotes and heterozygotes. Additionally, cytochrome P450 activity was significantly elevated in resistant plants, enhancing the herbicide metabolism and resistance. This is the first global report of ALS resistance naturally occurring in V. sativa. These findings will aid in breeding herbicide-resistant V. sativa and improve resistance management.}, }
@article {pmid40321778, year = {2025}, author = {Walter, N and Gao, G and Sumrall, E}, title = {Nanoscale domains govern local diffusion and aging within FUS condensates.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6406576/v1}, pmid = {40321778}, issn = {2693-5015}, abstract = {Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here, we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labeled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein Fused in Sarcoma (FUS) as a model for condensates implicated in ALS, we discover that RNA and protein diffusion is confined within distinct nanometer-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. During condensate aging, these nanodomains reposition, facilitating FUS fibrilization at the condensate surface, a transition enhanced by FDA-approved ALS drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating biomolecule sequestration and percolation, offering insights into condensate aging and disease-related transitions.}, }
@article {pmid40321197, year = {2025}, author = {Rennels, CF and Rosow, L and Pantilat, S and Bell, BK and Lomen-Hoerth, C and Cohen, E and Bischoff, KE}, title = {Characteristics and Motivations of People With Amyotrophic Lateral Sclerosis Who Pursue Medical Aid in Dying in California.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {3}, pages = {e200478}, pmid = {40321197}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: People with amyotrophic lateral sclerosis (ALS) disproportionately pursue medical aid in dying (MAID). We described characteristics and motivations of patients with ALS who sought MAID in California.<br><br>METHODS: This is a retrospective cohort study of patients followed in the ALS and Palliative Care clinics at the University of California, San Francisco, between September 2017 and October 2023 who obtained a MAID prescription under California's End of Life Option Act. We abstracted demographic and clinical information from the electronic health record. We reviewed clinician notes to gather salient themes regarding patients' motivations for MAID and calculated the frequencies of motivations reported by prescribing physicians on standardized forms.<br><br>RESULTS: Thirty-seven patients obtained a MAID prescription. The median age at first documented inquiry about MAID was 64.0 years, 51.4% identified as women, 83.8% were White, and 10.8% had Medicaid. All spoke English and had a care partner. Most (70.3%) had limb-onset ALS. The median ALS Functional Rating Scale-Revised score was 28.5/48 and the median forced vital capacity was 41.5% at time of first inquiry about MAID. Most patients (70.3%) inquired about MAID during their first visit with palliative care. Physicians wrote MAID prescriptions at a median of 76 days after first inquiry. Most patients (73.0%) took MAID medications to end their lives, at a median of 39.5 days after the prescription was written.Clinician notes revealed that patients were commonly motivated to pursue MAID by concerns about current and future suffering, loss of autonomy and enjoyable activities, and desire for control at the end of life. On standardized forms completed after patients died, physicians documented that "persistent and uncontrollable pain and suffering" was a less common reason that patients pursued MAID.<br><br>DISCUSSION: Patients with ALS who requested MAID were largely White and English speaking. Most patients inquired about MAID when they had moderate-stage ALS and were early in their course of palliative care. Motivations for pursuing MAID often involved the accumulated losses characterizing ALS and worries about the future. Future studies should incorporate diverse patient voices, explore barriers to accessing MAID, and consider whether any interventions can ameliorate issues driving requests for MAID in people with ALS.}, }
@article {pmid40320859, year = {2025}, author = {Watanabe, S and Yamanaka, K}, title = {Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {}, number = {}, pages = {e70016}, doi = {10.1002/bies.70016}, pmid = {40320859}, issn = {1521-1878}, support = {23K06826//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; 19KK0214//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; 22H00467//Ministry of Education, Culture, Sports, Science and Technology, Japan/Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //Mochida Memorial Foundation for Medical and Pharmaceutical Research/ ; //Kowa Life Science Foundation/ ; //Novartis Foundation/ ; }, abstract = {Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca[2+] transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.}, }
@article {pmid40320052, year = {2025}, author = {Nadeem, A and Sharma, P and Gupta, P and Sandeep, P and Sharma, B and Sharma, N and Yadav, M and Dhiman, N}, title = {Exploring Neuregulin3: From physiology to pathology, a novel target for rational drug design.}, journal = {Biochemical pharmacology}, volume = {}, number = {}, pages = {116964}, doi = {10.1016/j.bcp.2025.116964}, pmid = {40320052}, issn = {1873-2968}, abstract = {Neuregulin 3 (NRG3) is an epidermal growth factor related protein that binds to and stimulates the Erb-B2 receptor tyrosine kinase 4 (ErbB4). NRG3 is a multifunctional protein with fifteen alternative splicing isoforms categorized into four classes. Numerous physiological processes, such as the formation of cortical plate, cortical patterning, synaptic development, neuronal proliferation, regulation of neurotransmission, control of impulsive behavior, mammary gland morphogenesis, spermatogonial proliferation and cardiac homeostasis are influenced by NRG3. Besides its physiological roles, NRG3 also modulates anxiogenic phenotypes. It is a susceptibility gene for schizophrenia, autism spectrum disorder and Hirschsprung's Disease. Furthermore, anxiety during nicotine withdrawal is dependent on NRG3-ErbB4 signaling. Research on a range of solid carcinomas, such as brain tumors, ovarian cancer, gastrointestinal cancer and breast cancer, has demonstrated NRG3 gene as a therapeutic target. NRG3 also has potential involvement in epilepsy, angular limb malformation in Rambouillet rams, amyotrophic lateral sclerosis and polythelia. Nevertheless, little is known about the molecular characteristics, activities specific to isoforms, and molecular mechanisms of NRG3. Examining its potential involvement in a range of physiological processes and pathological states is a unique area that needs in-depth study and may offer new mechanistic insights and comprehension of these elements. Thus, the purpose of this review is to shed light on the utility of NRG3 as a potential target in various health and disease conditions.}, }
@article {pmid40319325, year = {2025}, author = {Mehdizadeh, S and Mamaghani, M and Hassanikia, S and Pilehvar, Y and Ertas, YN}, title = {Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {329}, pmid = {40319325}, issn = {1477-3155}, mesh = {*Exosomes/metabolism/chemistry ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; Animals ; *Drug Delivery Systems/methods ; *Neuropharmacology/methods ; Drug Carriers/chemistry ; }, abstract = {BACKGROUND: The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods.<br><br>MAIN BODY: This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions.<br><br>CONCLUSION: By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.}, }
@article {pmid40317507, year = {2025}, author = {Garret, MA and Namiranian, D and Milone, M and Varadhachary, A and Ho, D}, title = {Atypical Facial Onset Weakness in SOD1 ALS.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28428}, pmid = {40317507}, issn = {1097-4598}, }
@article {pmid40317297, year = {2025}, author = {Faltacco, V and Dalla Bella, E and Nigri, A and Telesca, A and Gandini, G and Riva, N and Vizziello, M and Medina, JP and Demichelis, G and Grisoli, M and Usai, S and Lauria, G and Consonni, M}, title = {Pathological laugher and crying in motor neuron diseases: a matter of bulbar and neurobehavioral involvement with sex imbalance.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {372}, pmid = {40317297}, issn = {1432-1459}, support = {2015-0023//Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia/ ; 1157625//Fondo Europeo di Sviluppo Regionale, Regione Lombardia (POR FESR 2014-2020)/ ; }, mesh = {Humans ; Female ; Male ; *Crying/psychology/physiology ; Middle Aged ; *Motor Neuron Disease/physiopathology/psychology/diagnostic imaging/complications/pathology ; Aged ; *Laughter/physiology/psychology ; Magnetic Resonance Imaging ; *Affective Symptoms/etiology/physiopathology ; *Sex Characteristics ; Adult ; }, abstract = {BACKGROUND: Emotional lability (EL), also known as pathological laughter and crying, is a common but understudied symptom in motor neuron diseases (MND): amyotrophic lateral sclerosis and primary lateral sclerosis. This study aimed to investigate the prevalence of EL in MND and to explore the independent frequency components of laughter and crying in relation to motor, cognitive, neuropsychiatric, and neuroimaging factors.<br><br>METHODS: A total of 198 incident MND patients were enrolled. The Centre of Neurological Study-Lability Scale was used to measure EL. Associations between EL and motor function, mood, neuropsychological variables, and structural MRI were examined, with cortical thinning measured on a subset of 48 patients.<br><br>RESULTS: EL was identified in 36% of patients showing more severe motor functional disabilities, heightened depressive and anxiety symptoms and behavioral changes than those without EL. Women exhibited more severe EL and altered mood with frequent crying episodes than men. EL was strongly correlated with bulbar involvement. Crying episodes were associated with mood disorders, while laughter correlated with disinhibition and emotional regulation difficulties. EL had a specific association with the thinning of frontal regions, including the right pars orbitalis, which was also linked to altered emotional and behavioral regulation.<br><br>CONCLUSION: These findings underscore the role of corticobulbar and frontal pathways in EL pathophysiology. The study highlights the distinct mechanisms underlying pathological crying and laughter and their independency from general cognitive decline. It emphasizes the need for clinicians to recognize EL as an independent symptom, necessitating targeted management strategies to improve patient outcomes and support caregivers.}, }
@article {pmid40316175, year = {2025}, author = {Iguchi, Y and Takahashi, Y and Li, J and Amakusa, Y and Kawakami, Y and Yoshimura, T and Chikuchi, R and Iida, M and Yokoi, S and Katsuno, M}, title = {Truncation mutation of CHMP2B disrupts late endosome function but reduces TDP-43 aggregation through HSP70 upregulation.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {105982}, doi = {10.1016/j.neuint.2025.105982}, pmid = {40316175}, issn = {1872-9754}, abstract = {TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This aggregation contributes substantially to the neurodegeneration of ALS and FTLD. The endosome, a key component of membrane trafficking in eukaryotic cells and is involved in the autophagy-lysosome pathway. Endosome-related genes such as CHMP2B, Alsin, and TMEM106B, are either causative or act as genetic modifiers in ALS and FTLD. However, the association between endosomal functions and TDP-43 aggregations remain poorly understood. The C-terminal truncation mutation CHMP2B, which causes frontotemporal dementia associated with chromosome 3 (FTD3), disrupts late endosome (LE)-lysosomes fusion. Nevertheless, FTD3 does not induce TDP-43 pathology. In this study, we showed that CHMP2B mutation-induced LE dysfunction promotes TDP-43 aggregate degradation through enhanced recruitment to juxtanuclear quality control compartments. Transcriptomic analysis revealed that CHMP2B[intron5] overexpression upregulates HSP70 expression. New insights into the connection between CMHP2B and HSP70 as well as the role of HSP70-mediated membrane trafficking in TDP-43 aggregation, offer a valuable understanding of the disease mechanism of ALS and FTLD.}, }
@article {pmid40314791, year = {2025}, author = {Iuzzolino, VV and Scaravilli, A and Carignani, G and Senerchia, G and Pontillo, G and Dubbioso, R and Cocozza, S}, title = {Mapping motor and extra-motor gray and white matter changes in ALS: a comprehensive review of MRI insights.}, journal = {Neuroradiology}, volume = {}, number = {}, pages = {}, pmid = {40314791}, issn = {1432-1920}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, yet with substantial clinical variability. Furthermore, beyond motor symptoms, ALS patients also show non-motor features, reflecting its classification as a multi-system disorder. The identification of reliable biomarkers is a critical challenge for improving diagnosis, tracking disease progression, and predicting patient outcomes. This review explores macro- and microstructural alterations in ALS, focusing on gray matter (GM) and white matter (WM) as observed through Magnetic Resonance Imaging (MRI). This approach synthesizes not only the expected involvement of motor areas but also highlights emerging evidence that these changes extend to extra-motor areas, such as the frontal and temporal lobes, underscoring the complex pathophysiology of ALS. The review emphasizes the potential of MRI as a non-invasive tool to provide new biomarkers by assessing both GM and WM integrity, a key advancement in ALS research. Additionally, it addresses existing discrepancies in findings and stresses the need for standardized imaging protocols. It also highlights the role of multi-modal MRI approaches in deepening our understanding of ALS pathology, emphasizing the importance of combining structural and diffusion MRI techniques to offer more comprehensive insights into ALS progression, ultimately advancing the potential for personalized treatment strategies and improving patient outcomes.}, }
@article {pmid40314217, year = {2025}, author = {Ju, T and Zhang, Y and Liu, L and Zhao, X and Li, X and Liu, C and Sun, S and Wu, LA}, title = {The role of gut microbiota-mitochondria crosstalk in neurodegeneration: Underlying mechanisms and potential therapies.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01419}, pmid = {40314217}, issn = {1673-5374}, abstract = {Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis, which refers to the crosstalk between the gut and the central nervous system. More importantly, mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain. Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases. Mitochondria are essential for meeting the host's substantial neuronal metabolic demands, maintaining excitability, and facilitating synaptic transmission. Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases. Therefore, this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration, as well as the existing potential therapeutic strategies for neurodegenerative disorders. These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases, and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases. However, this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases, such as Huntington's disease and Multiple sclerosis, and the potential therapeutic strategies were translated into clinical trials, which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.}, }
@article {pmid40313273, year = {2025}, author = {Dergai, O and Wuu, J and Koziczak-Holbro, M and Malaspina, A and Granit, V and Hernandez, JP and Cooley, A and Sachdev, R and Yu, L and Bidinosti, M and Flotte, L and Nash, M and Jennings, LL and Berry, JD and Bruijn, LI and Brachat, S and Benatar, M}, title = {Skeletal muscle biomarkers of amyotrophic lateral sclerosis: a large-scale, multi-cohort proteomic study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.23.25326161}, pmid = {40313273}, abstract = {BACKGROUND: Biomarkers with clear contexts-of-use are important tools for ALS therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.<br><br>METHODS: Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. SOMAmer (Slow Off-rate Modified Aptamer)-based relatively quantitative measurement of &#x223c;7,000 proteins was performed in plasma and CSF, with immunoassay validation of candidates of interest.<br><br>RESULTS: We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, while ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (e.g. PDLIM3, TNNT2, MYL11) or decrease (e.g. ANTXR2, ART3, MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11 and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.<br><br>CONCLUSION: We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease.<br><br>KEY MESSAGES: What is already known on this topic: There are currently few monitoring and disease progression biomarkers in ALS; and there is no published work from large-scale, multi-cohort proteomic studies that utilized longitudinal plasma and CSF samples to help fill this gap.What this study adds: Using Slow Off-rate Modified Aptamer (SOMAmer)-based methods, we have identified an array of novel biomarkers of disease state (i.e. differentially regulated in ALS vs. controls) and ALS disease progression. These included, among others, PDLIM3, MYL11, ANTXR2, ART3, and MSTN.Skeletal muscle is the likely source of many of these newly discovered biomarkers.How this study might affect research, practice or policy: These newly identified monitoring and disease progression biomarkers may be used to evaluate pharmacodynamic response in future clinical trials, thereby aiding ALS therapy development efforts.}, }
@article {pmid40313114, year = {2025}, author = {Zhou, M and Zheng, M and Liang, S and Li, M and Ma, J and Zhang, S and Song, X and Hu, Y and Lyu, Y and Ou, X and Yue, C}, title = {Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01507}, pmid = {40313114}, issn = {1673-5374}, abstract = {The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.}, }
@article {pmid40313084, year = {2025}, author = {Zhang, T and Yin, Y and Xia, X and Que, X and Liu, X and Zhao, G and Chen, J and Chen, Q and Xu, Z and Tang, Y and Qin, Q}, title = {Regulation of synaptic function and lipid metabolism.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01412}, pmid = {40313084}, issn = {1673-5374}, abstract = {Synapses are key structures involved in transmitting information in the nervous system, and their functions rely on the regulation of various lipids. Lipids play important roles in synapse formation, neurotransmitter release, and signal transmission, and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases. The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention, but their specific mechanisms remain to be fully understood. This review aims to explore how lipids regulate synaptic activity in the central nervous system, focusing on their roles in synapse formation, neurotransmitter release, and signal transmission. Additionally, it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation. This review shows that within the central nervous system, lipids are essential components of the cell membrane bilayer, playing critical roles in synaptic structure and function. They regulate presynaptic vesicular trafficking, postsynaptic signaling pathways, and glialneuronal interactions. Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts. Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles. Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis. Fatty acids are vital for energy metabolism and the synthesis of signaling molecules. Abnormalities in lipid metabolism may lead to impairments in synaptic function, affecting information transmission between neurons and the overall health of the nervous system. Therapeutic strategies targeting lipid metabolism, particularly through cholesterol modulation, show promise for treating these conditions. In neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, and amyotrophic lateral sclerosis, dysregulation of lipid metabolism is closely linked to synaptic dysfunction. Therefore, lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs. Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.}, }
@article {pmid40312886, year = {2025}, author = {Spisto, M and Moretta, P and Senerchia, G and Iuzzolino, VV and Aruta, L and Salvatore, E and Santangelo, G and Trojano, L and Dubbioso, R}, title = {Identifying Mild Behavioral and Neurocognitive Impairment in Amyotrophic Lateral Sclerosis (MBNI-ALS) Provides Key Prognostic Insights.}, journal = {European journal of neurology}, volume = {32}, number = {5}, pages = {e70171}, doi = {10.1111/ene.70171}, pmid = {40312886}, issn = {1468-1331}, support = {E53D23019760001//PRIN-PNRR2022/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/psychology ; Male ; Female ; *Cognitive Dysfunction/diagnosis/etiology ; Middle Aged ; Aged ; Prognosis ; Disease Progression ; Prospective Studies ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease encompassing cognitive and behavioral impairments. The Revised Diagnostic Criteria for ALS-frontotemporal spectrum disorder (ALS-FTDS), while widely adopted, may overlook subtle impairments such as memory and visuospatial deficits, limiting their prognostic value.<br><br>OBJECTIVES: This study aimed to apply the Mild Behavioral and Neurocognitive Impairment (MBNI) approach, adapted from other neurodegenerative diseases, to ALS patients and assess its prognostic utility for survival and disease progression.<br><br>METHODS: A prospective cohort of 201 ALS patients was evaluated between January 2018 and July 2024. Participants underwent comprehensive cognitive and behavioral assessments. The MBNI approach identified patients with mild cognitive impairment (MCI), mild behavioral impairment (MBI), or combined cognitive-behavioral impairment (MCBI). Prognostic value was analyzed using Kaplan-Meier survival curves, Cox proportional hazards models, and logistic regression for disease progression.<br><br>RESULTS: Mild cognitive and/or behavioral impairments were detected in 67% of patients classified as cognitively normal by ALS-FTDS criteria. At a median follow-up of 15&#x2009;months, these patients showed shorter tracheostomy-free survival (all p&#x2009;<&#x2009;0.005). MCI (HR5.3; CI 1.10-25.41; p&#x2009;=&#x2009;0.038) and frontotemporal dementia (HR6.2; Confidence Interval: 1.34-28.40; p&#x2009;=&#x2009;0.019) independently predicted poor outcomes. Logistic regression confirmed that MCBI and frontotemporal dementia were associated with rapid progression (both p&#x2009;<&#x2009;0.019).<br><br>CONCLUSION: The MBNI approach enhances the detection of mild cognitive and behavioral impairments in ALS, providing prognostic insights and improving stratification over the Revised Diagnostic Criteria for ALS-FTDS. This framework supports personalized care and the design of clinical trials targeting early disease stages.}, }
@article {pmid40312429, year = {2025}, author = {Ludolph, AC and Grandjean, H and Reviers, E and De Micheli, V and Bianchi, C and Cardosi, L and Russ, H and Silani, V}, title = {Author Correction: The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {15297}, doi = {10.1038/s41598-025-95009-7}, pmid = {40312429}, issn = {2045-2322}, }
@article {pmid40311838, year = {2025}, author = {Recher, M and Canon, V and Lockhart-Bouron, M and Hubert, H and Javaudin, F and Leteurtre, S and Mitha, A and , }, title = {The peak end-tidal carbon dioxide concentration recorded during cardiopulmonary resuscitation as an indicator of survival: a nationwide cohort study of pediatric out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {}, number = {}, pages = {110626}, doi = {10.1016/j.resuscitation.2025.110626}, pmid = {40311838}, issn = {1873-1570}, abstract = {BACKGROUND: Although the end-tidal carbon dioxide concentration (ETCO2) recorded during resuscitation has been reported as an indicator of survival in a few studies of pediatric in-hospital cardiac arrest, the relationship between ETCO2 and survival in pediatric out-of-hospital cardiac arrest (OHCA) has not previously been investigated (particularly with regard to the cause of the OHCA). This study aimed to determine whether quantitative measurement of ETCO2 during resuscitation is predictive of survival in cases of pediatric OHCA.<br><br>METHOD: This nationwide, population-based cohort study analyzed data from the French R&#xe9;AC OHCA registry, including all patients under 18 years of age with trauma-related OHCA or medical OHCA from 2011 to 2023. The highest ETCO2 value was recorded during advanced cardiopulmonary resuscitation. The main outcomes were return of spontaneous circulation (ROSC) and day (d)30 survival. Discriminant ability was evaluated using the area under the receiver operating characteristic curve (AUROC), and the Youden index was used to determine the optimal ETCO2 cut-off value.<br><br>RESULTS: A total of 1209 pediatric OHCAs (226 (19%) trauma-related and 983 (81%) medical) were included. The victims' median [interquartile range] age was 6 [0;14] years. ROSC was achieved in 347 (29%) cases and d30 survival was achieved in 61 (5%) cases. In both trauma-related and medical OHCAs, the peak recorded ETCO2 value was higher in patients who achieved ROSC and in d30 survivors. The AUROC [95% confidence interval] for the highest ETCO2 that predicted ROSC and d30 survival were respectively 0.808 [0.745-0.872] and 0.854 [0.761-0.947] for the trauma-related OHCA group and 0.803 [0.774-0.831] and 0.732 [0.676-0.787] for the medical OHCA group. In both groups, the probability of ROSC and d30 survival increased with higher ETCO2 values, with optimal cut-offs of 21 and 29 mmHg for trauma-related OHCA and 27 and 26 mmHg for medical OHCA, respectively.<br><br>CONCLUSIONS: Further studies are necessary to clarify the use of ETCO2 in optimizing pediatric ALS.}, }
@article {pmid40311553, year = {2025}, author = {Dulski, J and Pant, DC and Hoffman-Zacharska, D and Kwaśniak-Butowska, M and Wszolek, ZK and Sławek, J}, title = {KIF5A variant in familial dystonia: A clinicogenetic study of a large Roma kindred.}, journal = {Parkinsonism &amp; related disorders}, volume = {135}, number = {}, pages = {107825}, doi = {10.1016/j.parkreldis.2025.107825}, pmid = {40311553}, issn = {1873-5126}, abstract = {BACKGROUND: Mutations in the KIF5A gene were associated with several neurological diseases, including hereditary spastic paraplegia type 10, Charcot-Marie-Tooth type 2, amyotrophic lateral sclerosis, and neonatal intractable myoclonus. To date, none of the KIF5A variants was linked with dystonia. This study presents the first family with autosomal-dominant dystonia exhibiting incomplete penetrance, potentially linked to a KIF5A variant.<br><br>METHODS: Seven family members were recruited between 2017 and 2024. Detailed medical history and neurological examination were conducted for all. Genetic screening, including Sanger sequencing, MLPA analysis of SGCE, and PCR RFLP/BseRI for the common dystonia TOR1A mutation (c.907-909del), followed by whole exome sequencing, was performed on the proband and one affected relative. The genetic status of the remaining five individuals was assessed with Sanger sequencing.<br><br>RESULTS: A missense variant in the KIF5A c.118G&#xa0;>&#xa0;A was found in four affected and one asymptomatic individual, while it was absent in two non-affected individuals. The variant is rare in the general population (0.00001 in gnomAD 4.0), affects a highly conserved amino acid, and in silico models (M-CAP) indicates it is pathogenic. It was classified as likely pathogenic per ACMG criteria (PM1, PM2, PP2, PP3).<br><br>CONCLUSIONS: Our study suggests that KIF5A could represent a potential dystonia gene and sheds light on the broader role of motor proteins in human health and disease. This further expands the phenotypes associated with KIF5A and highlights the importance for clinicians to include this variant in their screening panels, as it tends to be underrepresented in current databases.}, }
@article {pmid40311013, year = {2025}, author = {Xu, Z and Yi, W and Guan, L and Tang, J and Feng, D and Zou, Y}, title = {Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00045}, pmid = {40311013}, issn = {1948-7193}, abstract = {Amyotrophic lateral sclerosis (ALS) is closely related to ubiquitin-positive inclusions formed by transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43). Previous experiments identified that the ALS-linked familial variant, N352S (asparagine substituted by serine), and subsequent phosphorylation of S352 (S352p) are associated with the aggregation of TDP-43. However, the underlying molecular mechanisms are still not fully understood. By performing all-atom explicit-solvent replica exchange molecular dynamics (REMD) simulations with a total simulation time of 100.8 μs, we scrutinized the impact of the N352S mutation and its phosphorylation variant S352p on the conformational ensembles of the TDP-43342-366 dimer. Our simulation results show that both the N352S and S352p variants could promote the formation of unstructured conformation and impede the formation of β-structure and helix content, and the inhibitive effect of S352P is more obvious. Further analyses suggest that the H-bonding and hydrophobic interaction among TDP-43342-366 peptides, as well as the R361-E362 salt bridge, are attenuated by N352S and S352p variants. Additional MD simulations show that N352S and S352p variants reduce the structural stability of the hydrophobic region and lower the number of H-bonds and contacts of two hydrophobic clusters, thus possessing a destabilization effect on the TDP-43282-360 protofibrils. Our results unmask the molecular mechanism of the N352S mutation and its phosphorylation variant S352p toward the inhibition of TDP-43342-366 aggregation and prove the protofibril-destabilizing effects of these two variants, which may be helpful for designing drugs for the treatment of ALS.}, }
@article {pmid40310505, year = {2025}, author = {Gautam, P and Yadav, R and Vishwakarma, RK and Pathak, A and Singh, C}, title = {Metabolic dysregulation in amyotrophic lateral sclerosis: insights from [1]H NMR-based metabolomics in a tertiary care center in India.}, journal = {Metabolic brain disease}, volume = {40}, number = {5}, pages = {196}, pmid = {40310505}, issn = {1573-7365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; *Metabolomics/methods ; Male ; Female ; India ; Middle Aged ; Case-Control Studies ; Adult ; Tertiary Care Centers ; Biomarkers/blood/metabolism ; Aged ; Pilot Projects ; Proton Magnetic Resonance Spectroscopy/methods ; Magnetic Resonance Spectroscopy/methods ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss, leading to severe physical impairment and mortality. Despite available treatments like Riluzole and Edaravone, their limited efficacy highlights the need for improved understanding of ALS pathology. This study has explored metabolic alterations in North Indian ALS patients using [1]H Nuclear Magnetic Resonance (NMR)-based metabolomics. A case-control study, involving 45 ALS patients and 30 healthy controls (HCs) was performed. Serum samples were analyzed using 600-MHz NMR spectrometer, revealing significant metabolic differences between ALS and HC groups. Multivariate analyses identified nine dysregulated metabolites-pyruvate, glutamine, histidine, isoleucine, leucine, imidazole, arginine, creatinine, and choline-with ROC analysis showing isoleucine as a promising biomarker (AUC 83%). Pathway enrichment analysis highlighted disruptions in key metabolic pathways, including the Glucose-Alanine Cycle, Urea Cycle, Ammonia Recycling, and the Warburg Effect, suggesting potential links to neuroinflammatory and mitochondrial dysfunction in ALS pathogenesis. This pilot study provides insight into ALS-specific metabolic alterations in Indian cohort and demonstrates the potential of these metabolites as diagnostic biomarkers. Our findings identify potential biomarkers that require validation in larger, multi-centric cohorts to support diagnosis, prognosis, and improved management of ALS.}, }
@article {pmid40310478, year = {2025}, author = {de Moura-Silva, IA and Rodrigues, BJS and Posso, DA and Bacarin, MA and Borella, J}, title = {Growth inhibition of Pontederia crassipes to imidazolinones herbicides-group exposure.}, journal = {Ecotoxicology (London, England)}, volume = {}, number = {}, pages = {}, pmid = {40310478}, issn = {1573-3017}, support = {001//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 001//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 21/2551-0000621-8//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado do Rio Grande do Sul/ ; }, abstract = {ALS-inhibiting imidazolinone herbicides are widely used for selective weed control in Clearfield[®] cropping systems. However, their physicochemical properties promote dispersion into adjacent aquatic environments, posing risks to non-target organisms such as aquatic macrophytes. This study aimed to elucidate the toxicological effects of the commercial formulation Kifix[®] (a mixture of imazapyr and imazapic) on Pontederia crassipes, with emphasis on its biochemical and physiological responses. Two experiments were conducted using herbicide concentrations ranging from 0.2-1.0 mg L[-1], alongside untreated controls. Multiple parameters were evaluated in leaves and roots at 7 and 14 days after application, including visual symptoms, chlorophyll index, growth parameters, chlorophyll a fluorescence, gas exchange, epidermal anatomy, reactive oxygen species, lipid peroxidation, electrolyte leakage, antioxidant enzyme activity, glycolate oxidase, glutathione S-transferase, and acetolactate synthase activity, as well as carbohydrate, amino acid, and protein content. Upon exposure, mature leaves exhibited photochemical impairment, compromising carbon assimilation and photorespiration, and leading to carbohydrate accumulation. Stomatal aperture and conductance were also negatively affected. Oxidative stress responses and antioxidant enzyme activity changed in both leaves and roots. Notably, acetolactate synthase activity increased in treated plants, while protein and amino acid contents remained unchanged. Overall, Kifix[®] significantly impaired P. crassipes, particularly by inhibiting the development of new tissues-such as leaves and plantlets essential for reproduction and spread-while also triggering physiological and biochemical disturbances in mature tissues.}, }
@article {pmid40310263, year = {2025}, author = {Alidoost, M and Huang, JY and Dermentzaki, G and Blazier, AS and Gaglia, G and Hammond, TR and Frau, F and McCorry, MC and Ofengeim, D and Wilson, JL}, title = {Uncovering New Therapeutic Targets for Amyotrophic Lateral Sclerosis and Neurological Diseases Using Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1002/cpt.3682}, pmid = {40310263}, issn = {1532-6535}, support = {//Sanofi iDEA-TECH/ ; }, abstract = {Although attractive for relevance to real-world scenarios, real-world data (RWD) is typically used for drug repurposing and not therapeutic target discovery. Repurposing studies have identified few effective options in neurological diseases such as the rare disease, amyotrophic lateral sclerosis (ALS), which has no disease-modifying treatments available. We previously reclassified drugs by their simulated effects on proteins downstream of drug targets and observed class-level effects in the EHR, implicating the downstream protein as the source of the effect. Here, we developed a novel ALS-focused network medicine model using data from patient samples, the public domain, and consortia. With this model, we simulated drug effects on ALS and measured class effects on overall survival in retrospective EHR studies. We observed an increased but non-significant risk of death for patients taking drugs with complement system proteins downstream of their targets and experimentally validated drug effects on complement activation. We repeated this for six protein classes, three of which, including multiple chemokine receptors, were associated with a significantly increased risk for death, suggesting that targeting proteins such as CXCR5, CXCR3, chemokine signaling generally, or neuropeptide Y (NPY) could be advantageous therapeutic targets for these patients. We expanded our analysis to the neuroinflammatory condition, myasthenia gravis, and neurodegenerative disease, Parkinson's, and recovered similar effect sizes. We demonstrated the utility of network medicine for testing novel therapeutic effects using RWD and believe this approach may accelerate target discovery in neurological diseases, addressing the critical need for new therapeutic options.}, }
@article {pmid40309800, year = {2025}, author = {Manai, AL and Caria, P and Noli, B and Contini, C and Manconi, B and Etzi, F and Cocco, C}, title = {VGF and Its Derived Peptides in Amyotrophic Lateral Sclerosis.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/brainsci15040329}, pmid = {40309800}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration in the neurons of the frontal cortex, spinal cord, and brainstem, altering the correct release of neurotransmitters. The disease affects every muscle in the body and could cause death three to five years after symptoms first occur. There is currently no efficient treatment to stop the disease's progression. The lack of identification of potential therapeutic strategies is a consequence of the delayed diagnosis due to the absence of accurate ALS early biomarkers. Indeed, neurotransmitters altered in ALS are not measurable in body fluids at quantities that allow for testing, making their use as diagnostic tools a challenge. Contrarily, neuroproteins and neuropeptides are chemical messengers produced and released by neurons, and most of them have the potential to enter bodily fluids. To find out new possible ALS biomarkers, the research of neuropeptides and proteins is intensified using mass spectrometry and biochemical-based assays. Neuropeptides derived from the proVGF precursor protein act as signaling molecules within neurons. ProVGF and its derived peptides are expressed in the nervous and endocrine systems but are also widely distributed in body fluids such as blood, urine, and cerebrospinal fluid, making them viable options as disease biomarkers. To highlight the proVGF and its derived peptides' major roles as ALS diagnostic biomarkers, this review provides an overview of the VGF peptide alterations in spinal cord and body fluids and outlines the limitations of the reported investigations.}, }
@article {pmid40309798, year = {2025}, author = {de Carvalho, M}, title = {Developments in Neurodegenerative Disorders: Highly Cited Articles Published in Brain Sciences in 2023-2024.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/brainsci15040345}, pmid = {40309798}, issn = {2076-3425}, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pose a significant and growing health concern, particularly in developed countries [...].}, }
@article {pmid40309789, year = {2025}, author = {Khan, S and Kallis, L and Mee, H and El Hadwe, S and Barone, D and Hutchinson, P and Kolias, A}, title = {Invasive Brain-Computer Interface for Communication: A Scoping Review.}, journal = {Brain sciences}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/brainsci15040336}, pmid = {40309789}, issn = {2076-3425}, abstract = {BACKGROUND: The rapid expansion of the brain-computer interface for patients with neurological deficits has garnered significant interest, and for patients, it provides an additional route where conventional rehabilitation has its limits. This has particularly been the case for patients who lose the ability to communicate. Circumventing neural injuries by recording from the intact cortex and subcortex has the potential to allow patients to communicate and restore self-expression. Discoveries over the last 10-15 years have been possible through advancements in technology, neuroscience, and computing. By examining studies involving intracranial brain-computer interfaces that aim to restore communication, we aimed to explore the advances made and explore where the technology is heading.<br><br>METHODS: For this scoping review, we systematically searched PubMed and OVID Embase. After processing the articles, the search yielded 41 articles that we included in this review.<br><br>RESULTS: The articles predominantly assessed patients who had either suffered from amyotrophic lateral sclerosis, cervical cord injury, or brainstem stroke, resulting in tetraplegia and, in some cases, difficulty speaking. Of the intracranial implants, ten had ALS, six had brainstem stroke, and thirteen had a spinal cord injury. Stereoelectroencephalography was also used, but the results, whilst promising, are still in their infancy. Studies involving patients who were moving cursors on a screen could improve the speed of movement by optimising the interface and utilising better decoding methods. In recent years, intracortical devices have been successfully used for accurate speech-to-text and speech-to-audio decoding in patients who are unable to speak.<br><br>CONCLUSIONS: Here, we summarise the progress made by BCIs used for communication. Speech decoding directly from the cortex can provide a novel therapeutic method to restore full, embodied communication to patients suffering from tetraplegia who otherwise cannot communicate.}, }
@article {pmid40309514, year = {2025}, author = {Li, V and Huang, Y}, title = {Oligonucleotide therapeutics for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {1}, pages = {1-11}, pmid = {40309514}, issn = {2750-6665}, abstract = {Recently there has been a surge in interest involving the application of oligonucleotides, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), for the treatment of chronic diseases that have few available therapeutic options. This emerging class of drugs primarily operates by selectively suppressing target genes through antisense and/or RNA interference mechanisms. While various commercial medications exist for delivering oligonucleotides to the hepatic tissue, achieving effective delivery to extra hepatic tissues remains a formidable challenge. Here, we review recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and 2'-O-hexadecyl (C16)-conjugation that work to extend the applicability of siRNAs and ASOs to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.}, }
@article {pmid40309037, year = {2025}, author = {Yu, Q and Mohammed Nazar, RB and Chen, S and Qian, Q and Wang, J and Chen, X}, title = {A novel SIGMAR1 missense mutation leads to distal hereditary motor neuropathy phenotype mimicking juvenile ALS: a case report of China.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1477518}, pmid = {40309037}, issn = {1664-8021}, abstract = {We present the case of a 16-year-old East Asian Chinese girl with a novel mutation in the SIGMAR1 gene, initially diagnosed as juvenile amyotrophic lateral sclerosis (JALS). At the age of five, she began to exhibit gait abnormalities while walking, a condition that persisted for 4 years until muscle weakness and atrophy emerged, predominantly affecting her distal muscles symmetrically. Electromyography (EMG) initially revealed early abonormal motor conduction, and subsequent examinations indicated neurogenic damage accompanied by localized denervation potentials. Whole-exome sequencing identified compound heterozygous mutations in the SIGMAR1 gene. Throughout the course of her illness, the patient exhibited slow disease progression without cognitive impairment or scoliosis development. We ultimately revised the diagnosis to distal hereditary motor neuropathy (dHMN). This study reports the case of SIGMAR1 new locus mutation leading to dHMN in China, contributing to the expansion of the dHMN genetic database. In our patient, the initial EMG findings indicated issues with neurogenic conduction, followed by a slow progression of the disease. Subsequently, EMG results revealed axonal damage and denervation potentials. These clinical features can easily lead to confusion with JALS. This insight is valuable for improving diagnostic accuracy and understanding the clinical spectrum of dHMN related to SIGMAR1 mutations.}, }
@article {pmid40307231, year = {2025}, author = {Yen, YP and Lung, TH and Liau, ES and Wu, CC and Huang, GL and Hsu, FY and Chang, M and Yang, ZD and Huang, CY and Zheng, Z and Zhao, W and Hung, JH and He, C and Nie, Q and Chen, JA}, title = {The motor neuron m6A repertoire governs neuronal homeostasis and FTO inhibition mitigates ALS symptom manifestation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4063}, pmid = {40307231}, issn = {2041-1723}, support = {NHRI-EX113-11330NI//National Health Research Institutes (NHRI)/ ; AS-GCP-113-L02//Academia Sinica/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Motor Neurons/metabolism/pathology ; *Methyltransferases/metabolism/genetics ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mice ; *Adenosine/analogs &amp; derivatives/metabolism ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism/antagonists &amp; inhibitors/genetics ; Homeostasis ; Disease Models, Animal ; Mice, Knockout ; Male ; Methylation ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a swiftly progressive and fatal neurodegenerative ailment marked by the degenerative motor neurons (MNs). Why MNs are specifically susceptible in predominantly sporadic cases remains enigmatic. Here, we demonstrated N[6]-methyladenosine (m[6]A), an RNA modification catalyzed by the METTL3/METTL14 methyltransferase complex, as a pivotal contributor to ALS pathogenesis. By conditional knockout Mettl14 in murine MNs, we recapitulate almost the full spectrum of ALS disease characteristics. Mechanistically, pervasive m[6]A hypomethylation triggers dysregulated expression of high-risk genes associated with ALS and an unforeseen reduction of chromatin accessibility in MNs. Additionally, we observed diminished m[6]A levels in induced pluripotent stem cell derived MNs (iPSC~MNs) from familial and sporadic ALS patients. Restoring m[6]A equilibrium via a small molecule or gene therapy significantly preserves MNs from degeneration and mitigates motor impairments in ALS iPSC~MNs and murine models. Our study presents a substantial stride towards identifying pioneering efficacious ALS therapies via RNA modifications.}, }
@article {pmid40306441, year = {2025}, author = {Chen, Y and Sun, S and Gao, N and Bai, Z and Yu, W and Zhao, B and Yun, Y and Sun, X and Lin, P and Li, W and Zhao, Y and Yan, C and Liu, S}, title = {Proximity extension assay reveals serum inflammatory biomarkers in two amyotrophic lateral sclerosis cohorts.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106933}, doi = {10.1016/j.nbd.2025.106933}, pmid = {40306441}, issn = {1095-953X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with both clinical and hereditary heterogeneity. Inflammation has been suggested to play an important role in ALS pathophysiology. In this study, we aimed to identify serum inflammatory alterations and develop effective inflammatory biomarkers to assist in the diagnosis of ALS. Through proximity extension assay (PEA), we investigated serum inflammatory alterations in two ALS cohorts compared with healthy controls (HCs), including sporadic ALS patients and genetic ALS patients. We found that CHIT1, OSM, SIRT2, CDCP1 and 5 other factors were significantly increased in sporadic ALS patients in both cohorts and that SIRT2, CDCP1 and 6 other factors were different between genetic ALS patients and HCs. Using XGBoost and binary logistic regression analysis, we developed a two-serum protein diagnostic panel (CHIT1 and CDCP1), and the area under the curve (AUC) was 0.904 in the original cohort and 0.907 in the replication cohort. Based on Mendelian Randomization (MR), OSM and SIRT2 are significantly associated with the risk of ALS. In conclusion, our study revealed a consistent and replicable serum inflammatory profile and developed a biomarker panel that can differentiate ALS patients from HCs in two cohorts, which may play an important role in advancing our current understanding of the inflammatory process and identifying novel therapeutic strategies for ALS patients.}, }
@article {pmid40306255, year = {2025}, author = {Bu, Y and Yuan, Y and Hu, F and Zhao, Q and He, C and Tang, L and Li, Y and Liu, Z and Weng, L and Du, J and Guo, J and Shen, L and Li, J and Yi, J and Cao, W and Xu, R and Tang, B and Wang, J}, title = {Retinal alterations induced by amyotrophic lateral sclerosis: An analysis using optical coherence tomography.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {136}, number = {}, pages = {111268}, doi = {10.1016/j.jocn.2025.111268}, pmid = {40306255}, issn = {1532-2653}, abstract = {OBJECTIVE: In this study, we aimed to investigate retinal changes in a large cohort of amyotrophic lateral sclerosis (ALS) patients and healthy controls (HCs) to further elucidate their relationship with ALS.<br><br>METHODS: This was a cross-sectional observational study. We evaluated retinal layer thickness in 134 ALS patients and 66 HCs using optical coherence tomography (OCT). Particularly, we focused on the macular region and peripapillary retinal nerve fiber layer (p-RNFL).<br><br>RESULTS: The examination of retinal layers in ALS patients revealed a significant change in the inner nuclear layer (INL), with a pattern of initial thickening followed by thinning, which correlated with disease stages, most notably in the inner nasal quadrant. Moreover, the p-RNFL in the temporal quadrant was thinner in ALS patients compared to HCs. In addition, ALS patients who developed bulbar symptoms exhibited marginally thinner p-RNFL in the temporal quadrant compared to those without bulbar symptoms. Interestingly, a thinner p-RNFL in the temporal quadrant did not correlate with faster disease progression.<br><br>CONCLUSION: This study reveals notable changes in the INL and p-RNFL thickness in ALS patients, highlighting the intricate relationship between retinal changes and ALS progression. Despite these retinal alterations, no correlation with disease progression rate was observed. These findings suggest that while OCT shows potential in monitoring ALS, its role in predicting disease course requires further investigation with long-term longitudinal studies and diverse patient cohorts.}, }
@article {pmid40305762, year = {2025}, author = {Manohar, R and Yang, FX and Stephen, CD and Schmahmann, JD and Eklund, NM and Gupta, AS}, title = {At-home wearables and machine learning capture motor impairment and progression in adult ataxias.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf154}, pmid = {40305762}, issn = {1460-2156}, abstract = {A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior. Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T). Remotely collected cross-sectional (n = 76) and longitudinal data (n = 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, showed differences between ataxia and control groups with high effect size, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.}, }
@article {pmid40305176, year = {2025}, author = {Erichsen, PA and Henriksen, EE and Nielsen, JE and Ejlerskov, P and Simonsen, AH and Toft, A}, title = {Immunological Fluid Biomarkers in Frontotemporal Dementia: A Systematic Review.}, journal = {Biomolecules}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/biom15040473}, pmid = {40305176}, issn = {2218-273X}, support = {0084960//Novo Nordisk Foundation/ ; R450-2023-989//Lundbeck Foundation/ ; }, mesh = {Humans ; *Frontotemporal Dementia/immunology/blood/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid/blood ; Alzheimer Disease/immunology/blood/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/blood/immunology/cerebrospinal fluid ; Chitinase-3-Like Protein 1/cerebrospinal fluid/blood ; Glial Fibrillary Acidic Protein/cerebrospinal fluid/blood ; Chemokine CCL2/cerebrospinal fluid/blood ; }, abstract = {Dysregulated immune activation plays a key role in the pathogenesis of neurodegenerative diseases, including frontotemporal dementia (FTD). This study reviews immunological biomarkers associated with FTD and its subtypes. A systematic search of PubMed and Web of Science was conducted for studies published before 1 January 2025, focusing on immunological biomarkers in CSF or blood from FTD patients with comparisons to healthy or neurological controls. A total of 124 studies were included, involving 6686 FTD patients and 202 immune biomarkers. Key findings include elevated levels of GFAP and MCP1/CCL2 in both CSF and blood and consistently increased CHIT1 and YKL-40 in CSF. Complement proteins from the classical activation pathway emerged as promising targets. Distinct immune markers were found to differentiate FTD from Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), with GFAP, SPARC, and SPP1 varying between FTD and AD and IL-15, HERV-K, NOD2, and CHIT1 differing between FTD and ALS. A few markers, such as Galectin-3 and PGRN, distinguished FTD subtypes. Enrichment analysis highlighted IL-10 signaling and immune cell chemotaxis as potential pathways for further exploration. This study provides an overview of immunological biomarkers in FTD, emphasizing those most relevant for future research on immune dysregulation in FTD pathogenesis.}, }
@article {pmid40304918, year = {2025}, author = {Anjum, F and Alsharif, A and Bakhuraysah, M and Shafie, A and Hassan, MI and Mohammad, T}, title = {Discovering Novel Biomarkers and Potential Therapeutic Targets of Amyotrophic Lateral Sclerosis Through Integrated Machine Learning and Gene Expression Profiling.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {2}, pages = {61}, pmid = {40304918}, issn = {1559-1166}, support = {KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; KSRG-2024-446//King Salman Center for Disability Research/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Machine Learning ; Receptors, Nicotinic/genetics/metabolism ; Gene Expression Profiling ; Biomarkers/metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; Transcriptome ; Membrane Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has multiple factors that make its molecular pathogenesis difficult to understand and its diagnosis and treatment during the early stages difficult to determine. Discovering novel biomarkers in ALS for diagnostic and therapeutic potential has become important. Consequently, bioinformatics and machine learning algorithms are useful for identifying differentially expressed genes (DEGs) and potential biomarkers, as well as understanding the molecular mechanisms and intricacies of diseases such as ALS. To achieve the aim of the present study, six datasets obtained from the Gene Expression Omnibus (GEO) were utilized and analyzed using an integrative bioinformatics and machine learning approach. Log transformation was done during data preprocessing, RMA normalization was performed, and the batch effect was corrected. Differential expression analysis identified 206 DEGs that were significantly associated with different biological processes, including muscle function, energy metabolism, and mitochondrial membrane activity. Functional enrichment analysis highlighted pathways, including those related to prion disease, Parkinson's disease, and ATP synthesis via chemiosmotic coupling. We employed a multi-step machine learning framework incorporating random forest, LASSO regression, and SVM-RFE to identify robust biomarkers. This approach identified three key genes, CHRNA1, DLG5, and PLA2G4C, which could be explored as promising biomarkers for ALS after further validation. The internal validation, including principal component analysis (PCA) and ROC-AUC analysis, demonstrated strong diagnostic potential of these hub genes, achieving an AUC of 0.96. This work highlights the utility of bioinformatics and machine learning in identifying key genes as biomarkers for diagnostic and therapeutic potential in ALS.}, }
@article {pmid40304712, year = {2025}, author = {Freisem, D and Hoenigsperger, H and Catanese, A and Sparrer, KMJ}, title = {Inborn errors of canonical autophagy in neurodegenerative diseases.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddae179}, pmid = {40304712}, issn = {1460-2083}, support = {CA 2915/4-1//German Research Foundation/ ; }, abstract = {Neurodegenerative disorders (NDDs), characterized by a progressive loss of neurons and cognitive function, are a severe burden to human health and mental fitness worldwide. A hallmark of NDDs such as Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases is disturbed cellular proteostasis, resulting in pathogenic deposition of aggregated protein species. Autophagy is a major cellular process maintaining proteostasis and integral to innate immune defenses that mediates lysosomal protein turnover. Defects in autophagy are thus frequently associated with NDDs. In this review, we discuss the interplay between NDDs associated proteins and autophagy and provide an overview over recent discoveries in inborn errors in canonical autophagy proteins that are associated with NDDs. While mutations in autophagy receptors seems to be associated mainly with the development of ALS, errors in mitophagy are mainly found to promote PD. Finally, we argue whether autophagy may impact progress and onset of the disease, as well as the potential of targeting autophagy as a therapeutic approach. Concludingly, understanding disorders due to inborn errors in autophagy-"autophagopathies"-will help to unravel underlying NDD pathomechanisms and provide unique insights into the neuroprotective role of autophagy, thus potentially paving the way for novel therapeutic interventions.}, }
@article {pmid40303620, year = {2025}, author = {Basiri, K and Paydari, H and Abbasi, F and Ansari, B}, title = {Upper Extremity Peripheral Nerve Ultrasonography, as a Diagnostic Aid in Amyotrophic Lateral Sclerosis.}, journal = {Advanced biomedical research}, volume = {14}, number = {}, pages = {22}, pmid = {40303620}, issn = {2277-9175}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening progressive motor neuron disease whose diagnosis is challenging because of lacking specific diagnostic means. The current study aims to assess the value of upper extremity peripheral nerves ultrasonography in ALS detection.<br><br>MATERIALS AND METHODS: In this case-control study, 30 ALS subjects were assessed regarding the cross-sectional area (CSA) of the proximal (at distal part of arm or the proximal of elbow) and distal (at wrist level) median and ulnar nerves, assessed via ultrasonography. Similarly, 30 age- and gender-matched healthy controls were evaluated. The receiver operating curve (ROC) was depicted to determine a cut-point for ALS-associated peripheral nerve involvement.<br><br>RESULTS: Proximal CSA and the proximal-to-distal ratio of the median nerve was remarkably lower in both upper extremities of the ALS subjects compared to the controls (P value < 0.05), while the distal median nerve CSAs did not differ between the groups (P value > 0.05). Distal ulnar nerve CSA in the right hand (P value = 0.007) and the proximal ulnar nerve CSA in the left hand (P value = 0.001) were remarkably lower in the cases than the controls, but the other measurements did not differ (P value > 0.05). There was no significant cut-points to differentiate ALS-affected peripheral nerves from the healthy controls (P value > 0.05).<br><br>CONCLUSION: Based on this study, CSA of the proximal median nerve in the cubital fossa seems a rational and valuable means to diagnose ALS; but the distal parts of the median nerve and the ulnar nerve in its all length remained a matter of debate.}, }
@article {pmid40303507, year = {2025}, author = {Verma, S and Khurana, S and Gourie-Devi, M and Anand, I and Vats, Y and Singh, A and Jothiramajayam, M and Kshetrapal, P and Sharma, A and Wajid, S and Ganguly, NK and Chakraborti, P and Taneja, V}, title = {Multiomics Approach Reveal Novel Insights in FUS Driven Juvenile Amyotrophic Lateral Sclerosis: A Family Quartet Analysis.}, journal = {Annals of neurosciences}, volume = {32}, number = {2}, pages = {78-89}, pmid = {40303507}, issn = {0972-7531}, abstract = {BACKGROUND: Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe form of motor neuron disease characterized by progressive loss of upper and lower motor neurons with an early onset (<25 years).<br><br>PURPOSE: Due to complex etiology and clinical heterogeneity, it is indispensable to unravel molecular mechanisms underlying JALS pathology. The study aimed to identify disease-specific signatures in a 14-years-old sporadic JALS patient.<br><br>METHODS: Genomic, transcriptomic, and metabolomic analysis of proband and first-degree relatives (FDR).<br><br>RESULTS: Exome sequencing identified a novel de novo frameshift variation (c.1465dupG: p.D490Gfs*26) in the fused in sarcoma (FUS) gene in proband. Interestingly, rare and potentially deleterious, disease-modifying variations in DDHD domain containing 1 (DDHD1) and fibrillin 2 (FBN2) were observed. Differentially expressed genes (DGEs) enriched in neuromuscular transmission and inflammatory response were identified by RNA-sequencing. In addition, alterations in purine and pyrimidine, vitamin B6, and sphingolipid metabolism reflect the involvement of inflammatory process in disease pathobiology.<br><br>CONCLUSION: Our findings suggest the involvement of multiple genetic factors coupled with hampered neuromuscular transmission and systemic inflammation in the onset and disease course of JALS.}, }
@article {pmid40302786, year = {2025}, author = {Vijayaraghavan, M and Murali, SP and Thakur, G and Li, XJ}, title = {Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1553658}, pmid = {40302786}, issn = {1662-5102}, abstract = {This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.}, }
@article {pmid40301571, year = {2025}, author = {Francesca, D and Rosalinda, DG and Luca, D and Rizzo, B and Matteo, B and Eveljn, S and Viola, C and Giovanni, C and Susanna, Z and Orietta, P and Stella, G}, title = {Cross-tissue MiRNA profiling of extracellular vesicles and PBMCs from amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {14976}, pmid = {40301571}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *MicroRNAs/genetics/metabolism ; *Extracellular Vesicles/metabolism/genetics ; *Leukocytes, Mononuclear/metabolism ; Male ; Female ; Gene Expression Profiling ; Middle Aged ; Aged ; Transcriptome ; }, abstract = {RNA-mediated toxicity, which can be controlled by alteration of gene expression, is considered a key event in Amyotrophic Lateral Sclerosis (ALS). Transcriptomic deregulation of miRNAs expression can spread via "horizontal" RNA transfer through extracellular vesicles (EVs) to act in conjunction with proteins, leading to changes in mRNA, which can provide early signals to indicate forthcoming neuropathological changes in the brain. The aim of this work is to compare expression profiles (obtained by miRNA-seq) from different tissues to highlight commonly expressed and tissue-specific miRNAs. miRNA species from plasma EVs were correlated with miRNA profiles obtained from peripheral blood mononuclear cells (PBMCs). Each tissue from ALS patients was compared to controls, revealing 159 deregulated (DE) miRNAs in Exosomes (EXOs), 247 DE miRNAs in PBMCs and 162 DE miRNAs in Microvesicles (MVs). Next, data were filtered to include only miRNAs expressed in disease samples (not in healthy subjects), to reduce the number of tissue- and ALS- specific miRNAs (EXO n = 22, MV = 11, PBMCs n = 8). We identified specific miRNAs and pathways related to each tissue. Interestingly, in PBMCs we found mainly neuro-linked pathways, such as neurotransmitters, brain and neuron development, while in EXOs, we found miRNAs implicated in MAPK and ERB signaling. In contrast, the altered pathways in MVs were not specific. This study shows that the composition of small RNA differs significantly between blood cells and its respective EVs fraction. Differentially expressed miRNAs can target definite transcripts in different cellular and molecular fractions. It is evident that, in terms of miRNAs cargo, MVs are not specific to ALS. Therefore, future studies will focus on the interaction between cells and EXOs.}, }
@article {pmid40301152, year = {2025}, author = {Armas, JMB and Taoro-González, L and Fisher, EMC and Acevedo-Arozena, A}, title = {Challenges of modelling TDP-43 pathology in mice.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {}, number = {}, pages = {}, pmid = {40301152}, issn = {1432-1777}, abstract = {TDP-43 is a normally nuclear RNA binding protein that under pathological conditions may be excluded from the nucleus and deposited in the cytoplasm in the form of insoluble polyubiquitinated and polyphosphorylated inclusions. This nuclear exclusion coupled with cytoplasmic accumulation is called TDP-43 pathology and contributes to a range of disorders collectively known as TDP-43 proteinopathies. These include the great majority of amyotrophic lateral sclerosis (ALS) cases, all limbic-predominant age-related TDP-43 encephalopathy (LATE), as well as up to 50% of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) cases. Thus, TDP-43 pathology is a common feature underlying a wide range of neurodegenerative conditions. However, modelling it has proven to be challenging, particularly generating models with concomitant TDP-43 loss of nuclear function and cytoplasmic inclusions. Here, focussing exclusively on mice, we discuss TDP-43 genetic models in terms of the presence of TDP-43 pathology, and we consider other models with TDP-43 pathology due to mutations in disparate genes. We also consider manipulations aimed at producing TDP-43 pathology, and we look at potential strategies to develop new, much needed models to address the many outstanding questions regarding how and why TDP-43 protein leaves the nucleus and accumulates in the cytoplasm, causing downstream dysfunction and devastating disease.}, }
@article {pmid40301025, year = {2025}, author = {Yamahara, N and Yoshikura, N and Yuhei, I and Shimohata, T}, title = {[Intravenous glucose infusion may have caused refeeding syndrome in a patient with advanced amyotrophic lateral sclerosis].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {}, number = {}, pages = {}, doi = {10.5692/clinicalneurol.cn-002086}, pmid = {40301025}, issn = {1882-0654}, abstract = {We present the case of a 69-year-old woman who underwent tracheostomy for advanced amyotrophic lateral sclerosis. The patient was treated with furosemide for leg edema. Body mass index was stable at 21.5 ‍kg/m[2]. The patient was admitted to our hospital after vomiting because of biliary infection. Fluid therapy with 286 ‍kcal/day of glucose was administered, followed by acute deterioration, including tachycardia (120 bpm), glucose intolerance, abdominal pain, hypophosphatemia (required intravenous phosphate supply; 60 ‍mmol/day), and hypokalemia (required intravenous potassium supply; 60 mEq/day). Refeeding syndrome was suspected, and the patient recovered with adjustments in serum electrolyte levels. We demonstrated that glucose infusion can cause refeeding syndrome in patients with advanced amyotrophic lateral sclerosis without low nutritional intake.}, }
@article {pmid40300682, year = {2025}, author = {Li, Z and Xing, J}, title = {Role of sirtuins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic potential.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {143591}, doi = {10.1016/j.ijbiomac.2025.143591}, pmid = {40300682}, issn = {1879-0003}, abstract = {The high incidence and mortality rate of cardiac arrest (CA) establishes it as a critical clinical challenge in emergency medicine globally. Despite continuous advances in advanced life support (ALS) technology, the prognosis for patients experiencing cardiac arrest remains poor, with cerebral ischemia and reperfusion injury (CIRI) being a significant determinant of adverse neurological outcomes and increased mortality. Sirtuins (SIRTs) are a class of highly evolutionarily conserved NAD[+]-dependent histone deacylenzymes capable of regulating the expression of various cytoprotective genes to play a neuroprotective role in CIRI. SIRTs mainly regulate the levels of downstream proteins such as PGC 1-α, Nrf 2, NLRP 3, FoxOs, and PINK 1 to inhibit inflammatory response, attenuate oxidative stress, improve mitochondrial dysfunction, promote angiogenesis, and inhibit apoptosis while reducing CIRI. Natural active ingredients are widely used in regulating the protein level of SIRTs in the body because of their multi-components, multi-pathway, multi-target, and minimal toxic side effects. However, these naturally active ingredients still face many challenges related to drug targeting, pharmacokinetic properties, and drug delivery. The emergence and vigorous development of new drug delivery systems, such as nanoparticles, micromilk, and exosomes, provide strong support for solving the above problems. In the context of the rapid development of molecular biology technology, non-coding RNA (NcRNA), represented by miRNA and LncRNA, offers great potential for achieving gene-level precision medicine. In the context of multidisciplinary integration, combining SIRTs proteins with biotechnology, omics technologies, artificial intelligence, and material science will strongly promote the deepening of their basic research and expand their clinical application. This review describes the major signaling pathways of targeting SIRTs to mitigate CIRI, as well as the current research status of Chinese and Western medicine and medical means for the intervention level of SIRTs. Meanwhile, the challenges and possible solutions in the clinical application of targeted drugs are summarized. In the context of medical and industrial crossover, the development direction of SIRTs in the future is discussed to provide valuable reference for basic medical researchers and clinicians to improve the clinical diagnosis and treatment effects of CIRI.}, }
@article {pmid40300213, year = {2025}, author = {Sun, Y and Vermulst, M}, title = {The hidden costs of imperfection: transcription errors in protein aggregation diseases.}, journal = {Current opinion in genetics &amp; development}, volume = {93}, number = {}, pages = {102350}, doi = {10.1016/j.gde.2025.102350}, pmid = {40300213}, issn = {1879-0380}, abstract = {At first glance, biological systems appear to operate with remarkable precision and order. Yet, closer examination reveals that this perfection is an illusion, biological processes are inherently prone to errors. Here, we describe recent evidence that indicates that errors that occur during transcription play an important role in neurological diseases. These errors, though transient, can have lasting consequences when they generate mutant proteins with amyloid or prion-like properties. Such proteins can seed aggregation cascades, converting wild-type counterparts into misfolded conformations, ultimately leading to toxic deposits seen in diseases like Alzheimer's and amyotrophic lateral sclerosis. These observations help to paint a fuller picture of the origins of neurodegenerative diseases in aging humans and suggest a unified mechanism by which they may arise.}, }
@article {pmid40299664, year = {2025}, author = {Nogueira-Machado, JA and Rocha-Silva, F and Gomes, NA}, title = {The Role of mTOR in Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {13}, number = {4}, pages = {}, doi = {10.3390/biomedicines13040952}, pmid = {40299664}, issn = {2227-9059}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a rare, progressive, and incurable disease characterized by muscle weakness and paralysis. Recent studies have explored a possible link between ALS pathophysiology and mTOR signaling. Recent reports have linked the accumulation of protein aggregates, dysfunctional mitochondria, and homeostasis to the development of ALS. mTOR plays a pivotal role in controlling autophagy and affecting energy metabolism, in addition to supporting neuronal growth, plasticity, and the balance between apoptosis and autophagy, all of which are important for homeostasis. Aim: This mini-review approaches the regulatory roles of mTOR signaling pathways, their interaction with other metabolic pathways, and their potential to modulate ALS progression. Significance: It discusses how these metabolic signaling pathways affect the neuromuscular junction, producing symptoms of muscle weakness and atrophy similar to those seen in patients with ALS. The discussion includes the concepts of neurocentric and peripheral and the possible connection between mTOR and neuromuscular dysfunction in ALS. Conclusions: It highlights the therapeutic potential of mTOR signaling and interconnections with other metabolic routes, making it a promising biomarker and therapeutic target for ALS.}, }
@article {pmid40299512, year = {2025}, author = {Eslami, M and Adampour, Z and Fadaee Dowlat, B and Yaghmayee, S and Motallebi Tabaei, F and Oksenych, V and Naderian, R}, title = {A Novel Frontier in Gut-Brain Axis Research: The Transplantation of Fecal Microbiota in Neurodegenerative Disorders.}, journal = {Biomedicines}, volume = {13}, number = {4}, pages = {}, doi = {10.3390/biomedicines13040915}, pmid = {40299512}, issn = {2227-9059}, abstract = {The gut-brain axis (GBA) represents a sophisticated bidirectional communication system connecting the central nervous system (CNS) and the gastrointestinal (GI) tract. This interplay occurs primarily through neuronal, immune, and metabolic pathways. Dysbiosis in gut microbiota has been associated with multiple neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In recent years, fecal microbiota transplantation (FMT) has gained attention as an innovative therapeutic approach, aiming to restore microbial balance in the gut while influencing neuroinflammatory and neurodegenerative pathways. This review explores the mechanisms by which FMT impacts the gut-brain axis. Key areas of focus include its ability to reduce neuroinflammation, strengthen gut barrier integrity, regulate neurotransmitter production, and reinstate microbial diversity. Both preclinical and clinical studies indicate that FMT can alleviate motor and cognitive deficits in PD and AD, lower neuroinflammatory markers in MS, and enhance respiratory and neuromuscular functions in ALS. Despite these findings, several challenges remain, including donor selection complexities, uncertainties about long-term safety, and inconsistencies in clinical outcomes. Innovations such as synthetic microbial communities, engineered probiotics, and AI-driven analysis of the microbiome hold the potential to improve the precision and effectiveness of FMT in managing neurodegenerative conditions. Although FMT presents considerable promise as a therapeutic development, its widespread application for neurodegenerative diseases requires thorough validation through well-designed, large-scale clinical trials. It is essential to establish standardized protocols, refine donor selection processes, and deepen our understanding of the molecular mechanisms behind its efficacy.}, }
@article {pmid40299102, year = {2025}, author = {Zhang, G and Huang, S and Wei, M and Wu, Y and Wang, J}, title = {Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects.}, journal = {Neurochemical research}, volume = {50}, number = {3}, pages = {155}, pmid = {40299102}, issn = {1573-6903}, support = {2023JJB140089//Guangxi Youth Science Foundation Project/ ; 82201694//the National Natural Scientific Foundation of China/ ; 2022AC21033//Guangxi Science and technology base and talent project/ ; 2022KY0349//Guangxi university young and middle-aged teachers' basic ability improvement project/ ; }, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Glutamate Plasma Membrane Transport Proteins/metabolism ; Glutamic Acid/metabolism ; }, abstract = {Excitatory amino acid transporters (EAATs) are pivotal regulators of glutamate homeostasis in the central nervous system and orchestrate synaptic glutamate clearance through transmembrane transport and the glutamine‒glutamate cycle. The five EAAT subtypes (GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, and EAAT5) exhibit spatiotemporal-specific expression patterns in neurons and glial cells, and their dysfunction is implicated in diverse neurological pathologies, including epilepsy, amyotrophic lateral sclerosis (ALS), schizophrenia, depression, and retinal degeneration. Mechanistic studies revealed that astrocytic GLT-1 deficiency disrupts glutamate clearance in ALS motor neurons, whereas GLAST genetic variants are linked to both epilepsy susceptibility and glaucomatous retinal ganglion cell degeneration. Three major challenges persist in ongoing research: ① subtype-specific regulatory mechanisms remain unclear; ② compensatory functions of transporters vary significantly across disease models; and ③ clinical translation lacks standardized evaluation criteria. The interaction mechanisms and dynamic roles of EAATs in neurological disorders were systematically investigated in this study, and an integrated approach combining single-cell profiling, stem cell-based disease modeling, and drug screening platforms was proposed. These findings lay the groundwork for novel therapeutic strategies targeting glutamate homeostasis.}, }
@article {pmid40299101, year = {2025}, author = {Sarkar, S and Porel, P and Kosey, S and Aran, KR}, title = {Unraveling the role of CGRP in neurological diseases: a comprehensive exploration to pathological mechanisms and therapeutic implications.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {436}, pmid = {40299101}, issn = {1573-4978}, mesh = {Humans ; *Calcitonin Gene-Related Peptide/metabolism/genetics ; Animals ; Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Nervous System Diseases/metabolism ; Signal Transduction ; Receptors, Calcitonin Gene-Related Peptide/metabolism ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Spinal muscular atrophy (SMA) are neurodegenerative diseases (NDDs) characterized by progressive neuronal degeneration. Recent studies provide compelling information regarding the contribution of Calcitonin Gene-Related Peptide (CGRP), a potent neuropeptide, in regulating neuroinflammation, vasodilation, and neuronal survival in these disorders. This review systematically delves into the multidimensional aspects of CGRP as both a neuroprotective agent and a neurotoxic factor in NDDs. The neuroprotective effects of CGRP include suppression of inflammation, regulation of intracellular signaling pathways, and promotion of neuronal growth and survival. However, under pathological conditions, its overexpression or dysregulation is associated with oxidative stress, excitotoxicity, and neuronal death. The therapeutic use of CGRP and its receptor antagonists in migraine provides substantial evidence for CGRP's therapeutic potential, which can be further explored for the management of NDDs. However, since the bidirectional nature of CGRP effects is evident, it is crucial to gain an accurate insight into its mechanisms to target only the neuropeptide's beneficial effects while completely avoiding the undesired consequences. Further studies should focus on understanding the context-dependent activity of CGRP in the hope of designing targeted therapy for NDDs, which could gradually transform the current pharmacological management of NDDs.}, }
@article {pmid40299083, year = {2025}, author = {Levison, LS and Blicher, JU and Andersen, H}, title = {Correction: Incidence and mortality of ALS: a 42-year population-based nationwide study.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {365}, doi = {10.1007/s00415-025-13076-2}, pmid = {40299083}, issn = {1432-1459}, }
@article {pmid40298821, year = {2025}, author = {Bortolotti, M and Polito, L and Battelli, MG and Bolognesi, A}, title = {Xanthine Oxidoreductase: A Double-Edged Sword in Neurological Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/antiox14040483}, pmid = {40298821}, issn = {2076-3921}, abstract = {Non-communicable neurological disorders are the second leading cause of death, and their burden continues to increase as the world population grows and ages. Oxidative stress and inflammation are crucially implicated in the triggering and progression of multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and even stroke. In this narrative review, we examine the role of xanthine oxidoreductase (XOR) activities and products in all the above-cited neurological diseases. The redox imbalance responsible for oxidative stress could arise from excess reactive oxygen and nitrogen species resulting from the activities of XOR, as well as from the deficiency of its main product, uric acid (UA), which is the pivotal antioxidant system in the blood. In fact, with the exception of stroke, serum UA levels are inversely related to the onset and progression of these neurological disorders. The inverse correlation observed between the level of uricemia and the presence of neurological diseases suggests a neuroprotective role for UA. Oxidative stress and inflammation are also caused by ischemia and reperfusion, a condition in which XOR action has been recognized as a contributing factor to tissue damage. The findings reported in this review could be useful for addressing clinical decision-making and treatment optimization.}, }
@article {pmid40298692, year = {2025}, author = {Petito, G and Del Fiore, VS and Cuomo, A and Cioffi, F and Cobellis, G and Lanni, A and Guerra, F and Bucci, C and Senese, R and Romano, R}, title = {Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376D TARDBP Pathogenetic Substitution.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/antiox14040401}, pmid = {40298692}, issn = {2076-3921}, support = {PRIN2022 PNRR N. P2022FBZXY//Ministero dell'universit&#xe0; e della ricerca/ ; D.M. n. 737 of 25.06.2021//Ministero dell'universit&#xe0; e della ricerca/ ; PRIN2022 N. 2022XTM2S3//Ministero dell'universit&#xe0; e della ricerca/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of upper and lower motor neurons in the brain, brainstem and spinal cord. About 10% of familial ALS cases are linked to pathogenetic substitution in TARDBP, the gene encoding the TDP-43 protein. A novel rare causative variant in TARDBP (p.G376D) was recently reported in ALS patients. It leads to TDP-43 cytoplasmic mislocalization, increased oxidative stress and reduced cell viability. However, functional studies on the effects of this molecular defect have not yet been carried out. Mitochondria are highly dynamic organelles, and their deregulation has emerged as a key factor in many diseases, among which is ALS. Therefore, this study aimed at determining the impact of this causative variant on mitochondria. In cellular models expressing TDP-43[G376D] and in fibroblasts derived from patients carrying this molecular defect, we observed alterations of mitochondrial functionality. We demonstrated increased localization of the mutated protein to mitochondria and a reduced abundance of subunits of complex I and complex II of the mitochondrial respiratory chain, associated with a decrease in mitochondrial membrane potential, in cellular respiration and in cytochrome C oxidase (COX) activity. Moreover, ALS cells showed increased mitochondrial fragmentation and reduced abundance of antioxidant enzymes causing increased oxidative stress. These results expand our knowledge about the molecular mechanisms underlying ALS pathogenesis associated with TDP-43 p.G376D and could help to identify new therapeutic strategies to counteract this disease.}, }
@article {pmid40298207, year = {2025}, author = {Radakovic, R and Gray, D and Trucco, AP and Bregola, A and Mioshi, E and Copsey, H and Dick, D and Newton, J and Colville, S and Pal, S and Chandran, S and Simmons, Z and Abrahams, S}, title = {Impact of apathy over the course of disease in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2495020}, pmid = {40298207}, issn = {2167-9223}, abstract = {Objective: Apathy is a common syndrome in amyotrophic lateral sclerosis (ALS), particularly Initiation apathy (lack of motivation for self-generated thoughts and/or actions). The aim was to determine how apathy subtypes change over time, and their impact on individuals' quality of life (QoL), caregiver-wellbeing and burden or strain. Methods: Forty-nine people living with ALS (pwALS) and their caregiver participated in interviews at three time-points (3-month intervals). They completed the Dimensional Apathy Scale (DAS), and assessments of depression, anxiety and emotional lability, cognitive-behavioral functioning and functional disability. PwALS QoL, caregiver burden or strain, caregiver-wellbeing and care-related QoL were measured. Results: At baseline, Initiation apathy was most common (38.8%, N = 19) followed by Emotional apathy (16.3%, N = 8). Lower caregiver-wellbeing was observed in Initiation apathy (p < 0.05) and Mixed-emotional apathy (p < 0.001) groups, where only Initiation apathy had higher caregiver burden or strain (p < 0.05) than those with no apathy. Over three visits (N = 31), there was an increase in Initiation apathy (p < 0.01) and Executive apathy (p < 0.05) over time. While controlling for functional disability, only increasing Emotional apathy was associated with increasing caregiver burden or strain (p < 0.05), decreasing caregiver-wellbeing (p < 0.001), and decreasing care-related QoL (p < 0.05). Conclusion: Initiation and Emotional apathy were variably associated with higher levels of caregiver burden or strain and decreased caregiver-wellbeing in ALS. As ALS progresses, Initiation and Executive apathy increased, while Emotional apathy has been shown to impact care-related QoL, caregiver-wellbeing and burden or strain. This has implications for understanding the progression of apathy subtypes and the interplay of caregiver-wellbeing, QoL, burden, or strain.}, }
@article {pmid40297747, year = {2025}, author = {Nara, T and Shibuya, K and Ikeda, S and Kuroiwa, R and Otani, R and Ogushi, M and Suichi, T and Shiko, Y and Takahashi, K and Misawa, S and Murata, A and Kuwabara, S}, title = {Different patterns of fasciculation in spinal and bulbar muscular atrophy and amyotrophic lateral sclerosis: a muscle ultrasonographic study.}, journal = {BMJ neurology open}, volume = {7}, number = {1}, pages = {e001065}, pmid = {40297747}, issn = {2632-6140}, abstract = {BACKGROUND: The usefulness of muscle ultrasonography for detection of fasciculations has been increasingly recognised, particularly in amyotrophic lateral sclerosis (ALS). This study aimed to elucidate distributions and characteristics of fasciculations in spinal and bulbar muscular atrophy (SBMA) and to compare the results of those in ALS.<br><br>METHODS: In 24 SBMA and 16 ALS patients, muscle ultrasonography was systematically performed in the tongue, upper limb muscles (biceps brachii, triceps brachii, first dorsal interosseous (FDI), abductor pollicis brevis and abductor digiti minimi), trunk muscles (Th10 paraspinals and rectus abdominis) and lower limb muscles (vastus lateralis, biceps femoris, tibialis anterior and gastrocnemius). We assessed the presence of fasciculations and the fasciculation intensity (scored from 0 to 3) for each muscle.<br><br>RESULTS: All SBMA and ALS patients showed fasciculations at least in two muscles. In SBMA patients, fasciculations were most frequently found in the tongue (100%), FDI (93%) and tibialis anterior (80%), whereas less frequently present in the proximal limb and trunk muscles, irrespective of age, disease duration and CAG repeat numbers. By contrast, in ALS patients, fasciculations were more diffusely distributed including the proximal limb and trunk muscles. When fasciculations were present, the intensity was higher in ALS patients, except for the tongue.<br><br>CONCLUSIONS: Whereas both diseases exhibit extensive fasciculations, the distribution and intensity are different. SBMA is characterised by prominent involvement in the tongue and distal limb muscles, suggesting different pathophysiology of motor neuronal death in SBMA and ALS.}, }
@article {pmid40296625, year = {2025}, author = {Barabadi, T and Mirjalili, ES and Mohamadi-Zarch, SM and Rahimi, H and Keshmirshekan, F and Bagheri, SM}, title = {Cell-Free DNA, a Noninvasive Biomarker for Prediction and Detection of Neurodegenerative Diseases, New Insights, and Perspectives.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273366438250408120558}, pmid = {40296625}, issn = {1996-3181}, abstract = {Neurodegenerative diseases pose serious threats to public health worldwide. Biomarkers for neurodegenerative disorders are essential to enhance the diagnostic process in clinical settings and to aid in the creation and assessment of effective disease-modifying treatments. In recent times, affordable and readily available blood-based biomarkers identifying the same neurodegenerative disease pathologies have been created, potentially transforming the diagnostic approach for these disorders worldwide. Emerging relevant biomarkers for α-synuclein pathology in Parkinson's disease include blood-based indicators of overall neurodegeneration and glial activation. Cell-free DNA (cfDNA), an encouraging non-invasive biomarker commonly utilized in oncology and pregnancy, has demonstrated significant potential in clinical uses for diagnosing neurodegenerative disorders. In this section, we explore the latest cfDNA studies related to neurodegenerative disorders. Moreover, we present a perspective on the possible role of cfDNA as a diagnostic, therapeutic, and prognostic indicator for neurodegenerative disorders. This review provides a summary of the most recent progress in biomarkers for neurodegenerative disorders such as Alzheimer's, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and traumatic brain injury.}, }
@article {pmid40295933, year = {2025}, author = {Yu, SF and Michon, M and Lingappa, AF and Paulvannan, K and Solas, D and Staats, K and Ichida, J and Dey, D and Rosenfeld, J and Lingappa, VR}, title = {An ALS assembly modulator signature in peripheral blood mononuclear cells: implications for ALS pathophysiology, therapeutics, and diagnostics.}, journal = {Clinical proteomics}, volume = {22}, number = {1}, pages = {16}, pmid = {40295933}, issn = {1542-6416}, support = {IL-2023-C4-L1//Target ALS/ ; W81XWH2210721//DOD CDMRP/ ; }, abstract = {Assembly modulators are a new class of allosteric site-targeted therapeutic small molecules, some of which are effective at restoring nuclear localization of TDP-43 in ALS cellular models, and which display efficacy in a variety of ALS animal models. These compounds have been shown to bind selectively to a small subset of protein disulfide isomerase (PDI), a protein implicated in ALS pathophysiology. The targeted subset of PDI is found within a novel, transient and energy-dependent multi-protein complex that includes other important members of the ALS interactome, such as TDP-43, RanGTPase, and selective autophagy receptor p62/SQSTM1. We demonstrate here that a similar multi-protein complex drug target is present in PBMCs as isolated by energy-dependent drug resin affinity chromatography (eDRAC) and characterized by mass spectrometry and by Western blot (WB). Signature alterations in the composition of the multi-protein complex in PBMCs from ALS patients compared to PBMCs from healthy individuals were identified by WB of eDRAC bound proteins, thereby extending earlier literature suggesting PBMC dysfunction in ALS. Changes in the PBMC drug target in ALS patients compared to healthy individuals include diminished p62/SQSTM1 and appearance of a 17 kDa post-translationally modified form of RanGTPase. These changes are not readily apparent from analysis of whole cell extracts, as the individual protein components within the drug target multi-protein complex comprise only small percentages of the total of those component proteins in the extract. Furthermore, whole blood from ALS patients shows a distinctive degradation of total RanGTPase not observed in blood from healthy individuals. This degradation appears to be rescued by treatment of whole blood from ALS patients for 72 h with ALS-active assembly modulator small molecules. Our findings are consistent with the hypothesis that ALS is fundamentally a disorder of homeostasis that can be detected early, prior to disability, in blood by the methods described, and restored to the healthy state by assembly modulator drug treatment.}, }
@article {pmid40295825, year = {2025}, author = {Hu, X and Xu, Y and Li, C and Mao, H and Liu, Z and Xiao, Y and Li, Y and Yang, X}, title = {A five-year examination into the occurrence of herbicide-resistant barnyardgrass populations in paddy from Jiangsu Province, China.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {14781}, pmid = {40295825}, issn = {2045-2322}, support = {2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 2023YFD1401100//National Key Research and Development Program of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; 32272565//National Natural Science Foundation of China/ ; }, abstract = {To assess resistance situation and evolutionary risks, 510 Echinochloa populations from 13 rice-growing regions in Jiangsu Province (2018-2022) were tested against seven herbicides (penoxsulam, quinclorac, cyhalofop-butyl, bispyribac-sodium, pretilachlor, metamifop, and florpyrauxifen-benzyl), with cross- and multiple-resistance patterns analyzed. Penoxsulam resistance increased ninefold over five years, while quinclorac resistance consistently exceeded 40% annually for four years. Cyhalofop-butyl and bispyribac-sodium resistance frequencies also rose annually, with the strongest resistance to penoxsulam and bispyribac-sodium observed in southern Jiangsu, particularly in Suzhou, Wuxi, Changzhou, and Zhenjiang. In northern Jiangsu, Huaian showed the highest resistance to multiple herbicides, while quinclorac resistance was widespread across all regions. Pretilachlor and metamifop resistance remained low, with only sporadic outbreaks, indicating that they continued to be used. However, prolonged use of single-site herbicides, particularly ALS inhibitors and ACCase inhibitors, has led to cross-resistance evolution. Multiple-resistance analysis indicated that quinclorac, penoxsulam, and cyhalofop-butyl should not be used in binary or ternary mixtures to control resistant Echinochloa. Notably, 14 populations exhibited florpyrauxifen-benzyl resistance, with 13 also showing quinclorac resistance, suggesting a potential link between prior quinclorac resistance and florpyrauxifen-benzyl resistance evolution, which warrants further investigation. This study clarifies herbicide resistance patterns in Echinochloa in Jiangsu Province, offering critical insights for resistance management strategies.}, }
@article {pmid40295163, year = {2025}, author = {Miyachi, S and Oshima, Y and Yazaki, K and Futaki, N and Shirai, Y and Tanei, ZI and Ikebe, Y and Iwata, I and Ujiie, H and Onozawa, M and Hirano, S and Tanaka, S and Yabe, I}, title = {An Autopsy Case of Amyotrophic Lateral Sclerosis With Sudden Death Showed Histological Features of Lewy Body Disease.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.70009}, pmid = {40295163}, issn = {1440-1789}, support = {//Mitsubishi Foundation Research Grant for Social Welfare Activities/ ; }, abstract = {We present the case of an 81-year-old man diagnosed with probable amyotrophic lateral sclerosis (ALS) based on the Updated Awaji criteria. The patient exhibited progressive motor neuron degeneration with muscle weakness, atrophy, and fasciculations primarily in the right lower limb and later extending to the right upper limb. Three months after being referred to a home care clinic, he collapsed in front of his family members and died. An autopsy revealed phosphorylated TDP-43 pathology consistent with ALS, with involvement of the hypoglossal nucleus, facial nerve nucleus, and medulla oblongata. Interestingly, widespread a-synuclein pathology indicative of diffuse neocortical type Lewy body disease (LBD; Braak stage 6) was identified, despite the absence of clinical parkinsonism or dementia with Lewy bodies (DLB) during his lifetime. The presence of autonomic symptoms such as constipation and urinary retention shortly before death may be attributable to a-synuclein pathology affecting the autonomic nervous system. The coexistence of ALS and LBD underscores the clinical challenge of diagnosing overlapping pathologies, as motor symptoms may obscure signs of LBD. Dopamine transporter imaging or MIBG myocardial scintigraphy might aid in identifying preclinical LBD in ALS patients with atypical symptoms. The patient died of respiratory failure due to extensive organizing pneumonia, but the possibility of sudden cardiac arrest could not be excluded. This case highlights the potential for coexisting neurodegenerative pathologies in ALS, emphasizing the importance of comprehensive evaluation when autonomic symptoms or other atypical features are present.}, }
@article {pmid40295049, year = {2025}, author = {Keul, J and Sperling, S and Rohde, V and Ninkovic, M}, title = {Advantages and Disadvantages of Drug Combination Treatment: Riluzole, Metformin and Dexamethasone Effect on Glioblastoma Cell.}, journal = {Anticancer research}, volume = {45}, number = {5}, pages = {1813-1823}, doi = {10.21873/anticanres.17561}, pmid = {40295049}, issn = {1791-7530}, abstract = {BACKGROUND/AIM: In glioblastoma multiforme (GBM), a deadly brain tumor, glucose is one of the main fuels for accelerated growth. Patients with GBM are also exposed to excess glucose through hyperglycemia in diabetes mellitus. In addition, dexamethasone (Dex), a corticosteroid commonly administered for controlling cerebral oedema, causes additional excess glucose. Therefore, targeting glucose metabolism is an attractive therapeutic intervention for GBM treatment. We have recently shown that riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), has an effect on some detrimental Dex-induced metabolic changes in GBM. Therefore, we examined the effect of the combination of metformin (Met), widely used to treat type 2 diabetes, and Ril on GBM cells.<br><br>MATERIALS AND METHODS: The 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability of U87MG after treatment with Ril, Met, Ril plus Met (Ril+Met) and the addition of Dex to this co-treatment. Cell migration was assessed by the xCELLigence system, matrix metalloproteinase 2 (MMP2) activation by zymography assay and gene expression by real-time polymerase chain reaction (RT-PCR).<br><br>RESULTS: Co-treatment with Ril and Met was effective in killing GBM cells and reducing the expression of genes involved in glucose and stem cell metabolism. Furthermore, combination of Ril and Met reduced MMP2 activation. But co-administration increased the migration of U87MG cells. The addition of Dex to this combination reversed the unfavorable effects of Ril+Met on cell migration.<br><br>CONCLUSION: Ril+Met co-treatment had a positive effect in terms of GBM cell death, decreased expression of genes involved in glucose metabolism and stemness, and reduced MMP2 activation. Disadvantage of Ril+Met treatment was increased cell migration. Taken together, these drug combinations may also allow the reduction of the concentration of Dex to minimize its side effects.}, }
@article {pmid40294721, year = {2025}, author = {Natala, SR and Habas, A and Stocking, EM and Orry, A and Abagyan, R and Makale, MT and Wrasidlo, W}, title = {Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {}, number = {}, pages = {130259}, doi = {10.1016/j.bmcl.2025.130259}, pmid = {40294721}, issn = {1464-3405}, abstract = {Inflammation is a key driver of the onset and progression of neurodegenerative diseases and cancer and can be caused by aggregated proteins, injured neurons or synapses, dysregulation of inflammatory control mechanisms, and other factors. Tolllike receptors (TLRs) are important mediators of inflammatory pathways, and their activation leads to pro-inflammatory cytokine release by immune cells in the periphery or in the central nervous system (CNS). TLR2 and TLR9 are implicated in the inflammatory pathogenesis of CNS degenerative diseases such as Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). They are also held to be important in the etiology of certain malignancies like inflammatory pancreatic ductal adenocarcinoma and glioblastoma. Inactivation of TLR2/9 in animal models of neurodegeneration has reduced pathological markers and diminished neuronal loss, while in animal models of cancer it has suppressed tumors. Therefore, TLR2 and TLR9 may be potential targets for the treatment of neurodegenerative disorders and cancers. We identified for the first time a key binding locus in TLR2/9 TIR domain which guided reversible covalent drug (RCD) design of a novel, first-in class series of dual TLR2/9 antagonists. Sub-micromolar antagonist concentrations potently inhibited TLR2 and TLR9 signaling induced by TLR2/9 specific agonists. Importantly, this series of antagonists did not discernably activate other TLRs and exhibited favorable in-vitro ADME and safety. The analogs described here may help realize effective TLR2/9 antagonism as a viable therapeutic strategy for inflammation driven CNS diseases and various malignancies with an inflammatory etiology.}, }
@article {pmid40294208, year = {2025}, author = {Winek, K and Soreq, H}, title = {Emerging roles of transfer RNA fragments in the CNS.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf130}, pmid = {40294208}, issn = {1460-2156}, abstract = {tRNA-derived small RNAs (tsRNAs), previously considered inactive tRNA degradation products, have now been shown to be functional small noncoding RNAs. They may play important roles within the central nervous system (CNS) and in brain-body interactions both during normal developmental stages as well as in diverse brain pathologies. Among the cell types found in the CNS, tsRNAs are most abundant in neurons. Correspondingly, neurons show cell type specific tRNA expression profiles when compared to other cells of the CNS under homeostatic conditions and defects in tRNA processing may lead to neurological disorders. Disease-specific tsRNA profiles have been identified in a number of CNS disorders including amyotrophic lateral sclerosis (ALS) and epilepsy. Elevated levels of specific tsRNAs have been found in the blood before the onset of epileptic seizures, and age-related, sex-specific loss of mitochondrial genome-originated tsRNAs in the nucleus accumbens of female patients is correlated to accelerated cognitive deterioration in Alzheimer's disease. Disease-related tsRNA signatures have also been identified in the cerebrospinal fluid of Parkinson's disease patients, and nucleated blood cells from ischemic stroke patients show specific elevation of cholinergic-targeted tsRNAs. The mechanisms of action of tsRNAs are still being elucidated but include targeting complementary mRNA to impact RNA levels and translation in a miRNA-like manner, direct interaction with RNA binding proteins, or interference with translation machinery. The function of tsRNAs may be affected by the chemical modifications they inherit from the originating tRNA molecules, which impact tsRNAs production and may modulate their interactions with proteins. Research on the genetics, biochemical properties and regulatory roles of tsRNAs has expanded rapidly in recent years, facilitated by novel sequencing strategies which include the removal of tRNA modifications and chemically blocked ends that hinder amplification and adapter ligation. Future in-depth profiling of tsRNAs levels, mode/s of function, and identification of interacting proteins and RNAs may together shed light on the tsRNAs impact on neuronal function, and enable novel diagnostics/therapeutics avenues for brain diseases in age, sex and disease-specific manner.}, }
@article {pmid40294152, year = {2025}, author = {Alfano, LN and Iammarino, MA and Reash, NF and Lowes, LP and Pietruszewski, L and Adderley, K and Humphrey, L and Knight, AB and Steiner, CL and Smith, MA and Sahenk, Z and Connolly, AM and Almomen, M and D'Ambrosio, ES and Peck, N and Peck, A}, title = {Validity and Reliability of Clinical and Patient-Reported Outcomes in Multisystem Proteinopathy 1.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70064}, pmid = {40294152}, issn = {2328-9503}, support = {//Cure VCP Disease Inc/ ; }, abstract = {OBJECTIVE: Valosin-containing protein (VCP)-associated multisystem proteinopathy 1 (MSP1) is caused by variants in the VCP gene. MSP1 results in various phenotypes including progressive myopathy, Paget's disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis, and parkinsonism, among others. Our study aimed to validate functional clinical outcome assessments (COA) and patient-reported outcomes (PRO) to inform clinical care practices and future clinical trial design. In addition, we evaluated the test-retest reliability of these COAs within clinics and remote environments.<br><br>METHODS: Patients completed a battery of COA and PRO across a 2-day traditional onsite visit and a 2-day remote visit within their home environment. All COA and PRO deemed safe and feasible to complete based on participants' level of function and/or home environment were collected at each visit.<br><br>RESULTS: Forty-six total patients enrolled in our study, 34 in our full study and 12 in an expanded remote-only cohort. Functional COA measured decline over reported disease duration in this cross-sectional group and significantly correlated with PRO (rho&#x2009;>&#x2009;0.5, p&#x2009;<&#x2009;0.001). Differences in lower and upper extremity involvement were noted across variant groups. Performance of functional COA was reliable and safe within and across onsite and remote testing environments (ICC&#x2009;>&#x2009;0.7, p&#x2009;<&#x2009;0.001).<br><br>INTERPRETATION: Functional COA and PRO are valid and reliable to measure abilities in participants with MSP1. Testing can be completed reliably within the home, which could expand equitable access to clinical care and/or future clinical trial participation. Prospective longitudinal data collection is ongoing to understand outcome sensitivity and meaningful change over time.}, }
@article {pmid40293530, year = {2025}, author = {Shahidehpour, RK and Katsumata, Y and Dickson, DW and Ghayal, NB and Aung, KZ and Wu, X and Phe, P and Jicha, GA and Neltner, AM and Archer, JRC and Corrada, MM and Kawas, CH and Ahmad Sajjadi, S and Woodworth, DC and Bukhari, SA and Montine, TJ and Fardo, DW and Nelson, PT}, title = {LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP.}, journal = {Acta neuropathologica}, volume = {149}, number = {1}, pages = {38}, pmid = {40293530}, issn = {1432-0533}, support = {R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; R01 AG061111, R01 AG057187, P30 AG072946, RF1 NS118584, T32 AG078110, R01 AG021055, P30 AG066519//National Institutes on Health, United States/ ; }, mesh = {Humans ; Male ; Female ; Aged ; *Frontotemporal Lobar Degeneration/pathology/diagnosis/genetics ; *TDP-43 Proteinopathies/pathology/diagnosis/genetics ; Diagnosis, Differential ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; Middle Aged ; *Brain/pathology ; Inclusion Bodies/pathology ; Dementia ; }, abstract = {A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LATE-NC Stage 3, TDP-43 proteinopathy is present in the middle frontal gyrus (MFG), thus posing a potential diagnostic challenge in differentiating these severe LATE-NC cases from FTLD-TDP. LATE-NC Stage 3 cases and other TDP-43 proteinopathies were analyzed from the University of Kentucky (total n = 514 with TDP-43 pathology assessed), The 90+ Study at the University of California Irvine (n = 458), and the Mayo Clinic (n = 5067) brain banks. Digital pathology was used to quantify pathology burden in a select subset of cases (n = 51), complemented by a previously-described manual counting method and expert neuropathologic examinations to evaluate qualitative features such as FTLD-TDP types and subtypes of neuronal cytoplasmic inclusions (NCIs). To evaluate clinical and genetic characteristics of LATE-NC Stage 3, data were analyzed from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data set and correlated with findings from the Alzheimer's Disease Genetics Consortium (ADGC). When using TDP-43 proteinopathy quantification in the MFG as a diagnostic criterion, more than 90% of cases could be classified as either LATE-NC Stage 3 or FTLD-TDP. Diagnostically challenging scenarios included a subset of FTLD-TDP Type B cases with relatively mild MFG TDP-43 pathology and a novel non-LATE-NC, non-FTLD-TDP pathologic subtype with severe MFG TDP-43 pathology. Taking these potential pitfalls into account, a classification schema was developed that could correctly diagnose all included cases. There was no difference in the Alzheimer's disease pathological load in LATE-NC Stages 2 versus 3. In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not. In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.}, }
@article {pmid40291738, year = {2025}, author = {Zhu, B and Van, R and Wang, H and Kuang, S and Jia, Y and Leon, EC and Yang, F and Zhang, J and Yang, J and Hong, H and Fleur Marie, L and Yu, A and Wang, J and Tanzi, RE and Zhang, CM and Mao, XM and Shao, Y and Ran, C}, title = {Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.12.648090}, pmid = {40291738}, issn = {2692-8205}, abstract = {Protein misfolding is a crucial pathological phenomenon driving neurodegenerative diseases that affect millions of people. Visualizing misfolded proteins would greatly facilitate early diagnosis, etiology elucidation, and therapy monitoring of neurodegeneration. Although several probes have been reported, versatile and sensitive detection in vivo is still challenging. We demonstrated that both generic and precise detection of misfolded proteins could be achieved with a chemiluminescence probe, ADLumin-1. For generic aspect, ADLumin-1 was highly sensitive to various misfolded proteins, showing up to 127.73-fold higher signal-to-noise ratio than gold standard dye of Thioflavin T. ADLumin-1 could also non-invasively visualize misfolded proteins in mouse models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. For precise aspects, ADLumin-1 can selectively detect α-synuclein in CSF at the femtomolar level by combining with protein misfolding cyclic amplification technology in vitro. In addition, ADLumin-1 enables selective in vivo imaging of misfolded α-synuclein in transgenic mice models by employing bioorthogonal chemiluminescence resonance energy transfer strategy. Combining generality and precision, our findings could be widely applied in preclinical and clinical studies of neurodegenerative diseases.}, }
@article {pmid40291716, year = {2025}, author = {Hnath, B and Dokholyan, NV}, title = {Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.07.647611}, pmid = {40291716}, issn = {2692-8205}, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, leading to controversy whether ALS is one disease or many diseases with a similar phenotype. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are only found in 2-3% of ALS cases, yet misfolded SOD1 is found in both sporadic (sALS) and familial (fALS) patients. Yet, mutations in TDP-43 or FUS increase the level of misfolded SOD1 on extracellular vesicles (EVs). Additionally, small EVs isolated from ALS patient samples caused cell death of wild type motor neurons and myotubules. The toxicity and protein alterations of ALS EVs have led to the theory that EVs are responsible for the spread of ALS. We hypothesize that previously-identified toxic trimeric SOD1 is spreading on EVs in ALS and altering the spread of other ALS-related proteins, linking them to a common mechanism. To test our hypothesis, we isolate EVs from motor neuron-like cells expressing trimer stabilizing mutations and perform a sandwich enzyme-linked immunoassay (ELISA) (CD9 capture antibody) to quantify whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is being affected by trimeric SOD1 utilizing endocytosis and exocytosis inhibitors, and determine if any specific EV-related proteins are altered with trimer stabilization. We establish that VAPB, VCP, and Stathmin-2 increase on EVs with trimer stabilization. The common pathway between SOD1 and three other ALS-associated proteins is affected by multiple pathways, including the Caveolae endocytosis pathway, suggesting a novel hybrid pathway of EV release present in ALS.}, }
@article {pmid40291709, year = {2025}, author = {Gao, G and Sumrall, ER and Walter, NG}, title = {Nanoscale domains govern local diffusion and aging within FUS condensates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.04.01.587651}, pmid = {40291709}, issn = {2692-8205}, abstract = {Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here, we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labeled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein Fused in Sarcoma (FUS) as a model for condensates implicated in ALS, we discover that RNA and protein diffusion is confined within distinct nanometer-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. During condensate aging, these nanodomains reposition, facilitating FUS fibrilization at the condensate surface, a transition enhanced by FDA-approved ALS drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating biomolecule sequestration and percolation, offering insights into condensate aging and disease-related transitions.}, }
@article {pmid40291645, year = {2025}, author = {Xie, L and Zhu, Y and Hurtle, BT and Wright, M and Robinson, JL and Mauna, JC and Brown, EE and Ngo, M and Bergmann, CA and Xu, J and Merjane, J and Gleixner, AM and Grigorean, G and Liu, F and Rossoll, W and Lee, EB and Kiskinis, E and Chikina, M and Donnelly, CJ}, title = {Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.07.646890}, pmid = {40291645}, issn = {2692-8205}, abstract = {TDP-43 mislocalization, aggregation, and loss of splicing function are neuropathological hallmarks in over 97% of Amyotrophic Lateral Sclerosis (ALS), 45% of Frontotemporal Lobar Degeneration (FTLD), and 60% of Alzheimer's Disease, which has been reclassified as LATE-NC. However, the mechanisms underlying TDP-43 dysfunction remain elusive. Here, we utilize APEX2-driven proximity labeling and mass spectrometry to characterize the context-dependent TDP-43 interactome in conditions of cytoplasmic mislocalization, impaired RNA-binding contributing to aggregation, and oxidative stress. We describe context-dependent interactors, including disrupted interactions with splicing-related proteins and altered biomolecular condensate (BMC) associations. By integrating ALS and FTLD snRNA-seq data, we uncover disease-relevant molecular alterations and validate our dataset through a functional screen that identifies key TDP- 43 regulators. We demonstrate that disrupting nuclear speckle integrity, particularly through the downregulation of the splicing factor SRRM2, promotes TDP-43 mislocalization and loss of function. Additionally, we identify NUFIP2 as an interactor associated with mislocalization that sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in patient tissue. We also highlight HNRNPC as a potent TDP-43 splicing regulator, where precise modulation of TDP-43 or HNRNPC can rescue cryptic exon splicing. These findings provide mechanistic insights and potential therapeutic targets for TDP-43 dysfunction.}, }
@article {pmid40290690, year = {2025}, author = {Cao, YK and Yang, SL and Wei, ZQ}, title = {Is the use of a transanal drainage tube effective in treating anastomotic leakage for mid-low rectal cancer.}, journal = {World journal of clinical oncology}, volume = {16}, number = {4}, pages = {99801}, pmid = {40290690}, issn = {2218-4333}, abstract = {BACKGROUND: Anastomotic leakage (AL) is a severe surgical complication for mid-low rectal cancers. The efficacy of transanal drainage tube (TDT) has rarely been reported.<br><br>AIM: To evaluate the efficacy of TDT after AL.<br><br>METHODS: A retrospective analysis was conducted on 68 patients with mid-low rectal cancer who underwent laparoscopic low anterior resection (LAR) and developed ALs. Leakage were identified using imaging studies and digital rectal examinations when local abscesses or systemic infections were present. In each patient, the leakage site was determined using the index finger and a drainage tube was inserted transanally to drain the abscesses and exudates outside the anus. The clinical outcomes of the patients following transanal drainage were analyzed.<br><br>RESULTS: A total of 43 patients received TDT treatment, while 25 patients did not receive TDT treatment. Among the patients in the TDT group, 9 required reoperation compared to 12 in the non-TDT group. In the TDT group, 76.74% of the patients were able to restore intestinal continuity, whereas only 40% of the patients in the non-TDT group achieved restored intestinal continuity. In the TDT group, 48.48% of patients developed LAR syndrome (LARS), whereas in the non-TDT group, 90% of patients developed LARS. The median drainage time was 7 days, the median postoperative hospital stay was 21 days, the median fasting time was 6.5 days, and the median hospitalization cost was 109205.93 RMB.<br><br>CONCLUSION: TDT use lowered reoperation rate but did not increase hospitalization expenses. After &#x2265; 1 year of follow-up, its use improved intestinal patency rate and reduced the incidence of LARS.}, }
@article {pmid40290679, year = {2025}, author = {Li, ZY and Li, T and Cai, HQ}, title = {Overview of serrated polyposis syndrome from pathophysiology, diagnosis, and management.}, journal = {World journal of clinical oncology}, volume = {16}, number = {4}, pages = {103343}, pmid = {40290679}, issn = {2218-4333}, abstract = {This editorial discusses Thompson et al's original article, which is published in the most recent edition of the World Journal of Clinical Oncology and sheds critical light on the intertwined issues of health anxiety and work loss in individuals diagnosed with serrated polyposis syndrome (SPS). SPS is rare, characterized by the development of multiple serrated colorectal polyps. This editorial provides an overview of SPS, including its pathophysiology, clinical presentation, diagnostic criteria, management strategies, and the psychosocial impact. SPS is linked to molecular alterations, which drive carcinogenesis. Colonoscopy and histological analysis are used for diagnosis. Genetic testing is also considered where there is a family history. Quality of life can be greatly impacted by the psychosocial effects of SPS, especially health anxiety. Further understanding of the molecular mechanisms and creating individualized surveillance are required.}, }
@article {pmid40290120, year = {2025}, author = {Hong, Y and Song, Y and Wang, W and Shi, J and Chen, X}, title = {Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.}, journal = {Genes &amp; diseases}, volume = {12}, number = {4}, pages = {101437}, pmid = {40290120}, issn = {2352-3042}, abstract = {Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.}, }
@article {pmid40289884, year = {2025}, author = {Janelidze, S and Ashton, NJ and Orduña Dolado, A and Nordström, U and Bali, D and Forsberg, KME and Keskin, I and Mastrangelo, A and Vacchiano, V and Liguori, R and Blennow, K and Zetterberg, H and Mattsson-Carlgren, N and Gonzalez-Ortiz, F and Parchi, P and Andersen, PM and Hansson, O}, title = {A comparison of p-tau assays for the specificity to detect tau changes in Alzheimer's disease.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {4}, pages = {e70208}, doi = {10.1002/alz.70208}, pmid = {40289884}, issn = {1552-5279}, mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/blood/diagnosis ; Female ; Male ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood/diagnosis ; Aged ; Sensitivity and Specificity ; Middle Aged ; Biomarkers/blood/cerebrospinal fluid ; Aged, 80 and over ; Immunoassay ; Phosphorylation ; }, abstract = {INTRODUCTION: We evaluated differences in p-tau levels between Alzheimer's disease (AD), a condition with brain-specific changes in p-tau, and amyotrophic lateral sclerosis (ALS), a condition associated with increases in peripheral p-tau levels.<br><br>METHODS: Cerebrospinal fluid and plasma from 668 participants were analyzed using immunoassays specific for the low-molecular-weight (LMW) tau isoforms present in the brain (i.e., p-tau217Lilly, p-tau181Lilly) and those that detect both LMW- and high-molecular-weight (HMW) tau expressed in the peripheral nervous system (i.e., p-tau217AlzPath, p-tau181UGOT).<br><br>RESULTS: Increases in plasma p-tau in ALS versus controls were significantly smaller for the LMW-specific p-tau assays (15.9%-20.5%) compared with non-specific assays (92.0%-121.3%). The LMW-specific p-tau assays showed significantly larger plasma p-tau increases in AD versus ALS, discriminating AD from ALS with areas under the curve (AUCs; 0.890.93) higher than the AUCs of the non-specific assays (0.54-0.74).<br><br>DISCUSSION: LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy are frequent.<br><br>HIGHLIGHTS: Increases in plasma phosphorylated tau (p-tau) in amyotrophic lateral sclerosis (ALS) versus controls were significantly smaller for low-molecular-weight (LMW)-specific p-tau assays (i.e., p-tau217Lilly, p-tau181Lilly) compared with p-tau assays that also detect high-molecular-weight (HMW) assays (i.e., p-tau217AlzPath, p-tau181UGOT). The LMW-specific p-tau assays showed significantly larger increases in plasma p-tau in AD versus ALS compared with the non-specific assays. The LMW-specific p-tau assays discriminated AD from ALS with higher precision, showing significantly better performance than the non-specific assays. LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy (such as ALS) are frequent.}, }
@article {pmid40289140, year = {2025}, author = {Meyer, T and Boentert, M and Großkreutz, J and Weydt, P and Bernsen, S and Reilich, P and Steinbach, R and Rödiger, A and Wolf, J and Weyen, U and Ludolph, AC and Weishaupt, J and Petri, S and Lingor, P and Günther, R and Löscher, W and Weber, M and Münch, C and Maier, A and Grehl, T}, title = {Motor phenotypes of amyotrophic lateral sclerosis - a three-determinant anatomical classification based on the region of onset, propagation of motor symptoms, and the degree of upper and lower motor neuron dysfunction.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {27}, pmid = {40289140}, issn = {2524-3489}, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), heterogeneity of motor phenotypes is a fundamental hallmark of the disease. Distinct ALS phenotypes were associated with a different progression and survival. Despite its relevance for clinical practice and research, there is no broader consensus on the classification of ALS phenotypes.<br><br>METHODS: An expert consensus process for the classification of ALS motor phenotypes was performed from May 2023 to December 2024. A three-determinant anatomical classification was proposed which is based on the (1) region of onset (O), (2) the propagation of motor symptoms (P), and (3) the degree of upper (UMN) and/or lower motor neuron (LMN) dysfunction (M). Accordingly, this classification is referred to as the "OPM classification".<br><br>RESULTS: Onset phenotypes differentiate the site of first motor symptoms: O1) head onset; O2d) distal arm onset; O2p) proximal arm onset; O3r) trunk respiratory onset; O3a) trunk axial onset; O4d) distal leg onset; O4p) proximal leg onset. Propagation phenotypes differentiate the temporal propagation of motor symptoms from the site of onset to another, vertically distant body region: PE) earlier propagation (within 12 months of symptom onset); PL) later propagation (without propagation within 12 months of symptom onset), including the established phenotypes of "progressive bulbar paralysis" (O1, PL), "flail-arm syndrome" (O2p, PL), and "flail-leg syndrome" (O4d, PL); PN) propagation not yet classifiable as time since symptom onset is less than 12 months. Phenotypes of motor neuron dysfunction differentiate the degree of UMN and/or LMN dysfunction: M0) balanced UMN and LMN dysfunction; M1d) dominant UMN dysfunction; M1p) pure UMN dysfunction ("primary lateral sclerosis", PLS); M2d) dominant LMN dysfunction; M2p) pure LMN dysfunction ("progressive muscle atrophy", PMA); M3) dissociated motor neuron dysfunction with dominant LMN and UMN dysfunction of the arms and legs ("brachial amyotrophic spastic paraparesis"), respectively.<br><br>CONCLUSION: This consensus process aimed to standardize the clinical description of ALS motor phenotypes in clinical practice and research - based on the onset region, propagation pattern, and motor neuron dysfunction. This "OPM classification" contributes to specifying the prognosis, to defining the inclusion or stratification criteria in clinical trials and to correlate phenotypes with the underlying disease mechanisms of ALS.}, }
@article {pmid40288877, year = {2025}, author = {Alcaraz, MR and Montemurro, M and Pisano, PL and Lombardi, JM and Bortolato, SA}, title = {Functional data analysis, a comprehensive framework for processing non-quadrilinear and low-selective data provided by four-way liquid chromatography analysis.}, journal = {Analytica chimica acta}, volume = {1356}, number = {}, pages = {344044}, doi = {10.1016/j.aca.2025.344044}, pmid = {40288877}, issn = {1873-4324}, abstract = {The chemometric treatment of higher-order chromatographic (LC) data often crashes due to two main effects: the chromatographic band shifts/warpings across samples and quasi-full overlaps between component signals, affecting their analytical selectivities. From a chemometric point of view, these phenomena have independent effects, although they can jointly contribute to the failure of the algorithms: 1) data multilinearity breaking, leading to the poor performance of multilinear decomposition algorithms, and 2) linear dependence between the analytes signals, causing the failure of folded models. Under this scenario, making chemometric processing feasible involves defining specific experimental conditions that minimize these effects or increasing the number of instrumental ways to deal with selectivity lost. This work presents the Functional Aligned of Pure Vectors (FAPV) algorithm for restoring four-way chromatographic data multilinearity and bearing the spectral overlap trouble. Simulated and experimental four-way data were used to test the FAPV analytical efficiency, covering a wide range of chromatographic artifacts. Based on a multi-injection procedure, the experimental case implied the chromatographic determination of two analytes with uncalibrated interferents in aqueous samples. Both data systems were subjected to FAPV and then processed by PARAFAC. Therefore, a comprehensive comparison was made with the most widely used chemometric models for non-multilinear chromatographic data (MCR-ALS and PARAFAC2). Moreover, the performance of the FAPV approach was compared with commonly used alignment procedures, e.g., correlation-optimized warping. The results (c.a. REPs of 10 % in both analytes from the experimental case) show the efficiency of the FAPV algorithm in solving the troubles observed in chromatographic/spectral data.}, }
@article {pmid40288591, year = {2025}, author = {Servi, R and Akkoç, RF and Aksu, F and Servi, S}, title = {Therapeutic Potential of Enzymes, Neurosteroids, and Synthetic Steroids in Neurodegenerative Disorders: A Critical Review.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {}, number = {}, pages = {106766}, doi = {10.1016/j.jsbmb.2025.106766}, pmid = {40288591}, issn = {1879-1220}, abstract = {Neurodegenerative disorders present a significant challenge to healthcare systems, mainly due to the limited availability of effective treatment options to halt or reverse disease progression. Endogenous steroids synthesized in the central nervous system, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG), and allopregnanolone (ALLO), have been identified as potential therapeutic agents for neurodegenerative diseases. Neurosteroids such as ALLO, DHEA, and PROG, as well as their synthetic analogs like Ganaxolene, Fluasterone, and Olexoxime, offer promising effects for conditions such as Alzheimer's disease (AD) and depression. Moreover, Brexanolone and Ganaxolone are synthetic steroids approved for the treatment of postpartum depression and epilepsy, respectively. Neurosteroids such as ALLO are crucial in modulating GABAergic neurotransmission and reducing neuroinflammation. These compounds enhance the activity of GABA-A receptors, leading to increased inhibitory signaling in the brain, which can help regulate mood, cognition, and neuroprotection. Small clinical trials and observational studies indicate that ALLO may have cognitive benefits, but no large-scale, definitive meta-analysis confirms a 20% improvement in AD patients. Mitochondrial dysfunction plays a vital role in the pathogenesis of numerous neurological diseases due to the high-energy demand and sensitivity of neurons to oxidative stress. Reduced mitochondrial function leads to amyloid-beta plaques and tau tangles accumulation in AD. In Parkinson's disease (PD), mitochondrial dysfunction resulting from the PINK1 or Parkin genes leads to energy deficiencies and the accumulation of toxic byproducts. Mutations in genes such as SOD1, C9orf72, and TDP-43 have been associated with mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS). Moreover, studies on these neurodegenerative diseases suggest that inflammation is not merely a consequence of neurodegeneration but is also an essential factor in this process. Many neurological disorders involve multifaceted interactions between genetics, the environment, and immune responses, making it difficult to pinpoint their exact causes. Future research aims to overcome these hurdles through genetic advances, regenerative medicine, and personalized therapies. Cutting-edge technologies such as artificial intelligence and high-throughput screening are expected to accelerate drug discovery and improve diagnostic accuracy. Increasing collaboration between interdisciplinary fields such as bioinformatics, neuroscience, and immunology will lead to innovative treatment strategies. This comprehensive review discusses the therapeutic effects of enzymes, neurosteroids, and synthetic steroids in different neurodegenerative diseases, particularly AD, PD, ALS, and MS. Potential challenges in the therapeutic use of neurosteroids, such as the limited bioavailability and off-target effects of synthetic steroids, are also discussed, and an up-to-date and comprehensive review of the impact of these steroids on neurodegenerative disorders is presented.}, }
@article {pmid40287755, year = {2025}, author = {Vizziello, M and Dellarole, IL and Ciullini, A and Pascuzzo, R and Lombardo, A and Bellandi, F and Celauro, L and Battipaglia, C and Ciusani, E and Rizzo, A and Catania, M and Devigili, G and Della Seta, SA and Margiotta, V and Consonni, M and Faltracco, V and Tiraboschi, P and Riva, N and Portaleone, SMS and Zanusso, G and Legname, G and Lauria, G and Dalla Bella, E and Moda, F}, title = {TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {49}, pmid = {40287755}, issn = {1750-1326}, support = {GR-2021-12372019//Ministero della Salute/ ; PNRR-MAD-2022-12376035//Ministero della Salute/ ; 5M-2018-23680266//Ministero della Salute/ ; RC//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; Aged ; *Olfactory Mucosa/metabolism/pathology ; Frontotemporal Dementia/metabolism ; Adult ; }, abstract = {BACKGROUND: In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS.<br><br>METHODS: OM samples were collected from patients with (a) sporadic motor neuron diseases (MND), including spinal ALS (n&#x2009;= 35), bulbar ALS (n&#x2009;= 18), primary lateral sclerosis (n&#x2009;= 10), and facial onset sensory and motor neuronopathy (n&#x2009;= 2); (b) genetic MND, including carriers of C9orf72[exp] (n&#x2009;= 6), TARDBP (n&#x2009;= 4), SQSTM1 (n&#x2009;= 3), C9orf72[exp]&#x2009;+ SQSTM1 (n&#x2009;= 1), OPTN (n&#x2009;= 1), GLE1 (n&#x2009;= 1), FUS (n&#x2009;= 1) and SOD1 (n&#x2009;= 4) mutations; (c) other neurodegenerative disorders (OND), including Alzheimer's disease (n&#x2009;= 3), dementia with Lewy bodies (n&#x2009;= 8) and multiple system atrophy (n&#x2009;= 6); and (d) control subjects (n&#x2009;= 22). All samples were subjected to SAA analysis for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light chain (NfL) were also assessed in a selected number of patients.<br><br>RESULTS: TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND patients and 3/22 controls. Surprisingly, one presymptomatic individual also tested positive. As expected, OM of genetic non-TDP-43-related MND tested negative. Interestingly, fluorescence values from non-MND samples that tested positive were consistently and significantly lower than those obtained with sporadic and genetic MND. Furthermore, among TDP-43-positive samples, the lag phase observed in MND patients was significantly longer than that in non-MND patients. Plasma TDP-43 levels were significantly higher in sporadic MND patients compared to controls and decreased as the disease progressed. Similarly, plasma NfL levels were higher in both sporadic and genetic MND patients and positively correlated with disease progression rate (&#x394;FS). No significant correlations were detected between TDP-43_SAA findings and the biological, clinical, or neuropsychological parameters considered.<br><br>CONCLUSIONS: The OM of a subset of patients with sporadic MND can trigger seeding activity for TDP-43, as previously observed in genetic MND. Thus, TDP-43_SAA analysis of OM can improve the clinical characterization of ALS across different phenotypes and enhance our understanding of these diseases. Finally, plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.}, }
@article {pmid40287045, year = {2025}, author = {Dudzisz, K and Wandzik, I}, title = {Antisense Oligonucleotides: A Promising Advancement in Neurodegenerative Disease Treatment.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177644}, doi = {10.1016/j.ejphar.2025.177644}, pmid = {40287045}, issn = {1879-0712}, abstract = {Antisense oligonucleotides (ASOs) are a class of therapeutics designed to modulate gene expression and have shown promise in the treatment of various neurodegenerative diseases. As of March 2025, four ASO-based therapies have received approval for the treatment of neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and hereditary transthyretin amyloidosis (ATTR). These approvals underscore the therapeutic potential of ASOs as effective treatments for neurodegenerative diseases by addressing specific genetic abnormalities. This is best demonstrated by clinical studies in more than a dozen ASOs, which could pave the way for the development of new therapeutics soon. Moreover, the ongoing extended clinical studies, which target presymptomatic carriers, have significant potential to cure familial ALS based on the SOD1 gene mutation. This review provides an update on clinical trials, highlighting promising results and the challenges encountered.}, }
@article {pmid40286820, year = {2025}, author = {Cepica, TB and Xie, L and Faden, DF and Stone, CJ and Feng, R and Werth, VP and Chong, BF}, title = {Regarding Wu et al's "Response to Cepica et al's 'Smoking status is a negative predictor of six-month cutaneous lupus activity trends: a prospective cohort study.'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.04.050}, pmid = {40286820}, issn = {1097-6787}, }
@article {pmid40286795, year = {2025}, author = {Murdock, BJ and Zhao, B and Webber-Davis, IF and Teener, SJ and Pawlowski, KD and Famie, JP and Piecuch, CE and Jang, DG and Feldman, EL and Zhao, L and Goutman, SA}, title = {Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression.}, journal = {Med (New York, N.Y.)}, volume = {}, number = {}, pages = {100673}, doi = {10.1016/j.medj.2025.100673}, pmid = {40286795}, issn = {2666-6340}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure and limited treatment options. The immune system is implicated in disease pathology, unlocking a potential therapeutic avenue. However, it is unclear whether immune changes are a cause or consequence of disease progression.<br><br>METHODS: Peripheral immune cells were longitudinally measured at monthly intervals in 55 ALS and 50 control participants. 22 peripheral immune markers in the blood were assessed using flow cytometry, and clinical progression was assessed using the revised ALS functional rating scale (ALSFRS-R). Individual immune markers, their trajectories, and overall variability were compared in ALS versus control participants; ALS participants were also stratified by clinical progression rates and assessed similarly across progression groups. Finally, a novel, lagged linear regression model correlated the rate of immune changes to subsequent downstream ALSFRS-R changes.<br><br>FINDINGS: Numerous immune markers were dysregulated in ALS versus control participants, with altered levels, trajectories, or variability in immune populations and surface markers. ALS participants had increased immune variability relative to control participants; within ALS participants, faster progressors overall had decreased marker variability. Finally, natural killer (NK) cell numbers, NK cell subpopulations, and NK cell surface markers were significantly associated with downstream ALS progression.<br><br>CONCLUSIONS: The immune system is dysregulated in ALS and more consistently dysregulated in faster ALS progression, and immune dysregulation occurs upstream of clinical changes. These findings suggest that the immune system is a causal factor of ALS progression in human patients.<br><br>FUNDING: CReATe Consortium, NIH, Target ALS, DoD, ALSA.}, }
@article {pmid40285687, year = {2025}, author = {Altemus, JJ and Lay, MA and Thompson, VF and Schwartz, JC}, title = {Purification of Low-Complexity Domain Proteins FUS, EWSR1, and Their Fusions.}, journal = {Current protocols}, volume = {5}, number = {4}, pages = {e70136}, pmid = {40285687}, issn = {2691-1299}, mesh = {*RNA-Binding Protein FUS/isolation &amp; purification/chemistry/genetics/metabolism ; *RNA-Binding Protein EWS/isolation &amp; purification/chemistry/genetics/metabolism ; Humans ; *Oncogene Proteins, Fusion/isolation &amp; purification/chemistry ; Protein Domains ; }, abstract = {FET proteins are large multifunctional proteins that have several key roles in biology. The FET family of proteins, including FUS, EWSR1, and TAF15, play critical roles in transcription regulation, RNA processing, and DNA damage repair. These multifunctional RNA- and DNA-binding proteins are ubiquitously expressed and conserved across vertebrate species. They contain low-complexity (LC) domains that allow them to assemble and phase separate but also makes the proteins prone to aggregation. Aberrations in FET proteins, such as point mutations, aggregation, or translocations leading to fusion proteins, have been implicated in several pathologies, including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Ewing sarcoma. In vitro study of FET proteins is hampered by their propensity to aggregate, their disordered structure, and their susceptibility to proteolysis, making high-yield production difficult. Here, we present optimized methods for the purification of full-length FUS, EWSR1, and their fusion proteins. These protocols enable researchers to overcome issues related to aggregation and solubility, facilitating biochemical and biophysical studies of these critical yet complex proteins. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Purification of EWSR1 and FUS proteins Alternate Protocol: Purification for fusion proteins.}, }
@article {pmid40285624, year = {2025}, author = {Vasta, R and Koumantakis, E and Canosa, A and Manera, U and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and Vergnano, F and Mandrioli, J and Simonini, C and Martinelli, I and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A}, title = {Phosphatemia is an Independent Prognostic Factor in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27252}, pmid = {40285624}, issn = {1531-8249}, support = {2017SNW5MB//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; 259867//European Commission's Health Seventh Framework Programme/ ; 101137074//European Union's Horizon 2020 research and innovation programme/ ; GA101017598//European Union's Horizon 2020 research and innovation programme/ ; PNRR-MAD-2022-12375731//Ministero della Salute/ ; RF-2016-02362405//Ministero della Salute/ ; }, abstract = {OBJECTIVE: The objective of this study was to evaluate the prognostic value of several muscle damage biomarkers.<br><br>METHODS: Data from Piemonte and Valle d'Aosta Amyotrophic Lateral Sclerosis (PARALS) were considered for this study. Survival was defined as the time from diagnosis to death, tracheostomy, or the censoring date. Blood levels of potassium, creatinine, creatine kinase, phosphorus, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) diagnosis were evaluated as potential prognostic biomarkers. A Cox model was developed for each biomarker and adjusted for sex, onset age, onset site, and diagnostic delay. Significant findings from PARALS were evaluated in the Pooled Resource Open-Access Amyotrophic Lateral Sclerosis Clinical Trials (PRO-ACT) database. Additionally, a joint model was constructed to evaluate the prognostic role of phosphatemia slope over time using longitudinal data from PRO-ACT.<br><br>RESULTS: A total of 1,444 and 1,023 patients were included in the PARALS and PRO-ACT cohorts, respectively. Only creatinine (hazard ratio [HR]&#x2009;=&#x2009;0.65, 95% confidence interval [CI]&#x2009;=&#x2009;0.50-0.85) and phosphorus (HR&#x2009;=&#x2009;1.14, 95% CI&#x2009;=&#x2009;1.04-1.24) showed a significant association with survival in the PARALS cohort. These findings were further validated in the PRO-ACT cohort (creatinine HR&#x2009;=&#x2009;0.21, 95% CI&#x2009;=&#x2009;0.13-0.35, p&#x2009;<&#x2009;0.0001; phosphorus HR&#x2009;=&#x2009;2.35, 95% CI&#x2009;=&#x2009;1.13-4.88, p&#x2009;=&#x2009;0.02). Longitudinal data from the PRO-ACT database showed that an increase of 0.1&#x2009;mmol/l per month in phosphate levels was also associated with a HR of 8.26 (95% CI&#x2009;=&#x2009;1.07-96.6, p&#x2009;=&#x2009;0.044).<br><br>INTERPRETATION: Creatininemia was confirmed as a prognostic marker in amyotrophic lateral sclerosis (ALS). Additionally, both phosphatemia levels at diagnosis and its rate of change over time were identified as a potential prognostic marker for ALS. As with other blood biomarkers, phosphate levels are cost-effective and minimally invasive to measure, supporting their potential use in clinical trials. ANN NEUROL 2025.}, }
@article {pmid40285121, year = {2025}, author = {Chatragadda, L and Fletcher, A and Zhong, S and Vargas, FA and Bhagat, N and Mankodiya, K and Delmonico, MJ and Solanki, D}, title = {Development and Assessment of a Soft Wearable for sEMG-Based Hand Grip Detection and Control of a Virtual Environment.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {8}, pages = {}, doi = {10.3390/s25082431}, pmid = {40285121}, issn = {1424-8220}, support = {N/A//Office of Undergraduate Research and Innovation, University of Rhode Island/ ; }, mesh = {Humans ; *Electromyography/methods/instrumentation ; *Hand Strength/physiology ; *Wearable Electronic Devices ; Male ; Female ; Middle Aged ; Adult ; Neurodegenerative Diseases/physiopathology ; Aged ; Hand/physiology ; Feasibility Studies ; }, abstract = {BACKGROUND: As the number of individuals diagnosed with neurodegenerative disorders (NDs) rises, there is a growing need to enhance both the quantity and quality of approaches used to treat these debilitating conditions. The progression of NDs can cause muscle weakness in the lower or upper limbs. We particularly focus on the area of the upper limb, specifically grip rehabilitation, by developing a system (VRGrip) that can reliably record electromyography (EMG) events of the hand flexor muscles to control an adaptive and engaging game using grip exertion. The purpose of this study was to determine the feasibility of using the VRGrip system.<br><br>METHODS: We prototyped a three-component wearable system consisting of an e-textile forearm band (E-band), data acquisition module (DAM), and a computer game. This allows participants to play a game by squeezing their dominant hand. A feasibility study was completed with 9 individuals who self-reported an ND (including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and essential tremor (ET)) and 12 individuals who self-reported to be relatively healthy (RH). Each participant completed 15 min of gameplay (three trials of five minutes), where they would squeeze a resistive ball to trigger in-game actions. The user experience was then evaluated via a User Satisfaction Evaluation Questionnaire (USEQ; scored 0-30, with 30 being best).<br><br>RESULTS: Analysis of the grip detection reliability during the feasibility study resulted in an F1 score of 0.8343 &#xb1; 0.1208 for the healthy participant group and 0.8401 &#xb1; 0.1034 for the ND participant group. The USEQ (Avg. score: 4.65 &#xb1; 0.51) indicated that participants found the system comfortable, engaging, and enjoyable. Additionally, we potentially identified age-related changes in muscle fatigue.<br><br>CONCLUSION: The results of this study demonstrate that our VRGrip system could be used for hand grip detection in a virtual environment. In the future, we aim to conduct longitudinal studies to determine if repeated use of the system has merit for grip rehabilitation.}, }
@article {pmid40284554, year = {2025}, author = {Tamai, R and Kiyoura, Y}, title = {Candida Infections: The Role of Saliva in Oral Health-A Narrative Review.}, journal = {Microorganisms}, volume = {13}, number = {4}, pages = {}, doi = {10.3390/microorganisms13040717}, pmid = {40284554}, issn = {2076-2607}, support = {21K10233, 23K09511//KAKEN/ ; }, abstract = {Candida species, particularly Candida albicans, are causative agents of oral infections to which immunocompromised patients are especially susceptible. Reduced saliva flow (xerostomia) can lead to Candida overgrowth, as saliva contains antibacterial components such as histatins and β-defensins that inhibit fungal growth and adhesion to the oral mucosa. Candida adheres to host tissues, forms biofilms, and secretes enzymes required for tissue invasion and immune evasion. Secretory asparaginyl proteinases (Saps) and candidalysin, a cytolytic peptide toxin, are vital to Candida virulence, and agglutinin-like sequence (Als) proteins are crucial for adhesion, invasion, and biofilm formation. C. albicans is a risk factor for dental caries and may increase periodontal disease virulence when it coexists with Porphyromonas gingivalis. Candida infections have been suggested to heighten the risk of oral cancer based on a relationship between Candida species and oral squamous cell carcinoma (OSCC) or oral potentially malignant disorder (OPMD). Meanwhile, β-glucan in the Candida cell wall has antitumor effects. In addition, Candida biofilms protect viruses such as herpesviruses and coxsackieviruses. Understanding the intricate interactions between Candida species, host immune responses, and coexisting microbial communities is essential for developing preventive and therapeutic strategies against oral Candida infections, particularly in immunocompromised individuals.}, }
@article {pmid40284406, year = {2025}, author = {Ansari, UA and Srivastava, A and Srivastava, AK and Pandeya, A and Vatsa, P and Negi, R and Singh, A and Pant, AB}, title = {Targeting TDP-43 Proteinopathy in hiPSC-Derived Mutated hNPCs with Mitoxantrone Drugs and miRNAs.}, journal = {Pharmaceutics}, volume = {17}, number = {4}, pages = {}, doi = {10.3390/pharmaceutics17040410}, pmid = {40284406}, issn = {1999-4923}, support = {5/4-5/3/9/DHR/Neuro/2021-NCD-1//Indian Council of Medical Research/ ; }, abstract = {Background/Objectives: TDP-43 mutation-driven Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is one of the most prominent forms (approximately 97%) in cases of sporadic ALS. Dysfunctional autophagy and lysosomal function are the prime mechanisms behind ALS. Mitoxantrone (Mito), a synthetic doxorubicin analog, is an inhibitor of DNA and RNA synthesis/repair via intercalating with nitrogenous bases and inhibiting topoisomerase II. The therapeutic potential of miRNAs associated with disease conditions has also been reported. This study explores the therapeutic potential of Mito along with miRNAs against mutated TDP-43 protein-induced proteinopathy in human-induced pluripotent stem cell (hiPSC)-derived human neural progenitor cells (hNPCs). Methods: HiPSCs mutated for TDP-43 were differentiated into hNPCs and used to explore the therapeutic potential of Mito at a concentration of 1 μM for 24 h (the identified non-cytotoxic dose). The therapeutic effects of Mito on miRNA expression and various cellular parameters such as mitochondrial dynamics, autophagy, and stress granules were assessed using the high-throughput Open Array technique, immunocytochemistry, flow cytometry, immunoblotting, and mitochondrial bioenergetic assay. Results: Mutated TDP-43 protein accumulation causes stress granule formation (G3BP1), mitochondrial bioenergetic dysfunction, SOD1 accumulation, hyperactivated autophagy, and ER stress in hNPCs. The mutated hNPCs also show dysregulation in six miRNAs (miR-543, miR-34a, miR-200c, miR-22, miR-29b, and miR-29c) in mutated hNPCs. A significant restoration of TDP-43 mutation-induced alterations could be witnessed upon the exposure of mutated hNPCs to Mito. Conclusions: Our study indicates that miR-543, miR-29b, miR-22, miR-200c, and miR-34a have antisense therapeutic potential alone and in combination with Mitoxantrone.}, }
@article {pmid40284160, year = {2025}, author = {Fernandez-Pombo, A and Izquierdo, AG and Canton-Blanco, A and Garcia-Sobrino, T and Hervás, D and Martínez-Olmos, MA and Pardo, J and Crujeiras, AB}, title = {Blood DNA Methylation in Nuclear and Mitochondrial Sequences Links to Malnutrition and Poor Prognosis in ALS: A Longitudinal Study.}, journal = {Nutrients}, volume = {17}, number = {8}, pages = {}, doi = {10.3390/nu17081295}, pmid = {40284160}, issn = {2072-6643}, support = {CPII22/00008//Instituto de Salud Carlos III/ ; CIBEROBN//Instituto de Salud Carlos III/ ; IN607B-20240301//Xunta de Galicia/ ; CPII22/00008//Instituto de Salud Carlos III/ ; JR23/00042//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *DNA Methylation ; *Amyotrophic Lateral Sclerosis/genetics/complications/blood/mortality ; Male ; Female ; Middle Aged ; *Malnutrition/genetics/blood/complications ; Longitudinal Studies ; Aged ; Prognosis ; Disease Progression ; Nutritional Status ; Biomarkers/blood ; *DNA, Mitochondrial/blood/genetics ; Oxidative Stress ; Epigenesis, Genetic ; }, abstract = {Background: Malnutrition in amyotrophic lateral sclerosis (ALS) is associated with disease severity, and epigenetic regulation may be involved. The aim of this study was to assess the methylation levels of specific DNA sequences from the nuclear and mitochondrial genomes in a population with ALS to elucidate their relationship with nutritional status and the evolution of the disease. Methods: Patients with ALS were evaluated between 2013 and 2021 (n = 66). They were categorized according to their nutritional status, using the Global Leadership Initiative on Malnutrition (GLIM) criteria, and disease progression, using the ALS Functional Rating (ALSFRS-R) Scale. DNA samples were extracted from leukocytes at the time of diagnosis for analysis of DNA methylation levels of markers of oxidative stress, mitochondrial function and global methylation (D-loop, GSTP1, and LINE-1). Results: According to the GLIM criteria, 29 (43.9%) patients had malnutrition (22.7%-moderate; 21.2%-severe), which was positively correlated with ALS disease progression (r = 0.414; p < 0.01) and death (r = 0.687; p < 0.01). Mortality occurred in 43.9% of the patients (median time to death, 18.7 (1.7-82.7) months). A significant association was observed between DNA methylation levels of the D-loop, GSTP1, and the CpG1 site of LINE-1 and malnutrition, disease progression at diagnosis, and death. The D-loop was the best predictor of malnutrition (AUC, 0.79; p < 0.01), disease progression (AUC, 0.70; p < 0.01), and mortality (AUC, 0.71; p < 0.01). Conclusions: This study revealed, for the first time, the early detection of D-loop methylation levels as a potential biomarker of nutritional status in patients with ALS, which may be useful for personalized nutritional management aimed at counteracting disease progression.}, }
@article {pmid40284157, year = {2025}, author = {Sousa-Catita, D and Mascarenhas, P and Oliveira, C and Grunho, M and Santos, CA and Cabrita, J and Correia, P and Fonseca, J}, title = {Nutrition and Survival of 150 Endoscopic Gastrostomy-Fed Patients with Amyotrophic Lateral Sclerosis.}, journal = {Nutrients}, volume = {17}, number = {8}, pages = {}, doi = {10.3390/nu17081292}, pmid = {40284157}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/therapy/complications ; *Gastrostomy/methods/mortality ; Male ; Female ; Aged ; *Enteral Nutrition/methods/mortality ; *Nutritional Status ; Middle Aged ; Kaplan-Meier Estimate ; Aged, 80 and over ; }, abstract = {Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and paralysis. Treatment focuses on symptom management, using medication, physiotherapy, and nutritional support. In this context, endoscopic gastrostomy (PEG) can provide adequate feeding, hopefully improving nutrition and preventing complications. Methods: We studied ALS patients undergoing PEG over three months post-procedure, using anthropometry ((BMI)-body mass index; (MUAC)-mid-upper arm circumference; (TSF)-tricipital skinfold; (MAMC)-mid-arm muscle circumference) and laboratory data (Albumin; Transferrin; total cholesterol and hemoglobin), evaluating survival, complications, and nutritional/clinical status. Statistical analysis included Kaplan-Meier survival estimation and Cox regression to assess nutritional markers associated with survival. Results: 150 ALS patients underwent gastrostomy, mostly older adults (mean age: 66.1 years; median: 67). Mean survival was 527 [95% CI: 432-622] days, median 318 [95% CI: 236-400]. ALS bulbar subtype, MUAC and MAMC positively impacted PEG-feeding survival time (p < 0.05, Wald test). During the first three months of PEG feeding, each unit increase (cm) in MUAC and MAMC lowered death risk by 10% and 11%, respectively, highlighting the importance of nutrition care for survival. The bulbar subtype showed higher PEG feeding survival, with a 55.3% lower death hazard than the spinal subtype. There were no major PEG complications. Conclusions: ALS patients present a high risk of malnutrition. Patients that improved MAMC and MUAC in the first three PEG-fed months presented longer survival. Early PEG nutrition, even when some oral feeding is still possible, may reinforce the preventative role of enteral feeding in maintaining nutrition and potentially improving survival.}, }
@article {pmid40283960, year = {2025}, author = {Salomon-Zimri, S and Kerem, N and Linares, GR and Russek-Blum, N and Ichida, JK and Tracik, F}, title = {Elucidating the Synergistic Effect of the PrimeC Combination for Amyotrophic Lateral Sclerosis in Human Induced Pluripotent Stem Cell-Derived Motor Neurons and Mouse Models.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {4}, pages = {}, doi = {10.3390/ph18040524}, pmid = {40283960}, issn = {1424-8247}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the involvement of multiple pathways and mechanisms. The complexity of its pathophysiology is reflected in the diverse hypotheses relating to its underlying causes. Given this intricate interplay of processes, a combination therapy approach offers a promising strategy. Combination therapies have demonstrated significant success in treating complex diseases, where they aim to achieve synergistic therapeutic effects and reduce drug dosage. PrimeC is an oral combination treatment composed of a patented novel formulation consisting of specific and unique doses of two well-characterized drugs (ciprofloxacin and celecoxib). It aims to synergistically inhibit the progression of ALS by addressing key elements of its pathophysiology. Objectives: Demonstrating the synergistic effect of the PrimeC combination compared to each of its individual components, celecoxib and ciprofloxacin, and assessing its ability to improve the drug concentration profile and efficacy. Methods: The efficacy of the PrimeC combination was assessed in a survival assay using human induced pluripotent stem cell (iPSC)-derived motor neurons. Additionally, a drug profiling study was conducted, measuring drug levels in the brain and serum of C57BL mice treated with a single compound versus the combination. Results: Motor neurons modeling ALS treated with the PrimeC combination exhibited better survival rates compared to treatment with either individual compound alone. The enhanced efficacy of the combination was further supported by a drug concentration profiling study in rodents, demonstrating that the PrimeC combination resulted in increased ciprofloxacin concentrations in both brain tissue and serum-highlighting the optimized interaction and synergistic potential of its two comprising agents. Conclusions: Our findings support the potential of combination therapy as an effective strategy for ALS treatment. Specifically, the PrimeC combination demonstrated promising therapeutic effects, providing a strong rationale for its ongoing development as a targeted treatment for ALS.}, }
@article {pmid40283933, year = {2025}, author = {Martín-Ruiz, J and Maset-Roig, R and Caplliure-Llopis, J and Villarón-Casales, C and Alarcón-Jiménez, J and de Bernardo, N and Proaño, B and Menargues-Ramírez, R and Selvi-Sabater, P and de la Rubia-Ortí, JE}, title = {Enhanced Acute Muscle Activation in ALS Patients Following Liposomal Curcumin, Resveratrol, and Dutasteride Administration.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {4}, pages = {}, doi = {10.3390/ph18040497}, pmid = {40283933}, issn = {1424-8247}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of electrical activity and motor control at the muscular level. Therapeutic alternatives, such as the polyphenolic antioxidants curcumin and resveratrol in liposome form, or the drug dutasteride, could be effective for muscular activity. Objective: To measure the acute change in electrical muscle activation after administration of a combination of curcumin in liposomal form, resveratrol, and dutasteride in patients with ALS. Materials and methods: Patients with bulbar and spinal ALS were selected and randomly distributed into an intervention group (IG), which received an oral combination of curcumin in liposomal form/resveratrol[®] and dutasteride for 2 months, and a control group (CG), which received a placebo. Electrical activity to determine basal muscle activation and fasciculations was measured before and after the intervention using surface electromyography of the biceps brachii (BB), triceps brachii (TB), rectus femoris (RF), and tibialis anterior (TA). Within comparisons of pre and post-muscular variations in each group were conducted. Results: Electrical basal activity increased only for the IG in the right (p = 0.05; g = -0.45) and left (p = 0.004; g = -0.74) hemibody muscles and also presented less variation among them after treatment in the IG. For fasciculations, there was an increase in the total activation of the upper muscles in the IG (p = 0.017; g = -0.86) and for the lower muscles in the CG (p = 0.037; g = -0.68). The pattern of muscle activation remained constant in the IG but experienced variations in the CG.}, }
@article {pmid40283578, year = {2025}, author = {Mantle, D and Hargreaves, I}, title = {Coenzyme Q10 and the Blood-Brain Barrier: An Overview.}, journal = {Journal of clinical medicine}, volume = {14}, number = {8}, pages = {}, doi = {10.3390/jcm14082748}, pmid = {40283578}, issn = {2077-0383}, abstract = {Mitochondrial dysfunction is a common factor known to be involved in the pathogenesis of a number of neurological disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Given the importance of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, and the deficiency of CoQ10 reported in such neurological disorders, there is a rationale for investigating the potential therapeutic role of supplementary CoQ10. However, while there is evidence for the efficacy of CoQ10 supplementation in animal models of the above disorders, randomised controlled clinical trials supplementing CoQ10 in PD, AD, or ALS have had disappointing outcomes. This in turn may be a reflection of the current uncertainty as to whether CoQ10 can access the blood-brain barrier in human subjects. In an attempt to further elucidate the disparity in outcomes of such preclinical and clinical studies, in this article we have reviewed evidence from the peer-reviewed literature to establish the ability of CoQ10 to access the brain via the BBB.}, }
@article {pmid40283201, year = {2025}, author = {González-Sánchez, M and Ramírez-Expósito, MJ and Martínez-Martos, JM}, title = {Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/life15040647}, pmid = {40283201}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2-4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care-integrating physical therapy, respiratory support, nutritional management, and cognitive assessments-is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.}, }
@article {pmid40282367, year = {2025}, author = {Watanabe, Y and Nakagawa, T and Nakagawa, M and Nakayama, K}, title = {The Molecular Intersection of NEK1, C21ORF2, Cyclin F, and VCP in ALS Pathogenesis.}, journal = {Genes}, volume = {16}, number = {4}, pages = {}, doi = {10.3390/genes16040407}, pmid = {40282367}, issn = {2073-4425}, support = {23K06367//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *NIMA-Related Kinase 1/genetics/metabolism ; *Valosin Containing Protein/genetics/metabolism ; *Cyclins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Animals ; DNA Damage ; Mutation ; DNA Repair ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2 lead to the stabilization of NEK1, while cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention.}, }
@article {pmid40282285, year = {2025}, author = {Hohman, G and Watson, A and Eldeeb, MA}, title = {A Novel Approach to Relocate Misplaced Proteins in Cells.}, journal = {Biology}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/biology14040420}, pmid = {40282285}, issn = {2079-7737}, abstract = {Proper cellular function hinges on appropriate subcellular protein localization. When cellular proteins become mislocalized, they can accumulate, cause cellular damage, and disrupt many biochemical and cellular processes. Notably, mislocalized protein accumulation and the resulting cytotoxic effects are salient features of neurodegenerative diseases including Alzheimer's, Parkinson's disease, and ALS. The detrimental cellular consequences of mislocalized proteins accumulation make it crucial to develop techniques and approaches that counteract this malfunction. Remarkably, a recent study by Ng et al. introduced targeted relocalization-activating molecules (TRAMs) as a novel molecular tool for relocalizing endogenous target proteins to counteract disease-associated mislocalized proteins. The authors developed a quantitative single-cell analysis to evaluate the strength and relocalization capability of TRAMs by coupling a target protein and a shuttle protein. Herein, we briefly highlight and discuss the potential molecular implications for targeted protein relocalization as an effective approach for correcting mislocalized proteins.}, }
@article {pmid40282131, year = {2025}, author = {Monteiro, A and Ali, AM and Laranjeira, C}, title = {Lived Experiences of Physiotherapists in Caring for People with Advanced Amyotrophic Lateral Sclerosis in Portugal: A Phenomenological Study.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/bs15040510}, pmid = {40282131}, issn = {2076-328X}, support = {(UIDB/05704/2020 and UIDP/05704/2020)-and under the Scientific Employment Stimu-lus-Institutional Call (https://doi.org/10.54499/CEECINST/00051/2018/CP1566/CT0012, accessed on 1 March 2025).//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a disease that has a multidimensional impact on a person's life, with symptoms associated with a significant loss of autonomy. Specialized palliative care (PC) should be provided early and throughout the course of the disease. Indeed, physiotherapists should be understood as integral members of the multidisciplinary team in PC, in the care and improvement of the quality of life of these people. This study aimed to describe the lived experience of physiotherapists in the context of intervention in people with advanced ALS and their families. Descriptive phenomenology was employed as a framework for conducting semi-structured interviews to reveal experiences. Sixteen physiotherapists who performed interventions on at least one person with advanced ALS in the last 2 years were included in the study. The study involved conducting semi-structured individual interviews, through the Zoom[®] videoconferencing platform (version 6.4.3). Data were analyzed according to Giorgi's five-stage approach and managed using webQDA software (Version 3.0, University of Aveiro, Aveiro, Portugal). The COREQ checklist was applied in the study. Participants were mostly female (n = 12) and aged between 26 and 55 years (M = 36.81; SD = 6.75). Four constituents were identified: (1) undulating course of a complex disease; (2) barriers to person-centered care; (3) enablers of person-centered care; (4) transition between curative and palliative care. The findings illustrate the multidimensional impact of the disease trajectory on the person and their family. This study highlights the need to invest in specialized training for physiotherapists, contributing to a person-centered PC practice with an impact on promoting comfort and quality of life.}, }
@article {pmid40281300, year = {2025}, author = {Upadhayay, S and Soni, D and Dhureja, M and Temgire, P and Kumar, V and Arthur, R and Kumar, P}, title = {Role of Fibroblast Growth Factors in Neurological Disorders: Insight into Therapeutic Approaches and Molecular Mechanisms.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40281300}, issn = {1559-1182}, abstract = {In the last few decades, the incidence and progression of neurological disorders have consistently increased, which mainly occur due to environmental pollution, genetic abnormalities, and modern lifestyles. Several case reports suggested that these factors enhanced oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, leading to neurological disease. The pathophysiology of neurological disorders is still not understood, mainly due to the diversity within affected populations. Existing treatment options primarily provide symptomatic relief but frequently come with considerable side effects, including depression, anxiety, and restlessness. Fibroblast growth factors (FGFs) are key signalling molecules regulating various cellular functions, including cell proliferation, differentiation, electrical excitability, and injury responses. Hence, several investigations claimed a relationship between FGFs and neurological disorders, and their findings indicated that they could be used as therapeutic targets for neurological disorders. The FGFs are reported to activate various signalling pathways, including Ras/MAPK/PI3k/Akt, and downregulate the GSK-3β/NF-κB pathways responsible for anti-oxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, researchers are interested in developing novel treatment options for neurological disorders. The emergence of unreported FGFs contributes to our understanding of their involvement in these conditions and encourages further exploration of innovative therapeutic approaches. All the data were obtained from published articles using PubMed, Web of Science, and Scopus databases using the search terms Fibroblast Growth Factor, PD, HD, AD, ALS, signalling pathways, and neurological disorders.}, }
@article {pmid40281113, year = {2025}, author = {Sasaki, D and Tenda, M and Sohma, Y}, title = {Semi-synthesis of TDP-43 reveals the effects of phosphorylation in N-terminal domain on self-association.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {125}, pmid = {40281113}, issn = {2399-3669}, support = {JP21H02602, JP24K02153, JP24H01787, JP24K09344//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, abstract = {TDP-43, a nucleocytoplasmic shuttle protein consisting of 414 residues, forms self-association in the nucleus for physiological gene regulation, while aggregation into amyloid (consisting of aberrant β-sheets) in the cytoplasm causes neurodegenerative diseases such as amyotrophic lateral sclerosis. Post-translational phosphorylation of TDP-43 alters the self-association properties, which affects both the physiological function in the nucleus and the amyloidogenic potential in the cytoplasm, thereby impacting upon disease progression. However, insight into the role of per-residue phosphorylation in the self-association remains limited due to the difficulty in obtaining site-specifically phosphorylated TDP-43. Here, we demonstrate semi-synthesis of full-length TDP-43 that is uniformly phosphorylated at the 48th serine residue (designated as TDP1-414[pS48]). The synthetic scheme consisting of native chemical ligation followed by His-tag affinity chromatography efficiently gave TDP1-414(pS48) with a high purity. Interestingly, unlike non-phosphorylated TDP-43, the phosphorylated TDP-43 was found to have weak self-association property and to form aggregates that were not typical amyloid fibrils. Furthermore, chemical synthesis and three-dimensional structure analysis of the N-terminal domain (NTD, corresponding to TDP1-80) suggested that the phosphate ion at Ser48 weakens the inter-NTD interaction by inducing electrostatic repulsion. It significantly advances understanding of the pathological mechanisms involved in the post-translational modifications of TDP-43 associated with the neurodegenerative diseases.}, }
@article {pmid40280271, year = {2025}, author = {Kopalli, SR and Behl, T and Baldaniya, L and Ballal, S and Joshi, KK and Arya, R and Chaturvedi, B and Chauhan, AS and Verma, R and Patel, M and Jain, SK and Wal, A and Gulati, M and Koppula, S}, title = {Neuroadaptation in neurodegenerative diseases: compensatory mechanisms and therapeutic approaches.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {}, number = {}, pages = {111375}, doi = {10.1016/j.pnpbp.2025.111375}, pmid = {40280271}, issn = {1878-4216}, abstract = {Progressive neuronal loss is a hallmark of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and Amyotrophic Lateral Sclerosis (ALS), which cause cognitive and motor impairment. Delaying the onset and course of symptoms is largely dependent on neuroadaptation, the brain's ability to restructure in response to damage. The molecular, cellular, and systemic processes that underlie neuroadaptation are examined in this study. These mechanisms include gliosis, neurogenesis, synaptic plasticity, and changes in neurotrophic factors. Axonal sprouting, dendritic remodelling, and compensatory alterations in neurotransmitter systems are important adaptations observed in NDDs; nevertheless, these processes may shift to maladaptive plasticity, which would aid in the advancement of the illness. Amyloid and tau pathology-induced synaptic alterations in Alzheimer's disease emphasize compensatory network reconfiguration. Dopamine depletion causes a major remodelling of the basal ganglia in Parkinson's disease, and non-dopaminergic systems compensate. Both ALS and Huntington's disease rely on motor circuit rearrangement and transcriptional dysregulation to slow down functional deterioration. Neuroadaptation is, however, constrained by oxidative stress, compromised autophagy, and neuroinflammation, particularly in elderly populations. The goal of emerging therapy strategies is to improve neuroadaptation by pharmacologically modifying neurotrophic factors, neuroinflammation, and synaptic plasticity. Neurostimulation, cognitive training, and physical rehabilitation are instances of non-pharmacological therapies that support neuroplasticity. Restoring compensating systems may be possible with the use of stem cell techniques and new gene treatments. The goal of future research is to combine biomarkers and individualized medicines to maximize neuroadaptive responses and decrease the course of illness. In order to reduce neurodegeneration and enhance patient outcomes, this review highlights the dual function of neuroadaptation in NDDs and its potential as a therapeutic target.}, }
@article {pmid40280150, year = {2025}, author = {Singer-Clark, T and Hou, X and Card, NS and Wairagkar, M and Iacobacci, C and Peracha, H and Hochberg, LR and Stavisky, S and Brandman, D}, title = {Speech motor cortex enables BCI cursor control and click.}, journal = {Journal of neural engineering}, volume = {}, number = {}, pages = {}, doi = {10.1088/1741-2552/add0e5}, pmid = {40280150}, issn = {1741-2552}, abstract = {Decoding neural activity from ventral (speech) motor cortex is known to enable high-performance speech brain-computer interface (BCI) control. It was previously unknown whether this brain area could also enable computer control via neural cursor and click, as is typically associated with dorsal (arm and hand) motor cortex. Approach. We recruited a clinical trial participant with ALS and implanted intracortical microelectrode arrays in ventral precentral gyrus (vPCG), which the participant used to operate a speech BCI in a prior study. We developed a cursor BCI driven by the participant's vPCG neural activity, and evaluated performance on a series of target selection tasks. Main results. The reported vPCG cursor BCI enabled rapidly-calibrating (40 seconds), accurate (2.90 bits per second) cursor control and click. The participant also used the BCI to control his own personal computer independently. Significance. These results suggest that placing electrodes in vPCG to optimize for speech decoding may also be a viable strategy for building a multi-modal BCI which enables both speech-based communication and computer control via cursor and click. (BrainGate2 ClinicalTrials.gov ID NCT00912041).}, }
@article {pmid40279947, year = {2025}, author = {de Carvalho, M and Oliveira Santos, M and Swash, M}, title = {Subclinical involvement of small hand muscles in early amyotrophic lateral sclerosis: Selective susceptibility leads to 'split hand' phenomenon.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {173-177}, doi = {10.1016/j.clinph.2025.04.007}, pmid = {40279947}, issn = {1872-8952}, abstract = {OBJECTIVES: Split-hand phenomenon is common in patients with amyotrophic lateral sclerosis (ALS), but it is unknown if first dorsal interosseous (FDI) and abductor pollicis brevis (ABP) are affected earlier than abductor digiti minimi (ADM). We aimed to address this issue.<br><br>METHODS: One clinically normal hand from ALS patients was investigated, including needle EMG of the FDI, motor amplitude, distal latency, F-waves, neurophysiological index (NI) and split-hand index (SHI). Hands were categorised as G1 (normal FDI) and G2 (FDI with neurogenic changes). In patients who agreed EMG of the 3 muscles was done. A subset of G1 patients underwent a second evaluation 4-5&#xa0;months later.<br><br>RESULTS: We studied 133 patients; EMG of the 3 muscles was done in 77 patients. There was no evidence for an earlier loss of motor units in FDI/ABP. In G2 patients, CMAP amplitude and NI were significantly lower (p&#xa0;<&#xa0;0.001), but ADM changes were minor. Reassessment of G1 patients confirmed significant SHI, and amplitude and NI decrease in all muscles, but F-waves frequency remained stable in ADM.<br><br>CONCLUSIONS: Loss of motor units in the 3 hand muscles began in parallel, but ADM spinal motoneurons showed stronger resistance to degeneration.<br><br>SIGNIFICANCE: Dysfunction of intrinsic spinal circuits can influence split-hand phenomenon.}, }
@article {pmid40279084, year = {2025}, author = {Singh, P and Borkar, M and Doshi, G}, title = {Network pharmacology approach to unravel the neuroprotective potential of natural products: a narrative review.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {40279084}, issn = {1573-501X}, abstract = {Aging is a slow and irreversible biological process leading to decreased cell and tissue functions with higher risks of multiple age-related diseases, including neurodegenerative diseases. It is widely accepted that aging represents the leading risk factor for neurodegeneration. The pathogenesis of these diseases involves complex interactions of genetic mutations, environmental factors, oxidative stress, neuroinflammation, and mitochondrial dysfunction, which complicate treatment with traditional mono-targeted therapies. Network pharmacology can help identify potential gene or protein targets related to neurodegenerative diseases. Integrating advanced molecular profiling technologies and computer-aided drug design further enhances the potential of network pharmacology, enabling the identification of biomarkers and therapeutic targets, thus paving the way for precision medicine in neurodegenerative diseases. This review article delves into the application of network pharmacology in understanding and treating neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinal muscular atrophy. Overall, this article emphasizes the importance of addressing aging as a central factor in developing effective disease-modifying therapies, highlighting how network pharmacology can unravel the complex biological networks associated with aging and pave the way for personalized medical strategies.}, }
@article {pmid40278411, year = {2025}, author = {Di Sarno, A and Romano, F and Arianna, R and Serpico, D and Lavorgna, M and Savastano, S and Colao, A and Di Somma, C}, title = {Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View.}, journal = {Metabolites}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/metabo15040282}, pmid = {40278411}, issn = {2218-1989}, abstract = {Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.}, }
@article {pmid40277369, year = {2025}, author = {Kyheng, M and Babykina, G and Duhamel, A}, title = {Joint Latent Class Models: A Tutorial on Practical Applications in Clinical Research.}, journal = {Statistics in medicine}, volume = {44}, number = {8-9}, pages = {e70047}, doi = {10.1002/sim.70047}, pmid = {40277369}, issn = {1097-0258}, mesh = {Humans ; *Latent Class Analysis ; Software ; Longitudinal Studies ; Disease Progression ; *Models, Statistical ; *Biomedical Research/methods ; Linear Models ; Data Interpretation, Statistical ; Survival Analysis ; Computer Simulation ; }, abstract = {Joint latent class model is a statistical approach allowing to simultaneously account for two outcomes related to disease progression: A longitudinal measure (for example a biomarker) and time-to-event, in the context of a heterogeneous population. Within this approach, the linear mixed model, describing the longitudinal measure, is connected to the survival model, describing the risk of event occurrence, via a model for latent classes, describing an unobserved population heterogeneity; thus, the behavior of the two outcomes is assumed to be specific to each latent class. The theoretical properties of the model are established and the model is implemented in software. However, its complexity makes it difficult to manipulate by clinicians. In this paper, we propose a detailed tutorial for clinicians and applied statisticians on how to specify the model in R software in order to respond to concrete clinical questions, how to explore, manipulate, interpret the provided results. The tutorial is based on a real clinical dataset; for each clinical question the mathematical model specification and the R script for implementation are provided, and the estimation results and goodness-of-fit measures are detailed and interpreted.}, }
@article {pmid40277009, year = {2025}, author = {Rohrbaugh, MK and Houseman, G and Cunningham, A and Dobak, S and Ilieva, H and Kreher, M}, title = {The Impact of Cognitive Impairment on Advance Care Planning and Healthcare Utilization in People With ALS.}, journal = {The American journal of hospice &amp; palliative care}, volume = {}, number = {}, pages = {10499091251337464}, doi = {10.1177/10499091251337464}, pmid = {40277009}, issn = {1938-2715}, abstract = {ObjectiveHalf of people with amyotrophic lateral sclerosis (PALS) develop cognitive impairment and/or behavioral changes, which may affect decision-making ability and participation in advance care planning (ACP) discussions. We aimed to determine the impact cognitive impairment, as measured by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), has on PALS' ACP discussions and healthcare utilization.MethodsPALS from a retrospective chart review were categorized into 2 groups: cognitively intact or cognitively impaired (ALS Specific Score < 77, ALS Nonspecific Score < 24, ECAS Total Score < 105, and/or ECAS Behavior or Psychosis Score 1+). Documented advance directives (AD); ACP discussions; and rates of percutaneous endoscopic gastrostomy (PEG) placement, tracheostomy placement, hospitalization within 2 weeks of death, death in hospital, and hospice utilization were recorded. Late disease stage was defined as ALS Functional Rating Scale-Revised (ALSFRS-R) score ≤ 38. Group comparisons were completed using chi-square tests, Fisher's exact test, and independent samples t-tests with P < .05 significance.ResultsThirty-three (47.1%) of 70 PALS met ECAS criteria for cognitive impairment. Rates of AD for PEG placement, AD for tracheostomy placement, hospitalization within 2 weeks of death, death in hospital, and hospice enrollment were not significantly different between groups (P = .41, .62, .32, .30, .06, respectively) despite ALSFRS-R score ≥/< 38 (all P > .05). Conclusions: ACP discussions and healthcare utilization were not affected by cognitive impairment despite disease stage. It is unknown if cognitive impairment affects healthcare decision-making processes for PALS/families. Further research examining the effect of various provider communication strategies on outcomes is needed.}, }
@article {pmid40276954, year = {2025}, author = {Manini, A and Vasta, R and Brusati, A and Scheveger, F and Peverelli, S and Maranzano, A and Doretti, A and Gentile, F and Colombo, E and Brunetti, M and Moglia, C and Canosa, A and Manera, U and Grassano, M and Gentilini, D and Messina, S and Verde, F and Morelli, C and Landers, JE and Traynor, BJ and Chiò, A and Silani, V and Calvo, A and Ratti, A and Ticozzi, N}, title = {KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70059}, pmid = {40276954}, issn = {2328-9503}, support = {//Aldo Ravelli Center for Neurotechnology/ ; /AG/NIA NIH HHS/United States ; //Intramural Research Program of the National Institutes of Health/ ; 2018-12367768//Italian Ministry of Health/ ; PNC-E3-2022-23683266//Italian Ministry of Health/ ; RF-2021-12374238//Italian Ministry of Health/ ; //Dept. of Pathophysiology and Transplantation, Universit&#xe0; degli Studi di Milano/ ; //Italian Ministry of Education/ ; //Universit&#xe0; degli Studi di Milano/ ; //Experimental Brain Therapeutics/ ; }, abstract = {This study explored the impact of KIF5A rs113247976 (p.Pro986Leu), a risk allele for amyotrophic lateral sclerosis (ALS), on phenotypic variability in two Italian ALS cohorts (discovery, n = 865; replication, n = 1174). The minor allele (T) frequency was 0.015. No patients were homozygous (TT), allowing comparison between wild type and heterozygous carriers only. Heterozygous carriers showed faster disease progression (ALSFRS-R preslope). Findings were validated across both cohorts. Multiple linear regression identified p.Leu986 and age at onset as ALSFRS-R preslope predictors. In conclusion, heterozygous p.Leu986 in KIF5A is associated with faster ALS progression, supporting its consideration for genetic screening in clinical trials.}, }
@article {pmid40276468, year = {2025}, author = {Zhang, G and Chen, Y and Tang, L and Bai, L and Zhang, H and Liu, H and Fan, D}, title = {Impact of sleep quality on disease progression in early-stage amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1545463}, pmid = {40276468}, issn = {1664-2295}, abstract = {Non-motor symptoms are clinical manifestations of amyotrophic lateral sclerosis (ALS). However, few studies have examined these symptoms in patients with early-stage ALS. We conducted a cross-sectional study to explore non-motor symptoms in 69 patients with ALS within 18 months of disease onset. The Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Hospital Anxiety and Depression Scale (HADS) were used to evaluate sleep quality, daytime sleepiness, and anxiety and depression, respectively. Differences in the abovementioned non-motor symptoms between ALS patients and age-/sex-matched caregivers were examined, and correlations between these symptoms and the clinical features of ALS were analyzed. Compared to caregivers, ALS patients were more likely to report poor sleep [odds ratio (OR) and 95% confidence interval (95% CI) = 2.664, 1.276-5.560; p = 0.009] and excessive daytime sleepiness (EDS) [OR and 95% CI = 5.135, 1.640-16.072; p = 0.005]. The PSQI scores in ALS patients correlated significantly with the disease progression rate [ΔFS = (48-score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, ALSFRS-R)/disease duration] [β(95% CI) = 2.867 (0.397, 5.336), p = 0.024] and plasma neurofilament light chain (NfL) levels [β (95% CI) = 0.041 (0.012, 0.070), p = 0.008). Our results revealed that the patients with early-stage ALS experienced poor sleep quality and daytime sleepiness and suggested that low sleep quality may be related to more rapid disease progression. Confounders were not obvious in the early stage of ALS, and our results suggested that these symptoms may be related to more severe and extensive pathological changes in the central nervous system.}, }
@article {pmid40275673, year = {2025}, author = {Olmstead, AJ and Lee, J and Skrzat, S and Simmons, Z}, title = {Everyday Communication Experiences of Persons With Amyotrophic Lateral Sclerosis and Their Caregivers: Implications for Novel Speech Interventions.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28412}, pmid = {40275673}, issn = {1097-4598}, support = {/NH/NIH HHS/United States ; R01 DC021714/DC/NIDCD NIH HHS/United States ; }, abstract = {INTRODUCTION/AIMS: Speech intelligibility decline is a common in dysarthria secondary to amyotrophic lateral sclerosis (ALS). However, interventions that focus on improving speech may not be able to counteract decline as the disease progresses. Researchers have suggested interventions that help PALS's communication partners tune their speech perception systems to PALS's production. In the current study, we take a first step to establishing the need and enthusiasm for such interventions on the part of PALS and their caregivers (CPALS).<br><br>METHODS: PALS and CPALS recruited from the Greater Philadelphia chapter of the ALS association completed novel questionnaires probing their everyday speech communication and speech intervention experiences. Questions focused especially on changes in communication partners' ability to understand PALS' speech. Both quantitative and qualitative data were recorded.<br><br>RESULTS: PALS (n&#x2009;=&#x2009;21) and CPALS (n&#x2009;=&#x2009;22) reported speech as a primary mode of communication despite declines in intelligibility. However, most also indicated variability in PALS's speech intelligibility depending on the communication partner, indicating that frequent communication partners were better able to understand PALS's speech. Both groups reported interest in interventions supporting speech intelligibility and were most interested in speech interventions that included PALS and CPALS together.<br><br>DISCUSSION: PALS and especially CPALS in our study expressed interest in speech interventions that involved both parties. Thus, there is both a need for and a desire in the community for interactive speech interventions that support intelligibility. Additionally, our findings lend support to clinical approaches targeting frequent communication partners in addition to PALS.}, }
@article {pmid40275359, year = {2025}, author = {Grima, N and Smith, AN and Shepherd, CE and Henden, L and Zaw, T and Carroll, L and Rowe, DB and Kiernan, MC and Blair, IP and Williams, KL}, title = {Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {40}, pmid = {40275359}, issn = {1750-1326}, support = {Ideas Grant 2011120//National Health and Medical Research Council/ ; Investigator Grant 1176913//National Health and Medical Research Council/ ; Angie Cunningham PhD Scholarship and Project Grant-In-Aid Award//FightMND/ ; Discovery Grant//FightMND/ ; Grant-in-Aid//Motor Neurone Disease Research Australia/ ; R28AA012725/AA/NIAAA NIH HHS/United States ; Not applicable//Neuroscience Research Australia/ ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS.<br><br>METHODS: We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (% contribution of a transcript to total gene expression) and alternative splicing, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles.<br><br>RESULTS: Significant gene expression changes were observed in ALS cases for all five brain regions, with the cerebellum demonstrating the largest number of total (>&#x2009;3,000) and unique (60%) differentially expressed genes. Pathway enrichment and predicted activity were largely concordant across brain regions, suggesting that ALS-linked mechanisms, including inflammation, mitochondrial dysfunction and oxidative stress, are also dysregulated in non-motor brain regions. Switches in transcript usage were identified for a small set of genes including increased usage of a POLDIP3 transcript, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26-41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such as the STMN2 cryptic exon which was shown to have a pTDP-43 pathology-specific expression pattern. Finally, ALS patients with stage 4 pTDP-43 pathology demonstrated distinct gene and protein expression changes in the cerebellum.<br><br>CONCLUSIONS: Together our findings highlighted widespread transcriptome alterations in ALS post-mortem brain and showed that, despite the absence of pTDP-43 pathology in the cerebellum, extensive and pTDP-43 pathological stage-specific RNA changes are evident in this brain region.}, }
@article {pmid40273110, year = {2025}, author = {Souza, AA and Silva, STD and Régis, AMP and Aires, DN and Pondofe, KM and Melo, LP and Valentim, RAM and Lindquist, ARR and Macedo, LRD and Ribeiro, TS}, title = {Muscle strengthening in individuals with Amyotrophic Lateral Sclerosis: a systematic review with meta-analyses.}, journal = {PloS one}, volume = {20}, number = {4}, pages = {e0320788}, doi = {10.1371/journal.pone.0320788}, pmid = {40273110}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/rehabilitation/therapy ; *Muscle Strength/physiology ; *Resistance Training/methods ; *Exercise Therapy/methods ; }, abstract = {Despite the observed benefits of properly prescribed exercises for people with Amyotrophic Lateral Sclerosis (ALS), the scarcity of studies and lack of consensus on the effects of muscle-strengthening exercises on this population has a negative impact on their rehabilitation. This study aimed to evaluate the effects of muscle-strengthening interventions in individuals with ALS. This systematic review of intervention studies included clinical trials that performed non-respiratory muscle strengthening in people with ALS compared to non-strengthening interventions, usual care, or placebo. Such studies were obtained from the MEDLINE, EMBASE, Cochrane Library, SPORTDiscus, and Physiotherapy Evidence Database databases, with no language or publication date restrictions. The outcomes considered were peripheral muscle strength, functionality, fatigue, and adverse events. The Physiotherapy Evidence Database scale was used to analyze the risk of bias, while the Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of the evidence. Searches were conducted in October 2023 and eight studies were included, totaling 296 individuals. Seven of the eight studies showed superiority of the experimental intervention over the control, but this was not supported in the meta-analyses. Small sample size and high heterogeneity in the primary studies contributed significantly to the low quality of the evidence. There was no evidence of the superiority of interventions for muscle strengthening compared to interventions not aimed at strengthening, usual care, or placebo in terms of the outcomes analyzed immediately after the intervention. The quality of the evidence ranged from low to very low. Five of the studies evaluated adverse events, without reporting serious events. Interventions for muscle strengthening did not prove to be more effective when compared to the control group in the short term nor seem to produce serious adverse events. The low quality of the evidence indicates the need for studies with greater methodological rigor in this population, to more assertively assess the impacts of this intervention over the short, medium, and long term.}, }
@article {pmid40272376, year = {2025}, author = {Nguyen, THV and Ferron, F and Murakami, K}, title = {Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.5c00153}, pmid = {40272376}, issn = {1554-8937}, abstract = {Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three, classified as Betacoronaviruses, are highly transmissible and have caused severe pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms such as dry cough, fever, and breath shortness, which can progress to acute respiratory failure and death. Beyond respiratory effects, increasing evidence links HCoVs to neurological dysfunction. However, distinguishing direct neural complications from preexisting disorders, particularly in the elderly, remains challenging. This study examines the association between HCoVs and neurodegenerative diseases like Alzheimer disease, Parkinson disease, Lewy body dementia, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological effects of HCoV infections and their differential impact across age groups and sexes. A key aspect of this study is the investigation of the sequence and structural similarities between amyloidogenic and HCoV spike proteins, which can provide insights into potential neuropathomechanisms.}, }
@article {pmid40271431, year = {2025}, author = {Rana, A and Katiyar, A and Arun, A and Berrios, JN and Kumar, G}, title = {Natural sulfur compounds in mental health and neurological disorders: insights from observational and intervention studies.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1534000}, doi = {10.3389/fnut.2025.1534000}, pmid = {40271431}, issn = {2296-861X}, abstract = {Over the years, the global disease burden of neurological disorders (NDs) and mental disorders (MDs) has significantly increased, making them one of the most critical concerns and challenges to human health. In pursuit of novel therapies against MD and ND, there has been a growing focus on nutrition and health. Dietary sulfur, primarily derived from various natural sources, plays a crucial role in numerous physiological processes, including brain function. This review offers an overview of the chemical composition of several natural sources of the sulfur-rich substances such as isothiocyanates, sulforaphane, glutathione, taurine, sulfated polysaccharides, allyl sulfides, and sulfur-containing amino acids, all of which have neuroprotective properties. A multitude of studies have documented that consuming foods that are high in sulfur enhances brain function by improving cognitive parameters and reduces the severity of neuropathology by exhibiting antioxidant and anti-inflammatory properties at the molecular level. In addition, the growing role of natural sulfur compounds in repairing endothelial dysfunction, compromising blood-brain barrier and improving cerebral blood flow, are documented here. Furthermore, this review covers the encouraging results of supplementing sulfur-rich diets in many animal models and clinical investigations, along with their molecular targets in MD, such as schizophrenia, depression, anxiety, bipolar disorder, and autism spectrum disorder, and ND, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). The prospects of natural sulfur compounds show great promise as they have potential applications in nutraceuticals, medicines, and functional foods to enhance brain function and prevent diseases. However, additional research is required to clarify the mechanisms by which it works, enhance its bioavailability, and evaluate its long-term safety for broad use.}, }
@article {pmid40271315, year = {2025}, author = {Honda, N and Watanabe, Y and Honda, H and Uemoto, M and Fukuhara, H and Hanajima, R}, title = {Implications of Mutant SOD1 on RNA Processing and Interferon Responses in Amyotrophic Lateral Sclerosis: Omics Data Analysis.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e81045}, doi = {10.7759/cureus.81045}, pmid = {40271315}, issn = {2168-8184}, abstract = {INTRODUCTION: Cytoplasmic inclusions are observed in motor neurons in amyotrophic lateral sclerosis (ALS) associated with the Cu/Zn superoxide dismutase mutation (mtSOD1). Although these inclusions are a hallmark of the disorder, degeneration is not necessarily initiated in the cytoplasm, nor are these structures the culprit of ALS. The nucleus stores genetic material and acts as the cell's control center, and a small fraction of mtSOD1 is reported to be distributed in the nucleus. We hypothesized that mtSOD1 in the nucleus contributes to motor neuron degeneration.<br><br>METHODS: We explored the roles of mtSOD1 in relation to nuclear proteins, chromosomal DNA, and mRNA expression. An immortalized cell line derived from a transgenic ALS mouse model expressing mtSOD1-L126delTT with a FLAG was used for stable immunoprecipitation of mtSOD1-binding molecules using shotgun proteomics and chromatin immunoprecipitation-sequencing (ChIP-seq). We also examined mRNA expression by silencing whole SOD1 (innate mouse Sod1 and mtSOD1) or mtSOD1 alone and compared these patterns against those in non-silenced counterparts.<br><br>RESULTS: We identified 392 mtSOD1-interacting proteins in the nucleus. Gene ontology (GO) revealed these proteins to be enriched for "mRNA processing." Notably, more than 11% of mtSOD1-interacting proteins were expressed concurrently with previously reported wild-type TAR DNA-binding protein 43 (TDP-43)-interacting proteins. ChIP-seq revealed that mtSOD1-interacting DNA portions showed a preference for zinc finger protein-binding motifs. GO analysis of the ChIP-seq data revealed that "mRNA processing" was again enriched among the genes harboring mtSOD1-binding domains. RNA expression analyses revealed that the presence of mouse Sod1 and mtSOD1 induced the overexpression of molecules related to "type 1 IFN responses."<br><br>CONCLUSIONS: We revealed that mtSOD1 interacted with nuclear proteins and specific DNA segments and that RNA expression was notably altered when mouse Sod1 and mtSOD1 were silenced. These interactions could play a pivotal role in motor neuron degeneration.}, }
@article {pmid40271071, year = {2025}, author = {Luo, H and Wei, S and Fu, S and Han, L}, title = {Role of Achyranthes aspera in neurodegenerative diseases: current evidence and future directions.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1511011}, doi = {10.3389/fphar.2025.1511011}, pmid = {40271071}, issn = {1663-9812}, abstract = {Neurodegenerative diseases are caused by the progressive degeneration of neurons and/or their myelin sheaths, ultimately leading to cognitive and motor dysfunction. Due to their complex pathogenesis and the limited efficacy of therapeutic drugs, these diseases have attracted significant attention. Achyranthes aspera, belongs to family Amaranthaceae, has been extensively used in the traditional and folk medicines for the treatment of various ailments. Modern research has revealed that Achyranthes aspera possesses various pharmacological effects, including cardiocerebrovascular protection, immune regulation, antioxidation, and anti-aging. Furthermore, the neuroprotective effects of Achyranthes aspera have been confirmed by numerous scientific studies. This review focuses on the primary pharmacological effects and mechanisms of Achyranthes aspera in the prevention and treatment of neurodegenerative diseases, as well as their potential application prospects. This review aims to provide insights into the potential clinical applications and research directions of Achyranthes aspera in neurodegenerative diseases.}, }
@article {pmid40268233, year = {2025}, author = {Basak, B and Holzbaur, ELF}, title = {Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis.}, journal = {Journal of molecular biology}, volume = {}, number = {}, pages = {169161}, doi = {10.1016/j.jmb.2025.169161}, pmid = {40268233}, issn = {1089-8638}, abstract = {Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.}, }
@article {pmid40267658, year = {2025}, author = {Orsucci, D and Vista, M and Santorelli, FM}, title = {Conversational AI in neurogenetics. The example of FUS gene.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123511}, doi = {10.1016/j.jns.2025.123511}, pmid = {40267658}, issn = {1878-5883}, }
@article {pmid40267619, year = {2025}, author = {Garnés-Camarena, O and Mahíllo-Fernández, I and Martínez-Ulloa, P and Mandeville, R and Lorenzo, O and Stashuk, DW}, title = {Towards early diagnosis of amyotrophic lateral sclerosis using near fibre EMG.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {114-122}, doi = {10.1016/j.clinph.2025.04.006}, pmid = {40267619}, issn = {1872-8952}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons and diagnosis is usually delayed several months. The continuous denervation and reinnervation associated with ALS are manifest in EMG signals as changes in motor unit potential (MUP) size, temporal dispersion and instability. Near Fibre EMG is a novel method to assess early changes in MUP temporal dispersion and instability using routinely recorded EMG signals in a semi-automated manner.<br><br>METHODS: Near Fibre EMG values from 2318 MUs, retrospectively sampled at the time of ALS diagnosis, from 96 muscles of 15 patients were compared with values from 3954 MUs sampled from 109 muscles of 84 reference subjects.<br><br>RESULTS: 30.1% and 46.1% of ALS MUs had MUPs with increased complexity or instability, respectively, and 17.4% had both. The potential importance and heightened sensitivity of NFEMG was highlighted when analyzing normal-sized motor units; as many as 24% of the normal-sized MUPs actually had significant instability, while 14% had increased complexity, and 7.4% had both.<br><br>CONCLUSIONS: Near Fibre EMG can characterize motor unit electrophysiological status and hence help quantify the degree, and course of denervation and reinnervation.<br><br>SIGNIFICANCE: Near-Fiber EMG offers the potential to facilitate earlier ALS diagnosis, which, as promising therapies become available, can be consequential.}, }
@article {pmid40267236, year = {2025}, author = {Zhong, H and Zhu, J and Liu, S and Zhou, D and Long, Q and Wu, C and Zhao, B and Cheng, C and Yang, Y and Wu, Q and Wu, Y and Li, C and Wang, Z and Wu, J and Guo, X and Zhi, D and Deng, Y and Wu, L}, title = {Linking DNA methylation in brain regions to Alzheimer's disease risk: a Mendelian randomization study.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf053}, pmid = {40267236}, issn = {1460-2083}, support = {//University of Hawai'i Cancer Center/ ; }, abstract = {AIM: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.<br><br>METHODS: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et&#xa0;al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). In our MR analyses, we integrated these mQTLs with single nucleotide polymorphisms (SNP)-ad risk summary statistics derived from 85&#x2009;934&#xa0;ad-related cases and 401&#x2009;577 normal controls.<br><br>RESULTS: Among 62&#x2009;554 cytosine-guanine dinucleotide (CpG) sites, we identified 597 CpG sites (CpGs) significantly associated with ad risk (false discovery rate (FDR)&#x2009;<&#x2009;0.05). Of these, 289 were confirmed through colocalization and summary-based MR (SMR) analyses, including one CpG site in CRBLM, 285 in DLPFC, one in FCTX, two in PONS, and one in TCTX. By integrating gene expression data, we identified 19 CpG sites with consistent associations across methylation levels, expression of eight target genes, and ad risk, including novel regulatory mechanisms involving RITA1's modulation of cg11558705 and PCGF3's regulation of cg10009224.<br><br>CONCLUSION: Our findings highlight brain region-specific DNA methylation as a mediator of genetic risk for ad, offering insights into ad pathogenesis and identifying potential therapeutic targets.}, }
@article {pmid40267187, year = {2025}, author = {Guillaud, L and Garanzini, A and Zakhia, S and De la Fuente, S and Dimitrov, D and Boerner, S and Terenzio, M}, title = {Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.}, journal = {Science advances}, volume = {11}, number = {17}, pages = {eadq6077}, doi = {10.1126/sciadv.adq6077}, pmid = {40267187}, issn = {2375-2548}, mesh = {*Adenosine Triphosphate/metabolism ; Humans ; Animals ; *Protein Aggregation, Pathological/metabolism/pathology ; Mice ; *Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Axons/metabolism ; Viscosity ; Mitochondria/metabolism ; Protein Aggregates ; Parkinson Disease/metabolism/pathology ; DNA-Binding Proteins/metabolism ; Alzheimer Disease/metabolism/pathology ; }, abstract = {Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.}, }
@article {pmid40265300, year = {2025}, author = {Xu, IQ and Guo, L and Xu, J and Setiawan, S and Deng, X and Lo, YL and Chai, JYH and Simmons, Z and Ramasamy, S and Yeo, CJJ}, title = {Predictive Analysis of Amyotrophic Lateral Sclerosis Progression and Mortality in a Clinic Cohort From Singapore.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28416}, pmid = {40265300}, issn = {1097-4598}, support = {C210112024//Agency for Science, Technology and Research/ ; IRNMR21CPGJJ//National Neuroscience Institute/ ; }, abstract = {INTRODUCTION: There is currently no comprehensive Amyotrophic Lateral Sclerosis (ALS) patient database in Singapore comparable to those available in Europe and the United States. We established the Singapore ALS registry (SingALS) to draw meaningful inferences about the ALS population in Singapore through developing statistical and machine learning-based predictive models.<br><br>METHODS: The SingALS registry was established through the retrospective collection of demographic, clinical, and laboratory data from 72 ALS patients at Tan Tock Seng Hospital (TTSH) and combining it with demographic and clinical data from 71 patients at Singapore General Hospital (SGH). The SingALS was compared against international ALS registries. Using comparative studies including survival and temporal feature analysis, we identified key factors influencing ALS survival and developed a machine learning model to predict survival outcomes.<br><br>RESULTS: Compared to Caucasian-dominant registries, such as the German Swabia registry, SingALS patients had longer average survival (50.51 vs. 31.0&#x2009;months), younger age of onset (56.18 vs. 66.6&#x2009;years), and lower bulbar onset prevalence (20.98% vs. 34.10%). Singaporean males had poorer outcomes compared to females, with a hazard ratio (HR) of 3.12 (p&#x2009;=&#x2009;0.008). Patients who died within 24&#x2009;months had an earlier need for being bedbound (p&#x2009;<&#x2009;0.004), percutaneous endoscopic gastrostomy (PEG) insertion (p&#x2009;=&#x2009;0.004) and non-invasive ventilation (NIV) (p&#x2009;<&#x2009;0.001). Machine learning and statistical analysis indicated that a steeper ALSFRS-R slope, higher alkaline phosphatase (ALP), white blood cell (WBC), absolute neutrophil counts, and creatinine levels are associated with worse mortality.<br><br>DISCUSSION: We developed a comprehensive Singaporean ALS registry and identified key factors influencing survival.}, }
@article {pmid40265276, year = {2025}, author = {Mendonça, IP and Peixoto, CA}, title = {The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases.}, journal = {Journal of neurochemistry}, volume = {169}, number = {4}, pages = {e70069}, doi = {10.1111/jnc.70069}, pmid = {40265276}, issn = {1471-4159}, support = {CNPq;#301891/2022-2//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; IAM-PROEP# 005-FIO-22//Instituto Aggeu Magalh&#xe3;es/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism ; *Neuroglia/metabolism/pathology/physiology ; Animals ; *Enteric Nervous System/pathology/metabolism ; }, abstract = {Over the past two decades, a growing number of studies have been conducted on the role of bidirectional communication through the gut-brain axis in the development of neurodegenerative diseases. These studies were driven by the curious fact that all of these diseases present varying degrees of intestinal involvement included in their wide range of symptoms. A population of cells belonging to the ENS, called enteric glial cells (EGCs), appears to actively participate in this communication between the intestine and the brain, but acting in a dualistic manner, sometimes in reactive gliosis releasing inflammatory mediators, sometimes promoting homeostasis and resilience in the face of inflammatory injuries. To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases.}, }
@article {pmid40264898, year = {2024}, author = {Kumar, J and Varela-Ramirez, A and Narayan, M}, title = {Development of novel carbon-based biomedical platforms for intervention in xenotoxicant-induced Parkinson's disease onset.}, journal = {BMEmat}, volume = {2}, number = {4}, pages = {}, pmid = {40264898}, issn = {2751-7446}, abstract = {Chronic exposure to herbicides, weedicides, and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we have investigated whether quinic- and chlorogenic-acid-derived Carbon Quantum Dots (QACQDs and ChACQDs, respectively) protect against a (pesticide) paraquat-insult model of PD. Our results indicated that both types of CQDs intervened in the soluble-to-toxic transformation of the amyloid-forming model protein Hen Egg White Lysozyme (HEWL). Furthermore, QACQDs and ChACQDs demonstrated antioxidant activity while remaining biocompatible in a human neuroblastoma-derived cell line (SH-SY5Y) up to 5 mg/ml and protected the cell line from the environmental neurotoxicant (paraquat). Importantly, both CQDs were found to protect dopaminergic neuronal ablation in a paraquat model of Parkinson's disease using the nematode C. elegans. Our results are significant because both plant-derived organic acids cross the blood-brain barrier, making them attractive for developing CQD architectures. Furthermore, since the synthesis of these CQDs was performed using green chemistry methods from precursor acids that cross the BBB, these engineered bionanomaterial platforms are tantalizing candidates for preventing neurodegenerative disorders associated with exposure to environmental neurotoxicants.}, }
@article {pmid40263468, year = {2025}, author = {Su, Y and Schwartz, M and Fayad, I and García, M and Zavala, MA and Tijerín-Triviño, J and Astigarraga, J and Cruz-Alonso, V and Liu, S and Zhang, X and Chen, S and Ritter, F and Besic, N and d'Aspremont, A and Ciais, P}, title = {Canopy height and biomass distribution across the forests of Iberian Peninsula.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {678}, pmid = {40263468}, issn = {2052-4463}, support = {ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-22-FAI1-0002//Agence Nationale de la Recherche (French National Research Agency)/ ; }, abstract = {Accurate mapping of vegetation canopy height and biomass distribution is essential for effective forest monitoring, climate change mitigation, and sustainable forestry. Here we present high-resolution remote sensing-based canopy height (10 m resolution) and above ground biomass (AGB, 50 m resolution) maps for the forests of the Iberian Peninsula from 2017 to 2021, using a deep learning framework that integrates Sentinel-1, Sentinel-2, and LiDAR data. Two UNET models were developed: one trained on Airborne Laser Scanning (ALS) data (MAE: 1.22 m), while another using Global Ecosystem Dynamics Investigation (GEDI) footprints (MAE: 3.24 m). External validation with 6,308 Spanish National Forest Inventory (NFI) plots (2017-2019) confirmed canopy height reliability, showing MAEs of 2-3 m in tree-covered areas. AGB estimates were obtained through Random Forest models that linked UNET derived height predictions to NFI AGB data, achieves an MAE of ~29 Mg/ha. The creation of high-resolution maps of canopy height and biomass across various forest landscapes in the Iberian Peninsula provides a valuable new tool for environmental researchers, policy makers, and forest management professionals, offering detailed insights that can inform conservation strategies, carbon sequestration efforts, and sustainable forest management practices.}, }
@article {pmid40262868, year = {2025}, author = {Shi, Y and Wu, Z and Cheng, R and Zhang, L and Guo, X and Li, X and Bi, Y}, title = {The Trp-574-Leu mutations together with enhanced metabolism contribute to cross-resistance to ALS inhibiting herbicides in Fimbristylis littoralis.}, journal = {Pesticide biochemistry and physiology}, volume = {210}, number = {}, pages = {106385}, doi = {10.1016/j.pestbp.2025.106385}, pmid = {40262868}, issn = {1095-9939}, abstract = {Fimbristylis littoralis Gaudich., an important weed in Chinese paddy fields, has caused significant yield losses in rice and other crops. Acetolactate synthase (ALS) inhibitors, such as halosulfuron-methyl, are widely used for weed control. This study identified a highly resistant population (R23-1) of F. littoralis to halosulfuron-methyl, with an exceptionally high resistance index (RI) of 3441.66. The resistant mechanisms of F. littoralis to ALS inhibitors have not been reported previously. We employed a comprehensive approach to address this, including whole-plant bioassay, ALS target gene sequencing, molecular docking, synergistic tests with metabolic enzyme inhibitors, glutathione S-transferases (GSTs) activity assays, and cross-resistance testing. The results revealed the first report of a Trp-574-Leu mutation in the ALS gene of the R23-1 population, which significantly increased binding energy, as shown by molecular docking analysis. Synergistic tests demonstrated that the cytochrome P450 monooxygenase (P450) inhibitor piperonyl butoxide (PBO) and the GSTs inhibitor 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) markedly enhanced the sensitivity of the R23-1 population to halosulfuron-methyl, with synergistic ratios of 4.11 and 8.15, respectively, while malathion had no effect. GST activity decreased in both populations after halosulfuron-methyl treatment, with the R23-1 population consistently showing significantly higher levels, peaking on day five. Furthermore, the R23-1 population demonstrated cross-resistance to multiple ALS inhibitors. These findings provide novel insights into the resistance mechanisms of F. littoralis and lay a theoretical foundation for developing effective strategies to mitigate or delay the evolution of resistance.}, }
@article {pmid40262704, year = {2025}, author = {Kim, HB and Ehsan, MF and Alshawabkeh, AN and Kim, JG}, title = {Electrochemical activation of alum sludge for the adsorption of lead (Pb(II)) and arsenic (As): Mechanistic insights and machine learning (ML) analysis.}, journal = {Bioresource technology}, volume = {}, number = {}, pages = {132563}, doi = {10.1016/j.biortech.2025.132563}, pmid = {40262704}, issn = {1873-2976}, abstract = {Alum sludge (AlS) has emerged as an effective adsorbent for anionic contaminants, with traditional activation methods like acid/base treatments and calcination employed to enhance its adsorption capacity. However, these approaches encounter significant drawbacks, including excessive waste generation, structural degradation, and limited efficacy for cationic contaminants. To overcome these challenges, this study proposes electrochemical activation as a sustainable method to enhance alum sludge adsorption performance by generating oxygen-containing functional groups (O-FGs) on its surface. In particular, cathodic activated AlS (E-AlS) leads to the formation of hydroxyl (-OH) and carboxyl (-COOH) groups, which served as key active sites for Pb(II) adsorption through complexation mechanisms. E-AlS effectively removed both Pb(II) and As within 4 h, showcasing its dual functionality for cationic and anionic contaminants. While HCl- and KOH-activated AlS also achieved 100 % Pb(II) removal, they caused substantial aluminum (Al) leaching, exceeding 1,000 mg/L, due to structural instability. In contrast, E-AlS minimized Al leaching, preserved structural integrity, and exhibited a 6.5-fold higher Pb(II) adsorption capacity than raw AlS. X-ray photoelectron spectroscopy (XPS) and machine learning (ML) validated the enhanced adsorption performance of E-AlS. These findings highlight electrochemical activation as a cost-effective and environmentally friendly remediation.}, }
@article {pmid40262277, year = {2025}, author = {Turner, N and Palmer, J and Faull, C and Davidson, S and Turner, MR and Wilson, E}, title = {Tracheostomy ventilation in ALS: healthcare practitioner perspectives on quality of life and implications for decision-making.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2495014}, pmid = {40262277}, issn = {2167-9223}, abstract = {Objectives: This qualitative study aimed to increase understanding of how healthcare practitioners (HCPs) perceive quality of life for people with ALS who use tracheostomy ventilation (TV) and the extent to which such views inform discussions regarding future treatment and care. Methods: A thematic analysis was applied to data derived from online semi-structured interviews with a professionally diverse group of 24 HCPs with experience of supporting people with ALS to use TV. Results: Four main themes relating to TV use emerged: i) Positive benefits; ii) Risks and challenges; iii) Factors influencing HCP perspectives; iv) Concepts informing HCP discussions. HCPs acknowledged that TV has the potential to extend life but were concerned with prolonging a serious decline in physical and cognitive functioning. HCPs tried to identify the 'tipping point' between quantity and quality of life for the individual and their family, taking into account the likelihood of a higher burden of care. HCPs drew on prior experience to assess anticipated quality of life, yet most HCPs in the UK have limited experience of TV for this group. HCPs also drew on principles of person-centered care, patient autonomy and value for money to guide their approach to discussing TV. Conclusions: HCP experience of positive outcomes of TV can foster a more proactive approach to initiating conversations about its potential use. Sharing best practice and improving guidance for HCPs may support early and on-going future care planning and enable people with ALS to make choices which are informed and in their best interests.}, }
@article {pmid40261626, year = {2025}, author = {Lum, JS and Brown, ML and Suters, SC and Yerbury, JJ and McAlary, L}, title = {In-Gel Zymography of Amyotrophic Lateral Sclerosis-Associated Variants of Superoxide Dismutase-1.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2918}, number = {}, pages = {221-228}, pmid = {40261626}, issn = {1940-6029}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Humans ; *Enzyme Assays/methods ; *Electrophoresis, Polyacrylamide Gel/methods ; }, abstract = {In-gel zymography allows the separation of protein via electrophoresis and subsequent measurement of enzymatic activity of enzymes from biological mixtures. The antioxidant enzyme superoxide dismutase 1 (SOD1) is an important cytosolic oxygen radical scavenging enzyme that has been implicated in a range of pathologies, including cancer, metabolic and neurodegenerative diseases, most notably amyotrophic lateral sclerosis (ALS). Here, we describe a method to detect and compare SOD1 activity from both cell and tissue samples. This method can be utilized to compare differences between ALS-associated SOD1 genetic variants and pharmacologically treated biological samples.}, }
@article {pmid40261116, year = {2025}, author = {Shneider, NA and Nesta, AV and Rifai, OM and Yasek, J and Elyaman, W and Aziz-Zaman, S and Lyu, MA and Levy, SHS and Hoover, BN and Vlad, G and Huang, M and Zeng, K and Sadeghi, T and Reddy, A and Flowers, CR and Parmar, S}, title = {Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDoa2400249}, doi = {10.1056/EVIDoa2400249}, pmid = {40261116}, issn = {2766-5526}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *T-Lymphocytes, Regulatory/transplantation ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; Treatment Outcome ; Neurofilament Proteins/blood ; }, abstract = {BACKGROUND: Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS.<br><br>METHODS: Participants with ALS received infusions of a fixed dose (100&#xd7;10[6] cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers.<br><br>RESULTS: Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66&#xb1;1.03 points/month before treatment, -0.41&#xb1;0.45/month during treatment, and -0.60&#xb1;0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1&#x3b4; (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GRO&#x3b1; (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants.<br><br>CONCLUSIONS: This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.}, }
@article {pmid40261114, year = {2025}, author = {Abati, E}, title = {Regulatory T Cell-Based Therapies - A New Piece of the ALS Therapeutic Puzzle?.}, journal = {NEJM evidence}, volume = {4}, number = {5}, pages = {EVIDe2500078}, doi = {10.1056/EVIDe2500078}, pmid = {40261114}, issn = {2766-5526}, }
@article {pmid40260525, year = {2025}, author = {Ganapule, A and Garg, D and Agarwal, A and Gupta, A and Rajan, R and Desai, S and Chandarana, M and Sidharth, S and Tripathi, M and Garg, A and Radhakrishnan, DM and Srivastava, AK}, title = {The Expanding Spectrum of Anti-IgLON5 Disease: A Case Series from an Indian Cohort.}, journal = {Annals of Indian Academy of Neurology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aian.aian_1073_24}, pmid = {40260525}, issn = {0972-2327}, abstract = {Anti-IgLON5 disease is an evolving entity that lies at the confluence of autoimmunity and neurodegeneration. Reports from India remain sparse. In this series, we describe seven Indian patients with anti-IgLON5-related disease. Patients presented across the fifth to eighth decades with a mean duration of illness of 16 months. All had movement disorders, which included gait ataxia, parkinsonism, and chorea. Six patients had sleep disturbances. Five had a frontal dysexecutive dementia phenotype. Two had epilepsy. Bulbar involvement was present in four, and one had amyotrophic lateral sclerosis (ALS)-like features. Magnetic resonance imaging was abnormal in two cases. Positron emission tomography of the brain also contributed to diagnosis. Combination immunotherapies were used in most of the patients, with three showing a sustained response and two deaths reported due to sepsis-related complications. It is important to recognize the increasing spectrum of IgLON5-related disease to enable timely initiation of immunotherapy before marked degeneration occurs.}, }
@article {pmid40260387, year = {2025}, author = {Guo, N and Huang, W and Huang, J and Liu, Y and Zhu, K and Gao, W}, title = {Global research trends in biomarkers, therapeutic targets, and drugs for amyotrophic lateral sclerosis: a bibliometric and visualization analysis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1588968}, pmid = {40260387}, issn = {1663-9812}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, marked by complex pathological mechanisms and a lack of effective treatments. Despite substantial global research efforts, no comprehensive bibliometric analysis has systematically mapped the evolution of ALS biomarkers, therapeutic targets, and pharmacological advancements.<br><br>METHODS: This study, based on 4,250 publications retrieved from the Web of Science Core Collection (2005-2025), employs bibliometric tools such as CiteSpace and VOSviewer to conduct the first multidimensional analysis of global trends in ALS biomarkers, therapeutic targets, and drug research.<br><br>RESULTS: The results revealed contributions from 20,168 authors across 92 countries, with annual publications growing at an average rate of 16.5%. The United States dominated research output, accounting for 34.07% (n=1,448, TLCS=7,100), while the United Kingdom achieved the highest research impact with an average of 68 citations per article. Leading institutions, including the University of Oxford and the University of Milan, consistently produced high-impact studies. Pioneering scholars such as Turner MR and Kiernan MC made significant contributions to advancing therapeutic targets and drug discovery. The interdisciplinary integration of molecular biology and genetics emerged as a core driver of progress in ALS research. Neurofilament light chain (NfL), antisense oligonucleotide (ASO) drugs, transcranial magnetic stimulation (TMS), oxygen free radicals (oxidative stress), and gene therapy have consistently remained central research focuses in the ALS therapeutic field. Looking ahead, stem cell therapy, blood-brain barrier (BBB) penetration technologies, and skeletal muscle targeting are poised to emerge as prominent research directions.<br><br>CONCLUSION: The United States dominates ALS research productivity, whereas the United Kingdom demonstrates superior citation influence. Despite China's substantial publication volume, its limited citation impact underscores the necessity for enhanced methodological rigor and strategic international collaboration. Current research priorities encompass NfL, TMS, and ASO therapies, with emerging innovations in stem cell therapy, BBB penetration technologies and skeletal muscle targeting showing therapeutic promise. Future directions should prioritize biomarker standardization, optimization of drug delivery systems, and Clinical Translation.}, }
@article {pmid40259632, year = {2025}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {In Response to "Homogeneous ALS Cohorts in Terms of Etiology, Onset Type and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection".}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70162}, doi = {10.1111/ene.70162}, pmid = {40259632}, issn = {1468-1331}, }
@article {pmid40259624, year = {2025}, author = {Finsterer, J}, title = {Homogeneous ALS Cohorts in Terms of Etiology, onset type, and Vaccination Status Are Required to Assess the Outcome of Their COVID Infection.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70161}, doi = {10.1111/ene.70161}, pmid = {40259624}, issn = {1468-1331}, }
@article {pmid40258293, year = {2025}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {Simple In-Cell Processing Enables Deep Proteome Analysis of Low-Input Caenorhabditis elegans.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.4c05003}, pmid = {40258293}, issn = {1520-6882}, abstract = {Caenorhabditis elegans is a widely used genetic model organism; however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach that can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LC-MS analysis, we identified over 9400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it to conventional lysis-based methods. Our data suggest superior performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower-input samples, including single worms. Then, we used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD1, a gene associated with amyotrophic lateral sclerosis. Analysis of 8800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics.}, }
@article {pmid40256588, year = {2024}, author = {Ahmady, H and Afrand, M and Motaqi, M and Meftahi, GH}, title = {Utilizing Sertoli Cell Transplantation as a Therapeutic Technique for the Management of Neurodegenerative Diseases.}, journal = {Archives of Razi Institute}, volume = {79}, number = {4}, pages = {701-710}, pmid = {40256588}, issn = {2008-9872}, mesh = {*Neurodegenerative Diseases/therapy ; Humans ; Male ; Animals ; *Sertoli Cells/transplantation ; }, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are defined by aberrant protein accumulation, brain atrophy, and gradual decline of neuronal function. Despite the considerable endeavors devoted to discovering treatments for NDs in recent decades, the demand for efficient therapeutic agents persists. Sertoli cells (SCs) play a crucial role in providing a supportive structure and environment for the development of germ cells. SCs, whether transplanted as xenogeneic or allogeneic cells, present a viable choice for enhancing graft persistence via the release of immunomodulatory and trophic factors, including neurturin (NTN), platelet-derived growth factor, Fas (CD95) ligand (FasL), glial-derived neurotrophic factor, interleukin 1 (IL1), brain-derived neurotrophic factor, interleukin 6 (IL6), transforming growth factors, and vascular growth factor, that protect replaced cells and tissues from the immune system. However, there is currently no cohesive evidence regarding the neuroprotective influence of the transplantation of SCs on NDs. Therefore, this review focuses on assessing stem cells' neuroprotective impact on neurodegenerative diseases in pre-clinical settings and presenting cohesive information. A comprehensive search was conducted between 2000 and 2022. In the identification stage, after a comprehensive search across databases, including Web of Science, Scopus, and PubMed/Medline, 103 papers were obtained. The search conducted in the present study yielded a total of nine relevant papers on the therapeutic effect of the transplantation of SCs on NDs. It was found that the transplantation of SCs exhibits a promising impact on enhancing the symptoms of neurological diseases in rats. The findings highlight the need for multiple standardized pre-clinical trials to find reliable information to confirm the utilization of the transplantation of SCs and the reduction of the symptoms of neurodegenerative diseases.}, }
@article {pmid40255098, year = {2025}, author = {Regnault, R and Kouach, M and Goossens, L and Thuru, X and Bailly, C and Goossens, JF}, title = {HR-MS Analysis of the Covalent Binding of Edaravone to 5-Formylpyrimidine Bases and a DNA Oligonucleotide Containing a 5-Formylcytidine Residue.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {39}, number = {14}, pages = {e10050}, doi = {10.1002/rcm.10050}, pmid = {40255098}, issn = {1097-0231}, support = {//Comit&#xe9; de l'Oise de la Ligue Contre le Cancer/ ; //French Ligue Against Cancer/ ; }, mesh = {Edaravone/chemistry ; *Mass Spectrometry/methods ; *Oligonucleotides/chemistry/metabolism ; *Pyrimidines/chemistry ; *DNA/chemistry ; *Cytidine/chemistry/analogs &amp; derivatives ; Cytosine/analogs &amp; derivatives ; }, abstract = {RATIONALE: Edaravone (EDA) is a radical scavenger and an antioxidant drug approved to treat amyotrophic lateral sclerosis and used as a research tool to explore treatment of neurodegenerative diseases and cancers. It is also a reactive agent, known as PMP (1-phenyl-3-methyl-5-pyrazolone), used for the analysis of polysaccharides composition. EDA can react with sugars and aromatic aldehydes. In this context, we have investigated the reactivity of EDA toward the biologically relevant formylated nucleobases, nucleosides, and an oligonucleotide containing a formylated residue.<br><br>METHODS: The formation of both mono- and bis-adducts between EDA and the formylated nucleobases (5-formyluracil (5fU) and 5-formylcytosine (5fC)) or the corresponding nucleosides 5-fdU and 5-fdC was characterized using high-resolution mass spectrometry (HR-MS). Similarly, the covalent binding of EDA to an 8-mer palindromic oligonucleotide d (TATG[*C]ATA) containing a single 5-fdC residue [*C] under physiological conditions was investigated using mass spectrometry.<br><br>RESULTS: For the first time, EDA is shown to react with formylated pyrimidines. Covalent and stable adducts were identified. EDA was found to react efficiently with the formylated oligonucleotide to generate mono- and bis-adducts. The rate of formation of the mono-adduct was five times higher than that of the bis-adduct. The reaction of EDA with aldehydic DNA modifications such as 5fU/5fC may have important consequences in terms of gene expression.<br><br>CONCLUSIONS: These observations raise implications for an epigenetic contribution to the mechanism of action of EDA. The biological implications of our in&#xa0;vitro results are discussed, notably in the frame of neurodegenerative diseases and cancers.}, }
@article {pmid40254405, year = {2025}, author = {Shevchuk, DV and Tukhvatulin, AI and Dzharullaeva, AS and Berdalina, IA and Zakharova, MN}, title = {Molecular Biomarkers of Neurodegeneration in Amyotrophic Lateral Sclerosis.}, journal = {Biochemistry. Biokhimiia}, volume = {90}, number = {2}, pages = {276-288}, doi = {10.1134/S0006297924604039}, pmid = {40254405}, issn = {1608-3040}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis/pathology/blood ; Biomarkers/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; Amyloid beta-Peptides/metabolism/blood ; Adult ; tau Proteins/metabolism/blood ; Clusterin ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease. However, definitive diagnosis could be delayed by up to 12 months due to the lack of specific and sensitive biomarkers for ALS. In our study, conducted for the first time on a large cohort of ALS patients (n = 100) within the Russian population, we assessed key biomarkers of neurodegenerative pathology, including β-amyloids (Aβ40 and Aβ42) and tau proteins (Tau-total and Tau-p181), as well as other pathogenetically relevant, promising biomarkers such as FGF-21, Kallikrein-6 (KLK-6), NCAM-1, Neurogranin (NRGN), TDP-43, Apolipoprotein E4, Clusterin (Apo J), Complement Factor H, Fetuin-A, α2-Macroglobulin, Apo AI, Apo CIII, Apo E, Complement C3, GDNF, sRAGE, and S100B protein. Significant differences between the ALS patients and the control group were observed for Aβ40 (p = 0.044), Aβ42 (p < 0.001), FGF-21 (p < 0.001), Tau-total (p = 0.001), Tau-p181 (p = 0.014), Clusterin (p < 0.001), Complement C3 (p = 0.001), and S100B (p = 0.024). A significant direct correlation was found between the ALSFRS-R score and concentrations of Aβ40 and Aβ42. Changes in the complement system (Complement C3 and Complement Factor H) were identified, highlighting critical role of neuroinflammatory processes in ALS pathogenesis. Additionally, increased levels of FGF-21 were observed in the patients with the bulbar onset of ALS. Significant increase in the concentration of the chaperone protein clusterin in the patients with rapid disease progression suggests its potential as a prognostic biomarker for motor neuron disease. Furthermore, its role in maintaining proteostasis could provide novel therapeutic targets.}, }
@article {pmid40254295, year = {2025}, author = {Epel, ES and White, KE and Brownell, KD and Rodin, J and Hollis, AL and Diefenbach, MA and Alegria, KE and Fromer, E and Czajkowski, SM and Bacon, SL and Revenson, TA and Ruiz, J and Maibach, E and , }, title = {Transforming Health Psychology and Behavioral Medicine to Address the Climate Crisis: A Call for Strategic Research and Advocacy.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {59}, number = {1}, pages = {}, doi = {10.1093/abm/kaae088}, pmid = {40254295}, issn = {1532-4796}, mesh = {Humans ; *Climate Change ; *Behavioral Medicine ; *Health Behavior ; Social Change ; }, abstract = {OBJECTIVE: The climate crisis poses the largest threat to human health and survival and has been a public health emergency for many years. It is causing harmful consequences for physical and mental health and is amplifying existing health inequities. In this call to action, we highlight the relevance of the health psychology and behavioral medicine communities in addressing the health impacts of climate change.<br><br>METHOD: We identify mitigation and adaptation climate health behaviors and social changes needed that underlie the three essential objectives to address climate change and its associated health consequences: (a) rapid decarbonization, (b) drawdown of atmospheric heat-trapping gases (sequestration), and (c) adap- tation.<br><br>RESULTS: To advance the behavioral and systemic changes necessary to protect health, we propose a 1-2-3 Transformational Model in which the larger field of health psychology and behavioral medicine promotes (1) One Health, human and planetary health by (2) targeting climate health behaviors, and (3) social change across major professional areas, including research, interventions, and education/advo- cacy. We urge the adoption of the social quantum change paradigm, a systems approach to understanding the process of social change, where systemic change is viewed as local to global, and the individual has an influential role.<br><br>DISCUSSION: These shifts in views, priorities, and methods will bolster hope, collective efficacy, and action to support the next generation of health psychology and behavioral medicine profession- als. With these changes, the health psychology and behavioral medicine communities can have a more immediate and meaningful impact on the climate crisis and its associated health consequences.}, }
@article {pmid40254133, year = {2025}, author = {Turner-Ivey, B and Jenkins, DP and Carroll, SL}, title = {Multiple Roles for Neuregulins and their ERBB Receptors in Neurodegenerative Disease Pathogenesis and Therapy.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2025.03.012}, pmid = {40254133}, issn = {1525-2191}, abstract = {The role that neurotrophins such as nerve growth factor play in the pathogenesis of neurodegenerative diseases has long been appreciated. However, the neuregulin (NRG) family of growth factors and/or their ERBB receptors have also been implicated in the pathogenesis of conditions such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In this review, we consider (1) the structural variability of NRG isoforms generated by alternative RNA splicing, the use of multiple promoters and proteolysis and the impact that this structural variability has on neuronal and glial physiology during development and adulthood. We discuss (2) the NRG receptors ERBB2, ERBB3 and ERBB4, how activation of each of these receptors further diversifies NRG actions in the central nervous system and how dementia-related proteins such as γ-secretase modulate the action of NRGs and their ERBB receptors. We then (3) turn to the abnormalities in NRG and ERBB expression and function evident in human AD and mouse AD models, how these abnormalities affect brain function, and attempts to use NRGs to treat AD. Finally, (4) we discuss NRG effects on the survival and function of neurons relevant to FTLD and ALS, alterations in NRG/ERBB signaling identified in these conditions and the recent discovery of multiple human pedigrees in which autosomal dominant FTLD/ALS potentially results from point mutations in ERBB4.}, }
@article {pmid40253599, year = {2025}, author = {Malik, M and Bhatti, T and Hodson-Tole, E and Onambele-Pearson, G and Chaouch, A}, title = {Physical activity in amyotrophic lateral sclerosis: a systematic review of the methodologies used to assess a possible association.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/21678421.2025.2488298}, pmid = {40253599}, issn = {2167-9223}, abstract = {Growing evidence suggests that strenuous physical activity (PA) may be associated with an increased risk of developing Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. However, there are inconsistent findings across studies that may reduce our understanding of any potential associations. We propose that these differences may reflect the tools used to record historical PA. We conducted a systematic review evaluating the risk of developing ALS due to PA. The inclusion criteria were met by 22/113 studies, and an association between increasing PA and ALS was found in 15 studies. Studies that found a positive association were more likely to have longer recall periods and convert data into Metabolic Equivalent of Task values. Studies that did not find an association with increasing PA were more likely to use questionnaires with no validity or reliability data. Questionnaires with validity data all showed at least a moderate correlation of PA compared to objective measures, with reliability ranging from poor to good. Study designs included prospective cohort and case-control, which may also contribute to heterogeneity in findings. This work highlights the need for consensus on the type of questionnaire to use to assess potential associations between PA and ALS.}, }
@article {pmid40252901, year = {2025}, author = {Baidya, AT and Dante, D and Das, B and Wang, L and Darreh-Shori, T and Kumar, R}, title = {Discovery and characterization of novel pyridone and furan substituted ligands of choline acetyltransferase.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {177638}, doi = {10.1016/j.ejphar.2025.177638}, pmid = {40252901}, issn = {1879-0712}, abstract = {The key to the management of two devastating diseases, namely Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) lies in an early diagnosis, which is difficult due to its multifactorial nature. However, a common hallmark of AD and ALS is degeneration of cholinergic system. Choline acetyltransferase (ChAT) has been proposed as a potential target for development of cholinergic-specific biomarker. However, lack of selective, potent, brain permeable molecular probes of ChAT hinder development of ChAT biomarkers. In this study, we have successfully utilised structure-based virtual screening approach and identified two ChAT inhibitors from a database of 1.4 million compounds. The compounds were then subjected to rigorous in vitro characterization. Compound V6 showed Ki value of 11 μM and IC50 value of 21.73 μM, while V15 showed Ki and IC50 values of 4.5 and 9.42 μM, respectively for ChAT enzyme. V6 and V15 showed good solubility of 0.21 mg/ml and 0.17 mg/ml respectively and cytotoxicity analysis indicated no toxicity. We also performed a 200 ns molecular dynamics simulation, which revealed the intricate interaction dynamics for V6 and V15 with ChAT binding pocket. Moreover, the Tanimoto similarity analysis indicated the novelty and structural diversity of the hits. In conclusion, these validated hits provide a platform to develop potent, selective, blood-brain barrier permeable small molecules as chemical probes of ChAT or as Positron Emission Tomography tracer for early diagnosis and/or in vivo monitoring of the effect of new therapeutic candidates in spectrum of neurodegenerative disorders, in which cholinergic deficit is one of the hallmarks.}, }
@article {pmid40252666, year = {2025}, author = {Balendra, R and Sreedharan, J and Hallegger, M and Luisier, R and Lashuel, HA and Gregory, JM and Patani, R}, title = {Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy.}, journal = {The Lancet. Neurology}, volume = {24}, number = {5}, pages = {456-470}, doi = {10.1016/S1474-4422(25)00109-7}, pmid = {40252666}, issn = {1474-4465}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *TDP-43 Proteinopathies/genetics/pathology ; *Mutation/genetics ; }, abstract = {Mutations in the TARDBP gene, which encodes the TDP-43 protein, account for only 3-5% of familial cases of amyotrophic lateral sclerosis and less than 1% of cases that are apparently idiopathic. However, the discovery of neuronal inclusions of TDP-43 as the neuropathological hallmark in the majority of cases of amyotrophic lateral sclerosis has transformed our understanding of the pathomechanisms underlying neurodegeneration. An individual TARDBP mutation can cause phenotypic heterogeneity. Most mutations lie within the C-terminus of the TDP-43 protein. In pathological conditions, TDP-43 is mislocalised from the nucleus to the cytoplasm, where it can be phosphorylated, cleaved, and form insoluble aggregates. This mislocalisation leads to dysfunction of downstream pathways of RNA metabolism, proteostasis, mitochondrial function, oxidative stress, axonal transport, and local translation. Biomarkers for TDP-43 dysfunction and targeted therapies are being developed, justifying cautious optimism for personalised medicine approaches that could rescue the downstream effects of TDP-43 pathology.}, }
@article {pmid40252655, year = {2025}, author = {Dame, PS}, title = {The four most common genetic subtypes of amyotrophic lateral sclerosis: state of the art and future directions.}, journal = {The Lancet. Neurology}, volume = {24}, number = {5}, pages = {380-381}, doi = {10.1016/S1474-4422(25)00117-6}, pmid = {40252655}, issn = {1474-4465}, }
@article {pmid40251832, year = {2025}, author = {Bresque, M and Esteve, D and Balmer, G and Hamilton, HL and Stephany, JS and Pehar, M and Vargas, MR}, title = {FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.70023}, pmid = {40251832}, issn = {1098-1136}, support = {R01NS122973/NH/NIH HHS/United States ; R01NS132760/NH/NIH HHS/United States ; }, abstract = {Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.}, }
@article {pmid40251218, year = {2025}, author = {Abid, MN and Siming, L and Chao, H and Amin, M and Sarwer, S}, title = {Enhancing faculty teaching performance through constructive leadership with a mediating role of job satisfaction.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {13454}, pmid = {40251218}, issn = {2045-2322}, mesh = {*Job Satisfaction ; *Leadership ; Humans ; Male ; Female ; Cross-Sectional Studies ; *Teaching ; Adult ; *Faculty/psychology ; Universities ; Pakistan ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {This study explored the impact of constructive leadership styles including transformational leadership (TLS), authentic leadership (ALS), and servant leadership (SLS) on faculty teaching performance (FTP), with job satisfaction (JS) acting as a critical mediator. Using a cross-sectional design and convenience sampling, data were collected from 346 faculty members across six universities in Lahore, Pakistan. Structural equation modeling (SEM) and regression analysis revealed that all three leadership styles significantly enhanced FTP, with transformational leadership showing the strongest influence. Authentic and servant leadership also demonstrated robust positive effects. Job satisfaction emerged as a pivotal mediator, strengthening the relationship between CLS and FTP.These findings highlight the transformative potential of constructive leadership in improving teaching performance and emphasize the critical role of department heads in fostering such practices. By prioritizing strategies to enhance employee motivation and satisfaction, institutions can improve retention, productivity, and overall academic excellence. This study reinforces existing literature on leadership and teaching performance while providing novel insights into the mediating role of job satisfaction, offering actionable implications for academic leadership and organizational development.}, }
@article {pmid40250284, year = {2025}, author = {Calma, AD and Pavey, N and Silva, CS and van den Bos, MAJ and Yiannikas, C and Farrar, MA and Kiernan, MC and Menon, P and Vucic, S}, title = {Diagnostic utility of threshold tracking TMS paradigms in early amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {174}, number = {}, pages = {105-113}, doi = {10.1016/j.clinph.2025.03.044}, pmid = {40250284}, issn = {1872-8952}, abstract = {OBJECTIVE: Threshold tracking transcranial magnetic stimulation (TMS) has exhibited utility as a diagnostic technique in Amyotrophic Lateral Sclerosis (ALS). Different threshold tracking paradigms have recently been proposed. The present study assessed the diagnostic utility of serial ascending and parallel threshold tracking TMS in ALS.<br><br>METHODS: Threshold tracking TMS was undertaken on 90 prospectively recruited participants suspected of ALS. Short interval intracortical inhibition (SICI) was recorded with serial ascending and parallel threshold tracking paradigms between Interstimulus Interval (ISI) 1-to-7&#xa0;ms. The primary outcome measure was differences in diagnostic utility of the paradigms in differentiating ALS from ALS mimicking disorders using receiver operating characteristic (ROC) analysis (DeLong statistical method).<br><br>RESULTS: Reduction in SICI reliably differentiated ALS from mimic disorders, irrespective of the threshold tracking paradigm. Comparison of area under the curve (AUC) established a significantly higher value for mean SICI (1-7&#xa0;ms) with the serial ascending SICI paradigm (0.81, 95&#xa0;% confidence interval 0.72-0.91) compared to the parallel paradigm (SICI 0.72, 95&#xa0;% confidence interval 0.61-0.83, p&#xa0;=&#xa0;0.0065). The better diagnostic utility of serial ascending paradigm was evident for SICI recorded between 1-to-5&#xa0;ms, and was maintained irrespective of disease onset site, degree of functional impairment, and the degree of lower motor neuron dysfunction. A comparable diagnostic utility across threshold tracking paradigms was evident in ALS participants who presented with a relative paucity of upper motor neuron signs.<br><br>CONCLUSION: While threshold tracking TMS reliably differentiated ALS from mimic disorders, the present study established better diagnostic utility with the serial ascending threshold tracking TMS paradigm.<br><br>SIGNIFICANCE: The serial ascending threshold tracking TMS should be used in a clinical setting as a diagnostic tool for ALS.}, }
@article {pmid40250093, year = {2025}, author = {Casiraghi, V and Pellegrini, E and Brusati, A and Peverelli, S and Invernizzi, S and Santangelo, S and Colombrita, C and Verde, F and Ticozzi, N and Silani, V and Ratti, A}, title = {Characterization of human healthy i[3] lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.}, journal = {Journal of the neurological sciences}, volume = {473}, number = {}, pages = {123508}, doi = {10.1016/j.jns.2025.123508}, pmid = {40250093}, issn = {1878-5883}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons. Neurodegeneration in ALS might be driven by proteotoxicity or neuroinflammation, which have also been proposed to be promoted by toxic components of the cerebrospinal fluid (CSF). We investigated the possible toxicity of ALS CSF on healthy induced pluripotent stem cells (iPSC)-derived integrated, inducible, and isogenic lower motor neurons (i[3]LMNs). CSFs were obtained from ALS patients homozygous for the risk UNC13A rs12608932 single nucleotide polymorphism (CC) and for the corresponding major allele (AA), ALS patients with C9ORF72 hexanucleotide repeat expansion, and individuals affected by normal pressure hydrocephalus as non-disease controls (ND). A chronic and low-dose sodium arsenite (ARS) treatment was used as positive control of oxidative stress. We found that 10 % ALS CSF treatment for 48 h was not sufficient to induce significant alterations in viability, autophagic flux, axonal degeneration, DNA damage, and Golgi apparatus integrity in healthy i[3]LMNs, in contrast to ARS treatment. Only UNC13A CC CSF significantly increased protein aggregation and Golgi apparatus fragments dimension. RNA-sequencing revealed that all ALS and ND CSFs induced expression changes of few genes, while chronic ARS deregulated the expression of thousands of genes, mostly involved in inflammation and synapse biology. In this work, we demonstrated that in our experimental settings only CSF from UNC13A CC patients induced some ALS-associated pathological features in healthy i[3]LMNs. Further studies will be required to elucidate the mechanistic link between the risk UNC13A genotype and CSF composition and toxicity.}, }
@article {pmid40249897, year = {2025}, author = {Siegler, JE and Galetta, SL}, title = {Editors' Note: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e213609}, doi = {10.1212/WNL.0000000000213609}, pmid = {40249897}, issn = {1526-632X}, }
@article {pmid40249896, year = {2025}, author = {Kawada, T}, title = {Reader Response: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e209943}, doi = {10.1212/WNL.0000000000209943}, pmid = {40249896}, issn = {1526-632X}, }
@article {pmid40249895, year = {2025}, author = {Vaage, AM and Nakken, O}, title = {Author Response: Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.}, journal = {Neurology}, volume = {104}, number = {9}, pages = {e209962}, doi = {10.1212/WNL.0000000000209962}, pmid = {40249895}, issn = {1526-632X}, }
@article {pmid40248372, year = {2025}, author = {Dai, ZS and Zhang, M and Deng, YY and Zhou, N and Tian, Y}, title = {Efficacy of a novel artificial liver versatile plasma purification system in patients with acute-on-chronic liver failure.}, journal = {World journal of gastroenterology}, volume = {31}, number = {14}, pages = {103892}, pmid = {40248372}, issn = {2219-2840}, mesh = {Humans ; *Acute-On-Chronic Liver Failure/mortality/therapy/blood ; Female ; Male ; Middle Aged ; Prospective Studies ; *Liver, Artificial ; Treatment Outcome ; Aged ; Patient Readmission/statistics &amp; numerical data ; Adult ; Length of Stay/statistics &amp; numerical data ; Kaplan-Meier Estimate ; Follow-Up Studies ; Peritonitis/epidemiology/etiology ; China/epidemiology ; }, abstract = {BACKGROUND: We have innovatively amalgamated membrane blood purification and centrifugal blood cell separation technologies to address the limitations of current artificial liver support (ALS) models, and develop a versatile plasma purification system (VPPS) through centrifugal plasma separation.<br><br>AIM: To investigate the influence of VPPS on long-term rehospitalization and mortality rates among patients with acute-on-chronic liver failure (ACLF).<br><br>METHODS: This real-world, prospective study recruited inpatients diagnosed with ACLF from the Second Xiangya Hospital of Central South University between October 2021 and March 2024. Patients were categorized into the VPPS and non-VPPS groups based on the distinct ALS models administered to them. Self-administered questionnaires, clinical records, and self-reported data served as the primary methods for data collection. The laboratory results were evaluated at six distinct time points. All patients were subjected to follow-up assessments for > 12 months. Kaplan-Meier survival analyses and Cox proportional hazards models were used to evaluate the risks of hospitalization and mortality during the follow-up period.<br><br>RESULTS: A cohort of 502 patients diagnosed with ACLF was recruited, with 260 assigned to the VPPS group. On comparing baseline characteristics, the VPPS group exhibited a significantly shorter length of stay, higher incidence of spontaneous peritonitis and pulmonary aspergillosis compared to the non-VPPS group (P < 0.05). Age [hazard ratio (HR) = 1.142, 95%CI: 1.01-1.23, P = 0.018), peritonitis (HR = 2.825, 95%CI: 1.07-6.382, P = 0.026), albumin (HR = 0.67, 95%CI: 0.46-0.942, P = 0.023), total bilirubin (HR = 1.26, 95%CI: 1.01-3.25, P = 0.021), international normalized ratio (HR = 1.97, 95%CI: 1.21-2.908, P = 0.014), and VPPS/non-VPPS (HR = 3.24, 95%CI: 2.152-4.76, P < 0.001) were identified as significant independent predictors of mortality in both univariate and multivariate analyses throughout the follow-up period. Kaplan-Meier survival analyses demonstrated significantly higher rehospitalization and mortality rates in the non-VPPS group compared to the VPPS group during follow-up of &#x2265; 2 years (log-rank test, P < 0.001).<br><br>CONCLUSION: These findings suggest that VPPS is safe and has a positive influence on prognostic outcomes in patients with ACLF.}, }
@article {pmid40247237, year = {2025}, author = {Pehlivanidis, A and Kouklari, EC and Kalantzi, E and Korobili, K and Tagkouli, E and Papanikolaou, K}, title = {Self-reported symptoms of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and affective lability in discriminating adult ADHD, ASD and their co-occurrence.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {391}, pmid = {40247237}, issn = {1471-244X}, abstract = {BACKGROUND: To diagnose and manage adults with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), or their co-occurrence (ADHD + ASD), clinicians must identify specific features that differentiate these diagnostic categories. Self-report questionnaires targeting specific features are widely used and, together with clinical assessments, provide reliable diagnoses. Although affective lability is present in various psychiatric disorders, it lacks specificity when screening for ADHD in the general population, and its discriminant value for ADHD, ASD, and ADHD + ASD has not been studied.<br><br>METHODS: This study involved 300 adults without intellectual developmental disorder (188 male) who received an ADHD (n&#x2009;=&#x2009;174), ASD (n&#x2009;=&#x2009;68), or ADHD&#x2009;+&#x2009;ASD (n&#x2009;=&#x2009;58) diagnosis after a multidisciplinary consensus decision according to DSM-5 criteria. Before clinical assessment, all patients requesting evaluation for one of these diagnoses completed questionnaires on an online platform. The assessment instruments included a modified version of the Barkley Adult ADHD Rating Scale (BAARS IV) for ADHD, the Autism Spectrum Quotient (AQ) and the Empathy Quotient (EQ) for ASD features, and the Affective Lability Scale (ALS) for affective lability. Total scores and sub-scores of the instruments were compared among the three groups. Additionally, stepwise logistic regression analyses were conducted to identify specific measures that contribute to group discrimination.<br><br>RESULTS: Results revealed distinct patterns in symptomatology as expected. The ADHD and the ADHD&#x2009;+&#x2009;ASD groups presented significantly higher ALS total score compared to ASD. Stepwise logistic regression analyses identified specific measures contributing to group differentiation. ASD vs. ADHD&#x2009;+&#x2009;ASD discrimination included BAARS IV current total score and EQ total score. The subscale anger from ALS in addition with BAARS IV past total score and AQ total score were the factors that discriminated ADHD diagnosis from the co-occurrence of ADHD and ASD. Finally, BAARS IV past total score, BAARS IV current inattention, AQ total score, and EQ total score were found to differentiate ADHD from ASD.<br><br>CONCLUSIONS: The study highlights the significance of incorporating emotional dimensions in diagnostic frameworks and may contribute valuable insights for clinicians differentiating neurodevelopmental conditions.}, }
@article {pmid40247229, year = {2025}, author = {Samudi Raju, C and Kono, M and Looi, KW and Ong, JX and Tan, CA and Ang, CS and Tan, PHY and Shamnugam, H and Sekaran, SDKC and Syed Omar, SF and Lum, LCS}, title = {Low atypical lymphocyte score as a predictor of non-severe dengue.}, journal = {BMC infectious diseases}, volume = {25}, number = {1}, pages = {551}, pmid = {40247229}, issn = {1471-2334}, abstract = {BACKGROUND: Severe dengue has been linked to the presence of atypical lymphocytes, which can be quantified using the Q-flag parameter on a hematology analyzer. A higher atypical lymphocyte count has previously been associated with severe dengue. We aimed to evaluate the feasibility of the atypical lymphocyte score to provide an early prognosis for dengue severity.<br><br>METHOD: A prospective observational study enrolled adult patients admitted to the Infectious Disease ward with a febrile illness of less than 7 days. Blood samples obtained daily until discharge, were processed with XN-20 hematology analyzer with specific attention given to atypical lymphocyte score. Severe dengue cases were classified according to the 2009 World Health Organization Classification.<br><br>RESULTS: A total of 287 cases of laboratory-confirmed dengue, including 25 severe cases, were included. Dengue fever compared to non-dengue patients manifested increased lymphocytes within the high fluorescent zone on Day 6, The atypical lymphocyte score (ALS) of severe dengue showed an early rise, reaching a saturation point of 300 and remaining stable within the timeframe of days 4 to 8 post-fever onset. All but one severe dengue patient had a score exceeding 100 on day 4 post fever onset.<br><br>CONCLUSION: An atypical lymphocyte score below 100 on day 4 post fever onset, may serve as a predictive indicator that severe dengue is less likely to develop, potentially allowing for a lower level of medical intervention. These findings may contribute to more efficient resource allocation during outbreaks.<br><br>TRIAL REGISTRATION: The study was registered under National Medical Research Registration of Malaysia, (NMRR-18-3347-45473, 1 Sept 2019).}, }
@article {pmid40245393, year = {2025}, author = {Musson, LS and Mitic, N and Leigh-Valero, V and Onambele-Pearson, G and Knox, L and Steyn, FJ and Holdom, CJ and Dick, TJ and van Eijk, RP and van Unnik, JW and Botman, LC and Beswick, E and Murray, D and Griffiths, A and McDermott, C and Hobson, E and Chaouch, A and Hodson-Tole, E}, title = {The Use of Digital Devices to Monitor Physical Behavior in Motor Neuron Disease: Systematic Review.}, journal = {Journal of medical Internet research}, volume = {27}, number = {}, pages = {e68479}, doi = {10.2196/68479}, pmid = {40245393}, issn = {1438-8871}, mesh = {Humans ; *Motor Neuron Disease/physiopathology ; *Exercise ; *Wearable Electronic Devices ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a progressive and incurable neurodegenerative disease. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the primary clinical tool for assessing disease severity and progression in MND. However, despite its widespread use, it does not adequately capture the extent of physical function decline. There is an urgent need for sensitive measures of disease progression that can be used to robustly evaluate new treatments. Measures of physical function derived from digital devices are beginning to be used to assess disease progression. There is value in establishing a consensus approach to standardizing the use of such devices.<br><br>OBJECTIVE: We aimed to explore how digital devices are being used to quantify free-living physical behavior in MND. We evaluated the feasibility and assessed the implications for monitoring physical behavior for future clinical trials and clinical practice.<br><br>METHODS: Systematic searches of 4 databases were performed in October 2023 and June 2024. Peer-reviewed English-language articles (including preprints) that examined how people living with MND used digital devices to assess their free-living physical behavior were included. Study reporting quality was assessed using a 22-item checklist (maximum possible score=44 points).<br><br>RESULTS: In total, 12 articles met the inclusion criteria for data extraction. All studies were longitudinal and observational in design, but data collection, analysis, and reporting protocols varied. Quality assessment scores ranged between 19 and 40 points. Sample sizes ranged between 10 and 376 people living with MND at baseline, declining over the course of the study. Most studies used an accelerometer device worn on the wrist, chest, hip, or ankle. Participants were typically asked to continuously wear devices for 1 to 8 days at 1- to 4-month intervals, with studies running for 12 weeks to 24 months. Some studies asked participants to wear the device continuously for the full duration. Studies derived traditional end points focusing on duration, intensity, and frequency of physical activity or nontraditional end points focusing on features of an individual's movement patterns. The correlation coefficients (r) between physical behavior end points and ALSFRS-R ranged from 0.31 to 0.78. Greater monitoring frequencies and improved end point sensitivity were shown to provide smaller sample size requirements and shorter durations for hypothetical clinical trials. People living with MND found using devices acceptable and reported a low burden. Adherence assessed in 8 (67%) studies was good, ranging from approximately 86% to 96%, with differences evident between wear locations. The perspectives of other end users and implications on clinical practice were not explored.<br><br>CONCLUSIONS: Remote monitoring of free-living physical behavior in MND is in its infancy but has the potential to quantify physical function. It is essential to develop a consensus statement, working toward agreed and standardized methods for data collection, analysis, and reporting.}, }
@article {pmid40244212, year = {2025}, author = {Zhang, M and Zhou, H and Pan, Y and Wei, L}, title = {A pregnant woman with a 5-year history of amyotrophic lateral sclerosis: A case report.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijgo.70173}, pmid = {40244212}, issn = {1879-3479}, support = {202414030736//Medical and Health Science and Technology Project of Shandong Province/ ; ZHKY202423//Chinese Nursing Association Scientific Research Project/ ; QDFY+X 2023125//the Clinical Medicine +X Project of the Affiliated Hospital of Qingdao University/ ; }, }
@article {pmid40244186, year = {2025}, author = {Hu, C and Jiang, Y and Ma, C and Xu, F and Cui, C and Du, X and Chen, J and Zhu, L and Yu, S and He, X and Yu, W and Wang, Y and Xu, X}, title = {Decreased Cdk2 Activity Hindered Embryonic Development and Parthenogenesis Induction in Silkworm, Bombyx mori L.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073341}, pmid = {40244186}, issn = {1422-0067}, support = {2021C02072//Technological Grant of Zhejiang for Breeding New Agricultural Varieties/ ; 32100377//National Natural Science Foundation of China/ ; CARS-18//Key Scientific and the China Agriculture Research System of MOF and MARA/ ; }, mesh = {Animals ; *Bombyx/embryology/genetics/enzymology ; *Parthenogenesis/drug effects ; *Cyclin-Dependent Kinase 2/metabolism/antagonists &amp; inhibitors/genetics ; *Embryonic Development/drug effects ; *Insect Proteins/metabolism/genetics/antagonists &amp; inhibitors ; Female ; }, abstract = {Cyclin-dependent protein kinase 2 (Cdk2), an important member of the serine/threonine-specific protein kinase family, plays a critical regulatory role in biological processes. Previous studies have demonstrated that Cdk2 is involved in the arrest and resumption of meiosis in mammalian oocytes. In this study, we explored the function of Cdk2 through parthenogenetic lines (PLs) and corresponding amphigonic lines (ALs) in a model lepidopteran insect silkworm, Bombyx mori L. Our findings revealed a positive correlation between Cdk2 activity and the parthenogenesis induction rate. The pharmacological inhibition of Cdk2 using the specific inhibitor AUZ454 not only significantly reduced the parthenogenesis induction rate but also caused developmental delays in embryos. These results demonstrate that Cdk2 is essential for parthenogenesis success and is a potential target gene for biological reproductive regulation.}, }
@article {pmid40244061, year = {2025}, author = {Tseriotis, VS and Liampas, A and Lazaridou, IZ and Karachrysafi, S and Vavougios, GD and Hadjigeorgiou, GM and Papamitsou, T and Kouvelas, D and Arnaoutoglou, M and Pourzitaki, C and Mavridis, T}, title = {Repulsive Guidance Molecule-A as a Therapeutic Target Across Neurological Disorders: An Update.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073221}, pmid = {40244061}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy ; *Nerve Tissue Proteins/metabolism/antagonists &amp; inhibitors/genetics ; *GPI-Linked Proteins/metabolism/antagonists &amp; inhibitors/genetics ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism/drug therapy ; }, abstract = {Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa's responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa's critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.}, }
@article {pmid40243827, year = {2025}, author = {Carvalho, MCR}, title = {Reviewed article: Almeida ALS, Sousa TMS, Caldeira TCM, Claro RM. Association between adherence to the Food Guide golden rule and health characteristics among adult Brazilian women: a cross-sectional study with VIGITEL data, 2018-2021. Epidemiol Serv Saude. 2025:34;20240232.}, journal = {Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do Brasil}, volume = {34}, number = {}, pages = {e20240232.b}, doi = {10.1590/S2237-96222025v34e20240232.b}, pmid = {40243827}, issn = {2237-9622}, }
@article {pmid40243826, year = {2025}, author = {Tramontt, C}, title = {Reviewed article: Almeida ALS, Sousa TMS, Caldeira TCM, Claro RM. Association between adherence to the Food Guide golden rule and health characteristics among adult Brazilian women: a cross-sectional study with VIGITEL data, 2018-2021. Epidemiol Serv Saude. 2025:34;20240232.}, journal = {Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do Brasil}, volume = {34}, number = {}, pages = {e20240232.a}, doi = {10.1590/S2237-96222025v34e20240232.a}, pmid = {40243826}, issn = {2237-9622}, }
@article {pmid40243810, year = {2025}, author = {Flores, SV and Lillo, P and Levi-Monsalve, A and Roco-Videla, &#xc1; and Montaña, R}, title = {Genetic ancestry and risk allele C9orf72 rs3849942 T for amyotrophic lateral sclerosis in Latin American populations.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {3-4}, pages = {379-381}, doi = {10.1080/21678421.2024.2447459}, pmid = {40243810}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/ethnology ; *C9orf72 Protein/genetics ; *Genetic Predisposition to Disease/genetics ; Latin America/epidemiology ; Alleles ; Female ; Male ; *Polymorphism, Single Nucleotide/genetics ; White People/genetics ; Middle Aged ; White ; }, abstract = {This study examines the relationship between genetic ancestry and the rs3849942 T allele, linked to ALS, in 347 Latin American individuals from the 1000 Genomes Project. Ancestry proportions were estimated using 446 AIMs, and associations were analyzed via logistic regression. Higher Native American ancestry significantly reduced the likelihood of carrying the T allele, while European ancestry increased it. These findings emphasize the importance of incorporating genetic diversity into ALS research.}, }
@article {pmid40243699, year = {2025}, author = {Xu, R and Kang, Q and Yang, X and Yi, P and Zhang, R}, title = {Unraveling Molecular Targets for Neurodegenerative Diseases Through Caenorhabditis elegans Models.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26073030}, pmid = {40243699}, issn = {1422-0067}, support = {32270739//National Natural Science Foundation of China/ ; }, mesh = {*Caenorhabditis elegans/genetics/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics/drug therapy/pathology ; *Disease Models, Animal ; Humans ; Caenorhabditis elegans Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion disease, represent a group of age-related disorders that pose a growing and formidable challenge to global health. Despite decades of extensive research that has uncovered key genetic factors and biochemical pathways, the precise molecular mechanisms underlying these diseases and effective therapeutic strategies remain elusive. Caenorhabditis elegans (C. elegans) has emerged as a powerful model organism for studying NDDs due to its unique biological features such as genetic tractability, conserved molecular pathways, and ease of high-throughput screening. This model provides an exceptional platform for identifying molecular targets associated with NDDs and developing novel therapeutic interventions. This review highlights the critical role of C. elegans in elucidating the complex molecular mechanisms of human NDDs, with a particular focus on recent advancements and its indispensable contributions to the discovery of molecular targets and therapeutic strategies for these NDDs.}, }
@article {pmid40243477, year = {2025}, author = {Romano, R and Del Fiore, VS and Ruotolo, G and Mazzoni, M and Rosati, J and Conforti, FL and Bucci, C}, title = {Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26072867}, pmid = {40243477}, issn = {1422-0067}, support = {PRIN2022 N. 2022XTM2S3//Ministero dell'universit&#xe0; e della ricerca/ ; PRIN2022 PNRR N. P2022FBZXY//Ministero dell'universit&#xe0; e della ricerca/ ; D.M. n. 737 of 25.06.2021//Ministero dell'universit&#xe0; e della ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Lysosomes/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Motor Neurons/metabolism/pathology ; *Mutation ; Fibroblasts/metabolism/pathology ; Male ; Female ; Induced Pluripotent Stem Cells/metabolism ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Consequent to the loss of these cells, neuromuscular functions decline, causing progressive weakness, muscle wasting, and paralysis, leading to death in 2 to 5 years. More than 90% of ALS cases are sporadic, while the remaining 10% of cases are familial, due to mutations in 40 different genes. One of the most common genes to be mutated in ALS is TARDBP (transactive response DNA binding protein 43), which encodes TDP-43 (TAR DNA-binding protein 43). A mutation in exon 6 of TARDBP causes the aminoacidic substitution G376D in the C-terminal region of TDP-43, leading to its cytoplasmic mislocalization and aggregation. In fibroblasts derived from patients carrying this mutation, we found a strong increase in lysosome number, with overexpression and higher nuclear translocation of the transcription factor TFEB. In contrast, lysosomal functionality was deeply compromised. Interestingly, lysosomal activity was unaffected at an early stage of the disease, worsening in more advanced stages. Moreover, we observed the same pathological phenotype in iPSC (induced pluripotent stem cells)-derived patient motor neurons carrying the G376D mutation. Therefore, this mutation compromises the functionality of lysosomes, possibly contributing to neurodegeneration.}, }
@article {pmid40243463, year = {2025}, author = {Fan, X and Diao, W and Wang, H and Yin, X and Qian, W}, title = {Interferon Regulatory Factors as a Potential Therapeutic Target for Neuroinflammation: A Focus on Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {7}, pages = {}, doi = {10.3390/ijms26072906}, pmid = {40243463}, issn = {1422-0067}, support = {82473926//National Natural Science Foundation of China/ ; 81872875//National Natural Science Foundation of China/ ; 81170317//National Natural Science Foundation of China/ ; 81473218//National Natural Science Foundation of China/ ; 81503077//National Natural Science Foundation of China/ ; JC2023042//the project of Nantong Natural Science Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Animals ; *Interferon Regulatory Factors/metabolism/genetics ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Signal Transduction ; Inflammation/metabolism ; }, abstract = {Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer's disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases.}, }
@article {pmid40241787, year = {2025}, author = {Wölfel, SM and Widmann, CN and Castro-Gomez, S and Weydt, P and Tacik, P and Heneka, MT}, title = {Cognitive capacity in amyotrophic lateral sclerosis: the value of diagnostic markers in cerebrospinal fluid and the influence of nutrition and pulmonary function.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf137}, pmid = {40241787}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is an incurable neurodegenerative disease that is fatal with a median of 3-4 years. It is characterized by degeneration of the first and second motor neurons. In addition to physical limitations, neuropsychological abnormalities occur in more than 50% of cases. This leads to a rapid loss of autonomy and increases the need for care. An individual prognosis for the course of the disease, in particular the development of cognitive and behavioural abnormalities, is not yet possible As part of our investigations, we focused on cognitive performance and behavioural abnormalities measured by the Edinburgh Cognitive and Behavioural ALS Screen in patients with amyotrophic lateral sclerosis and investigated possible prognostic biomarkers in cerebrospinal fluid as well as modifiable factors such as nutrition and lung function. A retrospective data analysis of 99 patients with amyotrophic lateral sclerosis cases examined between 2018 and 2021 at the Department for Neurodegenerative Diseases and Gerontopsychiatry at the University Hospital of Bonn, using Edinburgh Cognitive and Behavioural ALS Screen, revealed that elevated levels of total tau and phospho-tau 181 were associated with diminished performance of patients with amyotrophic lateral sclerosis on the Edinburgh Cognitive and Behavioural ALS Screen. Additionally, weight loss during the course of the disease has been observed to have a deleterious impact on cognitive performance. Moreover, we were able to demonstrate a previously insufficiently described correlation between abnormalities in the Edinburgh Cognitive and Behavioural ALS Screen and low-normal thiamine levels in serum. The hypothesis that reduced lung function has a negative effect on cognitive performance was not supported by our findings. The initial onset of amyotrophic lateral sclerosis, whether bulbar or spinal, does not appear to affect cognition and behaviour measured using Edinburgh Cognitive and Behavioural ALS Screen. Furthermore, our findings confirm the utility of the Edinburgh Cognitive and Behavioural ALS Screen in identifying a behavioural variant frontotemporal dementia in amyotrophic lateral sclerosis patients who have been previously diagnosed by experienced neurologists using the Rascovsky criteria. This development facilitates a more precise utilization of complex diagnostic instruments. Our results provide insight into the prognosis of patients with amyotrophic lateral sclerosis in terms of cognitive performance and behavioural abnormalities as the disease progresses, as well as potential therapeutic approaches to stabilize and support neuropsychological abnormalities. The importance of total tau as a widely available prognostic marker should be emphasized. Additionally, new avenues of research are emerging, particularly regarding the role of thiamine in amyotrophic lateral sclerosis.}, }
@article {pmid40241786, year = {2025}, author = {Hernández-Gloria, JJ and Jaramillo-Gonzalez, A and Savić, AM and Mrachacz-Kersting, N}, title = {Toward brain-computer interface speller with movement-related cortical potentials as control signals.}, journal = {Frontiers in human neuroscience}, volume = {19}, number = {}, pages = {1539081}, pmid = {40241786}, issn = {1662-5161}, abstract = {Brain Computer Interface spellers offer a promising alternative for individuals with Amyotrophic Lateral Sclerosis (ALS) by facilitating communication without relying on muscle activity. This study assessed the feasibility of using movement related cortical potentials (MRCPs) as a control signal for a Brain-Computer Interface speller in an offline setting. Unlike motor imagery-based BCIs, this study focused on executed movements. Fifteen healthy subjects performed three spelling tasks that involved choosing specific letters displayed on a computer screen by performing a ballistic dorsiflexion of the dominant foot. Electroencephalographic signals were recorded from 10 sites centered around Cz. Three conditions were tested to evaluate MRCP performance under varying task demands: a control condition using repeated selections of the letter "O" to isolate movement-related brain activity; a phrase spelling condition with structured text ("HELLO IM FINE") to simulate a meaningful spelling task with moderate cognitive load; and a random condition using a randomized sequence of letters to introduce higher task complexity by removing linguistic or semantic context. The success rate, defined as the presence of an MRCP, was manually determined. It was approximately 69% for both the control and phrase conditions, with a slight decrease in the random condition, likely due to increased task complexity. Significant differences in MRCP features were observed between conditions with Laplacian filtering, whereas no significant differences were found in single-site Cz recordings. These results contribute to the development of MRCP-based BCI spellers by demonstrating their feasibility in a spelling task. However, further research is required to implement and validate real-time applications.}, }
@article {pmid40180127, year = {2025}, author = {Kaltchenko, M and Kim, E and Radtke, S and Wan, J}, title = {Response to Li et al's "Comments on 'Dupilumab and neuropsychiatric outcomes in pediatric atopic dermatitis: A real-world cohort analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.03.081}, pmid = {40180127}, issn = {1097-6787}, }
@article {pmid40240969, year = {2025}, author = {Xia, H and Wang, ZH and Wang, XB and Gao, MR and Jiang, S and Du, XY and Yang, XL}, title = {Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {160}, pmid = {40240969}, issn = {1471-2377}, support = {2023B03003//Autonomous Region Key Research and Development Project/ ; 2022TSYCLJ0066//the Tian-Shan Talent Program/ ; 82371258//the National Natural Science Foundation of China/ ; ZYYD2022C17//the Central Guiding Local Science and Technology Development Special Fund Project/ ; }, abstract = {OBJECTIVE: This study aims to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy number and several common neurodegenerative diseases (NDs).<br><br>METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS) as instrumental variables (IVs). After screening for relevance and potential confounders, we estimated the association between mtDNA copy number and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS). Additionally, we validated our findings using GWAS data on mtDNA copy number from Longchamps et al., sourced from the Genetics Epidemiology Consortium and the UK Biobank (UKB) aging study cohort.<br><br>RESULTS: A GWAS analysis of 395,718 UKB participants found no significant association between mtDNA copy number and the risk of NDs, including AD (OR&#x2009;=&#x2009;0.956, P&#x2009;=&#x2009;0.708), PD (OR&#x2009;=&#x2009;1.223, P&#x2009;=&#x2009;0.179), ALS (OR&#x2009;=&#x2009;0.972, P&#x2009;=&#x2009;0.374), and MS (OR&#x2009;=&#x2009;0.932, P&#x2009;=&#x2009;0.789). Similarly, reverse MR analysis revealed no significant relationship between genetic predictions of NDs and mtDNA copy number: AD (OR&#x2009;=&#x2009;0.987, P&#x2009;=&#x2009;0.062), PD (OR&#x2009;=&#x2009;0.997, P&#x2009;=&#x2009;0.514), ALS (OR&#x2009;=&#x2009;0.974, P&#x2009;=&#x2009;0.706), and MS (OR&#x2009;=&#x2009;1.003, P&#x2009;=&#x2009;0.181).<br><br>CONCLUSION: Although mitochondrial dysfunction is implicated in the pathogenesis of NDs, no clear evidence supports a causal role for mtDNA copy number. The relationship between mtDNA copy number and NDs is likely mediated by more complex molecular regulatory mechanisms. Further research is required to elucidate these intricate interactions.}, }
@article {pmid40238886, year = {2025}, author = {Cheemala, A and Kimble, AL and Burrage, EN and Helming, SB and Tyburski, JD and Leclair, NK and Omar, OM and Zuberi, AR and Murphy, M and Jellison, ER and Reese, B and Hu, X and Lutz, CM and Yan, R and Murphy, PA}, title = {Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.}, journal = {Science advances}, volume = {11}, number = {16}, pages = {eads0505}, doi = {10.1126/sciadv.ads0505}, pmid = {40238886}, issn = {2375-2548}, mesh = {*Blood-Brain Barrier/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; *Mutation ; Humans ; *Endothelial Cells/metabolism/pathology ; Disease Models, Animal ; Brain/metabolism/pathology ; }, abstract = {Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 (Tardbp[G348C]) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.}, }
@article {pmid40237254, year = {2025}, author = {Russek, M and Peltner, J and Haenisch, B}, title = {Supplementing Single-Arm Trials with External Control Arms-Evaluation of German Real-World Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1002/cpt.3684}, pmid = {40237254}, issn = {1532-6535}, abstract = {As single-arm trials (SATs) are increasingly used in pharmaceutical research, the validity of such study designs needs to be critically assessed. We characterize the feasibility of supplementing SATs with real-world data (RWD)-derived external control arms by determining the proportion of SATs on breast cancer and amyotrophic lateral sclerosis (ALS) for which an external control arm based on RWD can be constructed. The main outcome measure is the number and percentage of trials for which all important eligibility criteria and at least one primary endpoint could be identified in one of five German RWD sources. We surveyed all SATs concerning breast cancer or ALS treatment registered in the European Union's clinical trial registers between 2004 and 2023. Ten out of 379 breast cancer SATs and 2 of 11 ALS SATs could feasibly be supplemented with RWD-derived external control arms, if all important eligibility criteria and a primary endpoint have to be identifiable in the RWD source. Ninety-three breast cancer trials had at least one outcome ascertainable in a RWD source, and 35 trials had all important eligibility criteria recorded in a RWD source. Nine ALS trials had at least one primary endpoint ascertainable in RWD sources, and 2 had all important eligibility criteria recorded in a RWD source. Our study shows that SATs with RWD-derived external control arms will rarely be suitable to establish treatment effects of medicines in the current setting for the investigated phenotypes and that SATs should be designed with limitations of the source of external controls in mind.}, }
@article {pmid40237114, year = {2025}, author = {Thompson, OL and Russell, JA and Stockman, SK and Swall, JL and Simmons, T}, title = {Assessing the effectiveness of alternate light sources in the search for skeletal remains.}, journal = {Journal of forensic sciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/1556-4029.70049}, pmid = {40237114}, issn = {1556-4029}, abstract = {Many search and recovery operations for human skeletal remains are unsuccessful due to difficulties recognizing bones in outdoor environments even when evidence indicates the last known whereabouts of missing individuals. Though the collagen component of bone is known to emit fluorescence, this property has not been leveraged consistently during skeletal remains searches. Thirty-six mock searches were completed in 5000 ft[2] zones of eastern deciduous forest by volunteers associated with the Virginia Department of Emergency Management. Pig and deer bones were scattered and partially concealed under brush and leaf cover. Pairs of volunteers were allowed up to 1 h to conduct searches in their usual pattern. Nighttime searches were conducted with handheld alternate light source (ALS) devices (uvBeast™, Crime-lite[®], ForenScope, and Labino AB), which produced ultraviolet (385-395 nm), violet (395-425 nm), blue (~455 nm), cyan (~510 nm), or green (~530 nm) lights. Filtered safety glasses were paired with appropriate ALS. Daytime searches were conducted under the same parameters, without ALS. Results indicated that (1) nighttime searches with ALS produced a recovery rate more than triple that of daytime searches (p < 0.0001) and that they were often completed more quickly, and (2) the violet Crime-lite[®], due to breadth of illumination and strength of fluorescent response, consistently produced the highest recovery rate (95%). Data suggest that nighttime searches with ALS can be used both as the primary search method for locating and recovering human skeletal remains, and as a secondary method for recovering any bones expected to be present but not found during daylight searches.}, }
@article {pmid40236412, year = {2025}, author = {Jude, JJ and Levi-Aharoni, H and Acosta, AJ and Allcroft, SB and Nicolas, C and Lacayo, BE and Card, NS and Wairagkar, M and Brandman, DM and Stavisky, SD and Willett, FR and Williams, ZM and Simeral, JD and Hochberg, LR and Rubin, DB}, title = {An intuitive, bimanual, high-throughput QWERTY touch typing neuroprosthesis for people with tetraplegia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.04.01.25324990}, pmid = {40236412}, abstract = {Recognizing keyboard typing as a familiar, high information rate communication paradigm, we developed an intracortical brain computer interface (iBCI) typing neuroprosthesis providing bimanual QWERTY keyboard functionality for people with paralysis. Typing with this iBCI involves only attempted finger movements, which are decoded accurately with as few as 30 calibration sentences. Sentence decoding is improved using a 5-gram language model. This typing neuroprosthesis performed well for two iBCI clinical trial participants with tetraplegia - one with ALS and one with spinal cord injury. Typing speed is user-regulated, reaching 110 characters per minute, resulting in 22 words per minute with a word error rate of 1.6%. This resembles able-bodied typing accuracy and provides higher throughput than current state-of-the-art hand motor iBCI decoding. In summary, a typing neuroprosthesis decoding finger movements, provides an intuitive, familiar, and easy-to-learn paradigm for individuals with impaired communication due to paralysis.}, }
@article {pmid40236149, year = {2025}, author = {Strell, P and Waldron, MA and Johnson, S and Shetty, A and Crane, AT and Steer, CJ and Low, WC}, title = {Characterization of the intraspecies chimeric mouse brain at embryonic day 12.5.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.31.646380}, pmid = {40236149}, issn = {2692-8205}, abstract = {Incidence of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis have increased dramatically as life expectancy at birth has risen year-over-year and the population ages. Neurological changes within the central nervous system, specifically the brain, include cell loss and deterioration that impact motor function, memory, executive function, and mood. Available treatments are limited and often only address symptomatic manifestations of the disease rather than disease progression. Cell transplantation therapy has shown promise for treating neurodegenerative diseases, but a source of autologous cells is required. Blastocyst complementation provides an innovative method for generating those autologous neural cells. By injecting mouse induced pluripotent stem cells (iPSCs) into a wild type (WT) mouse blastocyst, we generated a chimeric mouse brain derived of both donor and host neuronal and non-neuronal cells. An embryonic day 12.5 (E12.5), automated image analysis of mouse-mouse chimeric brains showed the presence of GFP-labeled donor-derived dopaminergic and serotonergic neuronal precursors. GFP-labeled donor-derived cholinergic precursor neurons and non-neuronal microglia-like and macrophage-like cells were also observed using more conventional imaging analysis software. This work demonstrates that the generation of mouse-mouse chimeric neural cells is possible; and that characterization of early neuronal and non-neuronal precursors provides a first step towards utilizing these cells for cell transplantation therapies for neurodegenerative diseases.}, }
@article {pmid40235960, year = {2025}, author = {Basgaran, A and Lymberopoulos, E and Burchill, E and Reis-Dehabadi, M and Sharma, N}, title = {Machine learning determines the incidence of Alzheimer's disease based on population gut microbiome profile.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf059}, pmid = {40235960}, issn = {2632-1297}, abstract = {The human microbiome is a complex and dynamic community of microbes, thought to have symbiotic benefit to its host. Influences of the gut microbiome on brain microglia have been identified as a potential mechanism contributing to neurodegenerative diseases, such as Alzheimer's disease, motor neurone disease and Parkinson's disease (Boddy SL, Giovannelli I, Sassani M, et al. The gut microbiome: A key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med. 2021;19(1):13). We hypothesize that population level differences in the gut microbiome will predict the incidence of Alzheimer's disease using machine learning methods. Cross-sectional analyses were performed in R, using two large, open-access microbiome datasets (n = 959 and n = 2012). Countries in these datasets were grouped based on Alzheimer's disease incidence and the gut microbiome profiles compared. In countries with a high incidence of Alzheimer's disease, there is a significantly lower diversity of the gut microbiome (P < 0.05). A permutational analysis of variance test (P < 0.05) revealed significant differences in the microbiome profile between countries with high versus low incidence of Alzheimer's disease with several contributing taxa identified: at a species level Escherichia coli, and at a genus level Haemophilus and Akkermansia were found to be reproducibly protective in both datasets. Additionally, using machine learning, we were able to predict the incidence of Alzheimer's disease within a country based on the microbiome profile (mean area under the curve 0.889 and 0.927). We conclude that differences in the microbiome can predict the varying incidence of Alzheimer's disease between countries. Our results support a key role of the gut microbiome in neurodegeneration at a population level.}, }
@article {pmid40235867, year = {2025}, author = {Sundararaju, U and Rajakumar, HK}, title = {Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {4}, pages = {103128}, pmid = {40235867}, issn = {1948-5204}, abstract = {Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al's systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR's clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR's reliability as a prognostic marker for GC.}, }
@article {pmid40235786, year = {2025}, author = {Wang, LP and Yang, C and Fu, JY and Zhang, XY and Shen, XM and Shi, NL and Wu, HL and Gao, XR}, title = {A preliminary study of steady-state visually-evoked potential-based non-invasive brain-computer interface technology as a communication aid for patients with amyotrophic lateral sclerosis.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {4}, pages = {3469-3479}, pmid = {40235786}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to severe disability and ultimately death. Communication difficulties are common in ALS patients as the disease progresses; thus, alternative communication aids need to be explored. This study sought to examine the use and effect of steady-state visually-evoked potential (SSVEP)-based non-invasive brain-computer interface (BCI) technology as a communication aid for patients with ALS and to examine possible influencing factors.<br><br>METHODS: In total, 12 patients with ALS were selected, and a 40-character target selection was performed using SSVEP-based non-invasive BCI technology. The patients were presented with specific visual stimuli, and nine-lead electroencephalogram (EEG) signals in the occipital region were acquired when the patients were looking at the target. Using the feature recognition analysis method, the final output was the characters recognized by the patients. The basic clinical data of the patients (e.g., age, gender, course of disease, affected area, and ALS functional scale score) were collected, and the BCI accuracy rate, information transmission rate, and average SSVEP recognition time were calculated.<br><br>RESULTS: The results revealed that the recognition efficiency of the ALS patients varied. The accuracy potential increased as the stimulus duration extended, highlighting the possibility for improvement via further optimization. The results also showed that the experimental design schedules typically used for healthy individuals may not be entirely suitable for ALS patients, which presents an exciting opportunity to tailor future studies to better meet the unique needs of ASL patients. Further, the results revealed the necessity of using customized experimental schedules in future studies, which could lead to more relevant and effective data collection for ALS patients.<br><br>CONCLUSIONS: The study found that SSVEP-based non-invasive BCI technology has promising potential as a communication aid for ALS patients. While further algorithm optimization and comprehensive studies with larger sample sizes are necessary, the initial findings are encouraging, and could lead to the development of more effective communication solutions that are specifically tailored to address the challenges faced by ALS patients.}, }
@article {pmid40235752, year = {2025}, author = {Huang, NX and Zeng, JY and Huang, HW and Fang, SY and Chen, S and Li, JQ and Chen, HJ and Zou, ZY}, title = {Association of glymphatic system disturbance with neural dysfunction in amyotrophic lateral sclerosis.}, journal = {Quantitative imaging in medicine and surgery}, volume = {15}, number = {4}, pages = {3445-3457}, pmid = {40235752}, issn = {2223-4292}, abstract = {BACKGROUND: Formation and aggregation of pathological proteins in the brain constitutes a critical hallmark of amyotrophic lateral sclerosis (ALS). However, the role of the glymphatic system in the clearance of pathological proteins in ALS remains unclear. The purpose of this cross-sectional study was to evaluate glymphatic system disturbance in ALS and its relation to neural function.<br><br>METHODS: This study included 38 healthy controls (HCs) and 30 patients with ALS who underwent diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). The disease severity, duration, and progression rate of ALS were recorded. Glymphatic system function was indirectly evaluated by DTI analysis along the perivascular space (ALPS) surrounding the deep medullary vein. Neural activity was examined in sensorimotor-related brain areas by measuring amplitude of low-frequency fluctuation (ALFF) based on rs-fMRI. A two-sample t-test or Mann-Whitney test was used to examine between-group differences in ALPS, diffusivities measured along the x-, y-, and z-axis in the association (Dxx_association, Dyy_association, Dzz_association) and projection (Dxx_projection, Dyy_projection, Dzz_projection) fiber areas, and ALFF indices. The associations between ALPS, diffusivities, ALFF, and clinical assessments were determined via Spearman correlation analysis, and diagnostic performance was evaluated with receiver operating characteristic curve analysis.<br><br>RESULTS: Patients with ALS exhibited significantly decreased ALPS and increased diffusivities (Dyy_association and Dyy_projection) as compared to HCs (all P values <0.05). Patients with ALS showed decreased ALFF in sensorimotor-related regions, including the bilateral primary motor and somatosensory areas (all P values <0.001) and left supplementary motor area (P=0.031). ALPS and diffusivities were correlated with ALFF in the sensorimotor-motor regions (all P values <0.05), and ALPS and ALFF correlated with disease severity and duration (all P values <0.05). ALPS, diffusivities, and ALFF showed moderate ability to diagnose ALS.<br><br>CONCLUSIONS: The glymphatic system function was impaired in ALS. This may contribute to spontaneous neural activity disturbance and could represent a mechanism for the development of sensorimotor deficits frequently observed in patients with ALS.}, }
@article {pmid40235273, year = {2025}, author = {Scelsa, SN and MacGowan, DJL}, title = {Disease Modification in SOD1-ALS With Tofersen May Result in Serious CNS Inflammation.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28413}, pmid = {40235273}, issn = {1097-4598}, }
@article {pmid40234983, year = {2025}, author = {Xie, Q and Li, K and Chen, Y and Li, Y and Jiang, W and Cao, W and Yu, H and Fan, D and Deng, B}, title = {Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {19}, pmid = {40234983}, issn = {2047-9158}, support = {81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that remains incurable. Although the etiologies of ALS are diverse and the precise pathogenic mechanisms are not fully understood, approximately 20% of ALS cases are caused by genetic factors. Therefore, advancing targeted gene therapies holds significant promise, at least for the 20% of ALS patients with genetic etiologies. In this review, we summarize the main strategies and techniques of current ALS gene therapies based on ALS risk genes, and review recent findings from animal studies and clinical trials. Additionally, we highlight ALS-related genes with well-understood pathogenic mechanisms and the potential of numerous emerging gene-targeted therapeutic approaches for ALS.}, }
@article {pmid40234916, year = {2025}, author = {Park, KH and Yu, E and Choi, S and Kim, S and Park, C and Lee, JE and Kim, KW}, title = {Optogenetic induction of TDP-43 aggregation impairs neuronal integrity and behavior in Caenorhabditis elegans.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {20}, pmid = {40234916}, issn = {2047-9158}, support = {NRF-2022R1A2C1003766//Ministry of Education, Science and Technology/ ; RS-2024-00331685//Ministry of Food and Drug Safety/ ; }, abstract = {BACKGROUND: Cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in neurons is one of the hallmarks of TDP-43 proteinopathy. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are closely associated with TDP-43 proteinopathy; however, it remains uncertain whether TDP-43 aggregation initiates the pathology or is a consequence of it.<br><br>METHODS: To demonstrate the pathology of TDP-43 aggregation, we applied the optoDroplet technique in Caenorhabditis elegans (C. elegans), which allows spatiotemporal modulation of TDP-43 phase separation and assembly.<br><br>RESULTS: We demonstrate that optogenetically induced TDP-43 aggregates exhibited insolubility similar to that observed in TDP-43 proteinopathy. These aggregates increased the severity of neurodegeneration, particularly in GABAergic motor neurons, and exacerbated sensorimotor dysfunction in C. elegans.<br><br>CONCLUSIONS: We present an optogenetic C. elegans model of TDP-43 proteinopathy that provides insight into the neuropathological mechanisms of TDP-43 aggregates. Our model serves as a promising tool for identifying therapeutic targets for TDP-43 proteinopathy.}, }
@article {pmid40234116, year = {2025}, author = {McHale-Owen, H and Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Phosphoglycerate kinase 1 as a therapeutic target in neurological disease.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molmed.2025.03.008}, pmid = {40234116}, issn = {1471-499X}, abstract = {Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.}, }
@article {pmid40232694, year = {2024}, author = {Ichikawa, Y and Sato, B and Hirano, SI and Takefuji, Y and Satoh, F}, title = {Hydrogen inhalation therapy may ameliorate amyotrophic lateral sclerosis.}, journal = {Medical gas research}, volume = {14}, number = {3}, pages = {149-150}, doi = {10.4103/2045-9912.390249}, pmid = {40232694}, issn = {2045-9912}, }
@article {pmid40232582, year = {2025}, author = {Mehrnoosh, F and Rezaei, D and Pakmehr, SA and Nataj, PG and Sattar, M and Shadi, M and Ali-Khiavi, P and Zare, F and Hjazi, A and Al-Aouadi, RFA and Sapayev, V and Zargari, F and Alkhathami, AG and Ahmadzadeh, R and Khedmatgozar, M and Hamzehzadeh, S}, title = {The role of Panax ginseng in neurodegenerative disorders: mechanisms, benefits, and future directions.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {183}, pmid = {40232582}, issn = {1573-7365}, mesh = {Humans ; *Panax ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Ginsenosides/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Huntington's disease (HD) represent a growing global health challenge, especially with aging populations. Characterized by progressive neuronal loss, these diseases lead to cognitive, motor, and behavioral impairments, significantly impacting patients' quality of life. Current therapies largely address symptoms without halting disease progression, underscoring the need for innovative, disease-modifying treatments. Ginseng, a traditional herbal medicine with well-known adaptogenic and neuroprotective properties, has gained attention as a potential therapeutic agent for neurodegeneration. Rich in bioactive compounds called ginsenosides, ginseng exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects, making it a promising candidate for addressing the complex pathology of neurodegenerative diseases. Recent studies demonstrate that ginsenosides modulate disease-related processes such as oxidative stress, protein aggregation, mitochondrial dysfunction, and inflammation. In AD models, ginsenosides have been shown to reduce amyloid-beta accumulation and tau hyperphosphorylation, while in PD, they help protect dopaminergic neurons and mitigate motor symptoms. Ginseng's effects in ALS, MS, and HD models include improving motor function, extending neuronal survival, and reducing cellular toxicity. This review provides a comprehensive overview of the neuroprotective mechanisms of ginseng, emphasizing its therapeutic potential across various neurodegenerative diseases and discussing future research directions for its integration into clinical practice.}, }
@article {pmid40232308, year = {2025}, author = {Wu, J and Xu, Y and Yin, T and Zhang, N and Fan, D and Ye, S}, title = {Unveiling structural damage of the corpus callosum in amyotrophic lateral sclerosis through diffusion tensor imaging and spread direction perspectives.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2490822}, doi = {10.1080/07853890.2025.2490822}, pmid = {40232308}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging/physiopathology ; *Corpus Callosum/pathology/diagnostic imaging ; *Diffusion Tensor Imaging/methods ; Male ; Female ; Middle Aged ; Aged ; Adult ; Motor Cortex/pathology/diagnostic imaging ; }, abstract = {OBJECTIVE: Damage to the corpus callosum (CC) in amyotrophic lateral sclerosis (ALS) patients has been confirmed via electrophysiological, neuroimaging, and autopsy studies. Additionally, the CC is hypothesized to serve as a pathway for the spread of pathological information. This study aimed to investigate whether the CC plays a mediating role in the symptomatic spread of ALS.<br><br>METHODS: In this observational study, diffusion tensor imaging (DTI) data were acquired from 45 individuals with the upper motor neuron-dominant (UMN-D) phenotype of ALS. The UMN-D ALS patients were categorized into two groups based on the direction of symptom spread, including 25 patients with horizontal spread (group H) and 20 patients with vertical spread (group V). Diffusivity indices were derived through whole-brain analysis and probabilistic fiber tracking.<br><br>RESULTS: According to the voxel-based analysis and tract-based spatial statistics, differences in axial diffusivity (AD) in the CC were observed between disease subgroups, with patients in group H showing higher AD values than those in group V. Fiber tracking analysis revealed persistent differences in the AD indices of CC-primary motor cortex (PMC) fibers between the two disease subgroups.<br><br>CONCLUSION: In UMN-D ALS patients, the direction of symptom spread may be related to the degree of CC involvement. The AD metric may be a more specific indicator of CC damage.}, }
@article {pmid40231507, year = {2025}, author = {Tecalco-Cruz, AC and Ramírez-Jarquín, JO and Medina Abreu, KH and Palacios-Serrato, EG and López-Cánovas, L and Zepeda-Cervantes, J and Oropeza-Martínez, E}, title = {Molecular Interplay of ISG15/ISGylation in Neuropathologies.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273378149250322050004}, pmid = {40231507}, issn = {1996-3181}, abstract = {ISG15 is a 15 kDa ubiquitin-like protein that covalently associates with its target proteins by a sequential enzymatic process known as ISGylation. Research on protein ISGylation has increased in recent years, and some studies have suggested that ISG15 is involved in neuroprotection and neurodegeneration mechanisms. This review outlines the current state of research on the implications of ISG15/ISGylation in other neuropathies such as malignant tumors, ataxia telangiectasia, ischemia, depression, and neurodegenerative diseases such as Alzheimer´s, Parkinson's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Based on the studies reported to date, ISG15/ ISGylation promotes the progression of brain tumors such as glioblastoma. Moreover, ISG15/ ISGylation seems to play a dual role in neuropathies, demonstrating a neuroprotective effect when there is acute brain damage, but ISG15/ISGylation is associated with reduced neuroprotection when there is chronic damage, such as in neurodegenerative diseases.}, }
@article {pmid40231293, year = {2025}, author = {Smyth, BR and Patwardhan, S and Turner, EL and McLintock, S}, title = {Using Functional Resonance Analysis Method (FRAM) Modelling to Assess the Factors That Slow or Prevent Clinicians in Performing Advanced Life Support (ALS) During Crash Calls to Park House Mental Health Hospital.}, journal = {Cureus}, volume = {17}, number = {4}, pages = {e82231}, pmid = {40231293}, issn = {2168-8184}, abstract = {This Quality Improvement Project (QIP) aimed to improve the response system for crash calls at Park House Mental Health Hospital, supported by the North Manchester General Hospital Crash Team. Using a functional resonance analysis method (FRAM), the team identified inefficiencies in the Advanced Life Support (ALS) process, with delayed responses increasing patient mortality risks. Interviews with staff helped create "work-as-imagined" (WAI) and "work-as-done" (WAD) models, highlighting the underperformed functions like ward entry protocols, and fully stocked crash trolleys. Recommendations, including access cards, stock changes, and live simulations, were implemented, in an aim to improve ALS provision.}, }
@article {pmid40230758, year = {2025}, author = {Bossei, AA and Al Zahrani, HA and Bossei, FA and Saadi, SM and Alsaedi, AS and Al Sulami, AQ and Al Asmari, EH and Aalam, AA and Khojah, IM}, title = {Emergency Physicians' Perceptions, Knowledge, and Attitudes Toward Family Presence During Resuscitation in the Emergency Department: A Multicenter Survey-Based Cross-Sectional Study.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e80612}, pmid = {40230758}, issn = {2168-8184}, abstract = {BACKGROUND: Cardiac arrest remains a significant public health issue, with high incidence rates in both in-hospital and out-of-hospital settings. The practice of family presence during resuscitation (FPDR) has gained attention for its potential benefits to patients and their families. This study evaluates the perceptions, knowledge, and attitudes of emergency physicians (EPs) regarding FPDR in the emergency department (ED) and aims to inform policy development at King Abdulaziz University Hospital in Jeddah, Saudi Arabia.<br><br>METHODS: &#xa0;A multicenter cross-sectional study was conducted from January to April 2023, surveying EPs from multiple EDs across the western region of Saudi Arabia. Participants, certified in basic (BLS) or advanced life support (ALS), completed an anonymous online survey adapted from previous studies.<br><br>RESULTS: Our study surveyed 122 EPs, with 112 completing the survey. Of the participants, 49.1% were aged 25-29 years, 61.6% were men, and 58.9% had 1-4 years of work experience. Awareness of FPDR was reported by 67.9% (n = 76) of participants. Only 3.6% (n = 4) had a policy allowing FPDR, while 6.3% (n = 7) had a policy prohibiting it. Additionally, 49.1% (n = 55) supported implementing an FPDR policy. Awareness of FPDR was significantly higher among younger, male, and more experienced physicians (p < 0.05). Higher perception and practice scores were observed among those aware of FPDR, those who had participated in CPR with a family member, and those without a prohibiting policy (p < 0.05).<br><br>CONCLUSION: EPs in the western region of Saudi Arabia generally support FPDR, recognizing its potential benefits. However, concerns about its impact on performance and medicolegal issues warrant further exploration. To implement effective FPDR policies, these concerns must be addressed, along with efforts to promote awareness and training. Future research should expand to include broader healthcare settings and multidisciplinary teams to develop comprehensive, evidence-based guidelines.}, }
@article {pmid40229738, year = {2025}, author = {Abdoalsadig, E and Hamid, M and Peck, A and Johar, L and Kimonis, V}, title = {Utilization of CoRDS registry to monitor quality of life in patients with VCP multisystem proteinopathy.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {178}, pmid = {40229738}, issn = {1750-1172}, mesh = {Humans ; Registries ; *Quality of Life ; Female ; Male ; *Valosin Containing Protein/genetics/metabolism ; Middle Aged ; Aged ; Myositis, Inclusion Body/genetics ; Adult ; Amyotrophic Lateral Sclerosis/genetics ; Osteitis Deformans/genetics ; Frontotemporal Dementia/genetics ; }, abstract = {BACKGROUND: VCP disease, also known as multisystem proteinopathy, is a rare, autosomal dominant, adult-onset, neuromuscular disease that is caused by variants in the valosin-containing protein (VCP) gene. VCP disease may exhibit one or more of the following primary features: inclusion body myopathy, Paget's disease of bone (PDB), Frontotemporal dementia, and amyotrophic lateral sclerosis. Due to its progressive nature, death normally occurs in their sixties due to respiratory and cardiac failure. The purpose of this study is to utilize the Cure VCP Disease patient registry hosted by the Coordination of Rare Diseases at Sanford (CoRDS) to conduct a prospective natural history study.<br><br>METHODS: Seventy-nine participants enrolled in the patient registry and answered demographic, VCP variant type, Patient-reported outcome measures (PROMs), and quality of life (QOL) questionnaires over the course of 3&#xa0;years. We additionally investigated if any sex differences existed and if genotype-phenotype correlations affected the rate of progression of the varying clinical manifestations.<br><br>RESULTS: Overall, participants' mobility declined significantly as the disease progressed. Participants reported a 0.6% decline in upper extremity function, 1.2% decline in lower extremity function, and 0.3% decline in cognitive function per year of age. Furthermore, participants reported a 1.6% decline in upper and lower extremity function and a 0.1% decline in cognitive function per year of disease duration. The highest PROMs correlations were noted between overall health and lower extremity function, upper extremity function, fatigue, and the ability to perform vigorous activities. Genotype-phenotype correlations revealed no significant differences except for the absence of PDB in the p.Arg159Cys group.<br><br>CONCLUSION: The VCP CoRDS Registry was found to be a valuable tool for monitoring the QOL in patients with VCP disease and capturing patient perspectives for future clinical trials.}, }
@article {pmid40229540, year = {2025}, author = {Ghimire, S and Kreilaus, F and Rosa Porto, R and Anderson, LL and Yerbury, JJ and Arnold, JC and Karl, T}, title = {Behavioural effects of oral cannabidiol (CBD) treatment in the superoxide dismutase 1 G93 A (SOD1[G93 A]) mouse model of amyotrophic lateral sclerosis.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40229540}, issn = {1432-2072}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well as cognitive and other behavioural domains at later disease stages. No effective treatment for ALS is currently available. Elevated neuroinflammation, oxidative stress and alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory and anti-oxidant properties. Thus, we evaluated the remedial effects of chronic oral cannabidiol (CBD) treatment on ALS-relevant behavioural domains in the copper-zinc superoxide dismutase 1 (SOD1) mouse model of ALS that carries a G93A mutation (SOD1[G93A]).<br><br>METHODS: Male and female SOD1[G93A] and wild&#xa0;type-like (WT) littermates were fed either a control (CHOW) or CBD-enriched chow diet (equivalent to a dose of 36 mg/kg per day) beginning from 10 weeks of age. Bodyweight and motor performance were recorded weekly from 11 to 19 weeks and open field behaviours at 12 and 18 weeks. Mice were also tested for prepulse inhibition (PPI), social behaviours, as well as fear-associated memory.<br><br>RESULTS: CBD treatment ameliorated the bodyweight loss in female SOD1[G93A] mice, tended to reinstate sociability in SOD1[G93A] males, strengthened social recognition memory in SOD1[G93A] females, and improved the PPI response in younger SOD1[G93A] females at higher prepulse intensities. CBD had no effect on motor impairments but instead reversed the anxiolytic-like phenotype of 12-week-old male SOD1[G93A] mice and decreased the acoustic startle response and strengthened cue freezing in male mice.<br><br>CONCLUSION: Thus, the current remedial oral dose of CBD delayed disease progression (inferred by bodyweight) in both male and female mice and improve specific cognitive deficits of SOD1[G93A] mice in a sex specific manner without altering the motor phenotype.}, }
@article {pmid40229296, year = {2025}, author = {Kumar, P and Bishnoi, R and Priyadarshini, P and Chhuneja, P and Singla, D}, title = {Understanding the structural basis of ALS mutations associated with resistance to sulfonylurea in wheat.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12855}, pmid = {40229296}, issn = {2045-2322}, mesh = {*Acetolactate Synthase/genetics/chemistry/metabolism ; *Triticum/genetics/enzymology/drug effects ; *Sulfonylurea Compounds/pharmacology/chemistry ; *Herbicide Resistance/genetics ; Molecular Docking Simulation ; Herbicides/pharmacology ; *Plant Proteins/genetics/chemistry/metabolism ; Molecular Dynamics Simulation ; *Mutation ; Pyridines/pharmacology/chemistry ; }, abstract = {Developing herbicide-tolerant wheat varieties is highly desirable for effective weed management and improved crop yield. The enzyme acetolactate synthase (ALS) is the target enzyme for the sulfonylurea class of herbicides. The structural analysis of mutable sites in ALS is crucial for the generation of herbicide-resistant crops. Previous studies indicated that mutant lines of Triticum aestivum ALS (TaALS) with amino acid substitutions at P174, G631, and G632 residues provided resistance to sulfonylurea herbicide, nicosulfuron. The present study aimed to provide structural insights into mutable residues causing sulfonylurea herbicide resistance to TaALS enzyme through in-silico molecular docking and simulation approaches. The molecular docking analysis suggested a single point mutation at TaALS-P174S, its double mutant conformations (TaALS-G632S/P174S and TaALS-G631D/G632S) and associated triple mutant conformation (TaALS-G631D/G632S/P174S) to have the lowest binding affinity with nicosulfuron than the wild-type conformation of TaALS. Furthermore, the molecular dynamic simulation study confirms the weakest and more stable binding of the triple mutant conformation with nicosulfuron. Our computational study identifies a triple mutant conformation (TaALS-G631D/G632S/P174S) to be more effective in developing sulfonylurea herbicide-resistant wheat crops.}, }
@article {pmid40226510, year = {2025}, author = {Ufarry Alvarado, AJ and Zaidi Pons, MA and Plaza Hernández, J and Torres Ortiz, C}, title = {Improvements of Paraquat Treatment in Liquid Media for Behavior and Neurodegenerative Tests.}, journal = {microPublication biology}, volume = {2025}, number = {}, pages = {}, pmid = {40226510}, issn = {2578-9430}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a disease characterized by misfolded and aggregated proteins that have toxic effects on motor neurons. The missense mutation, G85R, of the sod-1 gene associated with ALS displays locomotor impairments in Caenorhadbitis elegans (C. elegans). We treated the sod-1 (G85R) strain with 0 and 2.5 mM Paraquat treatments in a liquid M9 buffer for 4 hours and in solid NGM media for 18 hours. In both methodologies, the locomotion defects and neurodegeneration were significantly increased with 2.5 mM Paraquat. Our work provides evidence of methodology that is more cost effective, rapid and reproducible to perform behavior and neurodegenerative assay in worms.}, }
@article {pmid40225153, year = {2023}, author = {Fiorini, MR and Dilliott, AA and Farhan, SMK}, title = {Evaluating the Utility of REVEL and CADD for Interpreting Variants in Amyotrophic Lateral Sclerosis Genes.}, journal = {Human mutation}, volume = {2023}, number = {}, pages = {8620557}, pmid = {40225153}, issn = {1098-1004}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Computational Biology/methods ; *Genetic Predisposition to Disease ; *Genetic Variation ; *Software ; Genetic Association Studies ; Mutation ; Databases, Genetic ; Genetic Testing ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease affecting approximately two per 100,000 individuals globally. While there are many benefits to offering early genetic testing to people with ALS, this has also led to an increase in the yield of novel variants of uncertain significance in ALS-associated genes. Computational (in silico) predictors, including REVEL and CADD, are widely employed to provide supporting evidence of pathogenicity for variants in conjunction with clinical, molecular, and other genetic evidence. However, in silico predictors are developed to be broadly applied across the human genome; thus, their ability to evaluate the consequences of variation in ALS-associated genes remains unclear. To resolve this ambiguity, we surveyed 20 definitive and moderate ClinGen-defined ALS-associated genes from two large, open-access ALS sequencing datasets (total people with ALS = 8,230; controls = 9,671) to investigate REVEL and CADD's ability to predict which variants are most likely to be disease-causing in ALS. While our results indicate a predetermined pathogenicity threshold for REVEL that could be of clinical value for classifying variants in ALS-associated genes, an accurate threshold was not evident for CADD, and both in silico predictors were of limited value for resolving which variants of uncertain significance (VUS) may be likely pathogenic in ALS. Our findings allow us to provide important recommendations for the use of REVEL and CADD scores for variants and indicate that both tools should be used with caution when attempting to evaluate the pathogenicity of VUSs in ALS genetic testing.}, }
@article {pmid40222791, year = {2025}, author = {Bhardwaj, I and Singh, S and Ansari, AH and Rai, SP and Singh, D}, title = {Effect of stress on neuronal cell: Morphological to molecular approach.}, journal = {Progress in brain research}, volume = {291}, number = {}, pages = {469-502}, doi = {10.1016/bs.pbr.2025.01.010}, pmid = {40222791}, issn = {1875-7855}, mesh = {Humans ; Animals ; *Neurons/pathology/metabolism/physiology ; *Stress, Psychological/pathology/metabolism ; *Brain/pathology ; }, abstract = {Stress can be characterized as any perceived or actual threat that necessitates compensatory actions to maintain homeostasis. It can alter an organism's behavior over time by permanently altering the composition and functionality of brain circuitry. The amygdala and prefrontal cortex are two interrelated brain regions that have been the focus of initial research on stress and brain structural and functional plasticity, with the hippocampus serving as the entry point for most of this knowledge. Prolonged stress causes significant morphological alterations in important brain regions such as the hippocampus, amygdala, and prefrontal cortex. Memory, learning, and emotional regulation are among the cognitive functions that are adversely affected by these changes, including neuronal shrinkage, dendritic retraction, and synaptic malfunction. Stress perturbs the equilibrium of neurotransmitters, neuronal plasticity, and mitochondrial function at the molecular level. On the other hand, chronic stress negatively impacts physiology and can result in neuropsychiatric diseases. Recent molecular research has linked various epigenetic processes, such as DNA methylation, histone modifications, and noncoding RNAs, to the dysregulation of genes in the impacted brain circuits responsible for the pathophysiology of chronic stress. Numerous disorders, including neurodegenerative diseases (NDDs) including Alzheimer's, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, multiple sclerosis, and Parkinson's disease, have been linked to oxidative stress as a possible cause.}, }
@article {pmid40222103, year = {2025}, author = {Lum, JS and Brown, ML and Farrawell, NE and Bartlett, R and Chisholm, CG and Gorman, J and Dosseto, A and Dux, F and McInnes, LE and Ecroyd, H and McAlary, L and Crouch, PJ and Donnelly, PS and Yerbury, JJ}, title = {A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {115}, number = {}, pages = {105692}, doi = {10.1016/j.ebiom.2025.105692}, pmid = {40222103}, issn = {2352-3964}, abstract = {BACKGROUND: SOD1 mutations are a significant contributor of familial amyotrophic lateral sclerosis (ALS) cases. SOD1 mutations increase the propensity for the protein to misfold and aggregate into insoluble proteinaceous deposits within motor neurons and neighbouring cells. The small molecule, CuATSM, has repeatedly shown in mouse models to be a promising therapeutic treatment for SOD1-associated ALS and is currently in Phase II/III clinical trials for the treatment of ALS. We have previously shown CuATSM stabilises various ALS-associated variants of the SOD1 protein, reducing misfolding and toxicity. Two additional FDA-approved small molecules, ebselen and telbivudine, have also been identified to reduce mutant SOD1 toxicity, providing additional potential therapeutic candidates that could be used in combination with CuATSM. Here, we aimed to investigate if CuATSM, ebselen and telbivudine (CET) polytherapy could improve on the therapeutic efficacy of CuATSM monotherapy for the treatment of SOD1-associated ALS.<br><br>METHODS: We utilised a 3D checkerboard approach to investigate whether a matrix of different concentrations CuATSM, ebselen and telbivudine could provide therapeutic improvements on cell survival, SOD1 folding and aggregation in SOD1[G93A]-transfected NSC-34&#xa0;cells, compared to CuATSM alone. To progress the preclinical development of CET polytherapy, we evaluated the bioavailability and safety of in&#xa0;vivo polytherapy administration. Furthermore, we assessed and compared the effects of CET- and CuATSM-treatment on disease onset, motor function, survival and neuropathological features in SOD1[G93A] mice.<br><br>FINDINGS: CET polytherapy reduced inclusion formation and increased cell survival of NSC-34&#xa0;cells overexpressing SOD1[G93A] compared to higher concentrations of CuATSM monotherapy. In addition, CET administration was bioavailable and tolerable in mice. CET treatment in SOD1[G93A] mice delayed disease onset, reduced motor impairments, and increased survival compared to vehicle- and CuATSM-treated mice. In line with these findings, biochemical analysis of lumbar spinal cords showed CET administration improved SOD1 folding, decreased misfolded SOD1 accumulation, and reduced motor neuron loss.<br><br>INTERPRETATION: These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.<br><br>FUNDING: This work was supported by a FightMND Drug Development Grant, an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (No. 1194872) and a Motor Neuron Disease Research Institute of Australia Bill Gole Postdoctoral Fellowship.}, }
@article {pmid40222004, year = {2025}, author = {Oliveri, F and Bicaj, M and Cillerai, M and Cabona, C and Gemelli, C and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Prevalence of cognitive impairment in motor neuron diseases: alternative norming methods lead to considerably diverse estimates.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2025.2488294}, pmid = {40222004}, issn = {2167-9223}, abstract = {Objectives: Cognitive impairment (CI) is frequently observed in motor neuron diseases (MNDs), and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) represents the most widely used measure to evaluate it. For the Italian ECAS, two norming approaches are currently available: the "regression-based" (R) and the "2 standard deviation-based" (2SD). In this study, we therefore aimed at comparing those two methods for the detection of CI in MNDs. Methods: Raw ECAS scores from 160 MND patients were corrected using both the R and the 2SD methods. According to Strong's criteria, patients were then categorized as either cognitively normal (CN), with CI (ALSci), with behavioral impairment (ALSbi), or both (ALScbi). Results: Using the R approach, the frequency of below-cutoff performances was 3.12% for the ECAS total, 4.37% for the ALS specific, and 3.75% for the ALS nonspecific score. Using the 2SD method, the prevalence increased to 25.62% for the ECAS total, 21.25% for the ALS specific, and 23.12% for the ALS nonspecific score. The same increase was observed across all single tasks except for the digit span backward. The R-based frequency of Strong's diagnoses was 7.50% for ALSci, 15.62% for ALSbi, and 3.14% for ALScbi, which became 24.38% for ALSci, 8.75% for ALSbi and 10% for ALScbi with the 2SD method. Conclusions: The norming approach has a significant impact on the estimated prevalence of CI in MNDs, with the R method representing the most conservative one. These findings highlight the need for harmonized protocols in future studies evaluating CI in MNDs.}, }
@article {pmid40220918, year = {2025}, author = {Key, J and Almaguer-Mederos, LE and Kandi, AR and Sen, NE and Gispert, S and Köpf, G and Meierhofer, D and Auburger, G}, title = {ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation.}, journal = {Neurobiology of disease}, volume = {}, number = {}, pages = {106903}, doi = {10.1016/j.nbd.2025.106903}, pmid = {40220918}, issn = {1095-953X}, abstract = {The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.}, }
@article {pmid40220686, year = {2025}, author = {Coloma, L and Aramendia, J and Amigo, JM and Población, I and Alberquilla, F and Gorla, G and Huidobro, J and Torre-Fdez, I and Arana, G and Madariaga, JM}, title = {Analysis and interpretation of organic compounds in Martian meteorites with Raman imaging and chemometrics.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {338}, number = {}, pages = {126194}, doi = {10.1016/j.saa.2025.126194}, pmid = {40220686}, issn = {1873-3557}, abstract = {One of the focuses of the research being developed on Mars (and consequently in samples from Mars) is the detection and study of organic compounds. Perseverance rover, currently analysing the Martian surface, is equipped with top-level instrumentation to detect mostly organic molecules. One of the techniques being used is Raman spectroscopy, due to its capability to analyse both inorganic and organic compounds simultaneously and its non-destructive and non-invasive properties. Unfortunately, it becomes cumbersome to determine the belonging of specific Raman bands in complex mixtures composed of an undetermined number of organic and inorganic molecules. Therefore, the study of this mixed information must be carried out with dedicated Chemometrics methods in order to understand the number of compounds present in a mixture (using Principal Component Analysis - PCA) and to obtain the pure spectra and the relative intensity of each compound (using spectral unmixing methods like Multivariate Curve Resolution - MCR). This manuscript presents an analysis of specific areas from the NWA 6148 Martian Nakhlite using Raman imaging, coupled with principal component analysis (PCA) and multivariate curve resolution (MCR), to determine the spatial distribution and spectral signatures of all organic and inorganic molecules present in these areas. The proposed methodology could be applied to the laboratory study of the future Mars-returned samples and other extraterrestrial samples returned to Earth.}, }
@article {pmid40219902, year = {2025}, author = {Lapp, HS and Günther, R}, title = {SOD1-ALS mimicking an inflammatory neuropathy: a case report.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2025.2488296}, pmid = {40219902}, issn = {2167-9223}, abstract = {We present the case of a 36-year-old patient with a rapidly progressing SOD1-ALS, who was initially diagnosed as inflammatory acute motor axonal neuropathy due to contrast-enhancement of the lumbar spinal cord and a pure secondary motor neuron phenotype. Since the initiation of tofersen, disease progression and neurofilament levels impressively declined.}, }
@article {pmid40218232, year = {2025}, author = {Iglesias, M and Cascón, JA and Maimó, A and Albaladejo, A and Andreo, F and Fernández, AS and Palazón, MM and González-Posada, IM and García, RG and Cordovilla, R}, title = {Evaluation of Diaphragmatic Ultrasound in Respiratory Functional Assessment in Patients with ALS.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {7}, pages = {}, doi = {10.3390/diagnostics15070884}, pmid = {40218232}, issn = {2075-4418}, support = {becaPII2019//SOCIEDAD ESPA&#xd1;OLA DE NEUMOLOG&#xcd;A Y CIRUG&#xcd;A TOR&#xc1;CICA (SEPAR)/ ; }, abstract = {Background: Diaphragmatic ultrasound emerges as a valuable non-invasive method for assessing diaphragm functionality in patients with amyotrophic lateral sclerosis (ALS). This study aimed to evaluate diaphragmatic ultrasound parameters in ALS, compare them with respiratory function tests, and determine whether they are associated with the need for non-invasive ventilation (NIV). Methods: This was a prospective, descriptive, and multicenter study across five centers, enrolling patients with recent diagnoses of ALS. At three-monthly visits, participants underwent both diaphragmatic ultrasound and pulmonary function testing. The following variables were analyzed: withdrawal from this study due to NIV or death, excursion, velocity, thickness, thickening fraction, and spirometric and respiratory muscle function values. Results: A total of 41 patients were included. A total of 24 (61.5%) patients left this study before the final year: 17 due to initiation of NIV, 4 due to clinical deterioration without NIV, and 3 due to death. Statistically significant moderate correlations were observed between diaphragmatic excursion and velocity and FVC and supine FVC (p < 0.001) and with MIP and the SNIP test (p < 0.05). No correlation was observed with thickening fraction. Additionally, lower baseline values in excursion were significantly associated with study withdrawal, along with reduced lung function (FVC, supine FVC, and MEP (p < 0.001). Conclusions: assessing diaphragmatic excursion by ultrasonography may serve as a useful tool for monitoring patients with ALS.}, }
@article {pmid40217081, year = {2025}, author = {Baek, SH and Tae, WS and Auer, D and Kim, BJ}, title = {Brain diffusion tensor imaging changes linked to the split hand phenomenon in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {12450}, pmid = {40217081}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; *Diffusion Tensor Imaging/methods ; Female ; Aged ; Middle Aged ; *Brain/diagnostic imaging/pathology/physiopathology ; Pyramidal Tracts/diagnostic imaging/pathology/physiopathology ; Anisotropy ; White Matter/diagnostic imaging/pathology ; }, abstract = {The split-hand phenomenon is an early and specific feature of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the split-hand phenomenon in ALS is associated with the white matter degeneration of the brain. Patients diagnosed with clinically definite or probable ALS were prospectively recruited and underwent both nerve conduction studies to assess the split-hand index (SHI) and brain diffusion tensor imaging (DTI). Demographic, clinical, and electrophysiological data were all collected. A total of 35 patients with ALS (18 male; median age, 66.0 years) were enrolled in this study. The axial diffusivity (AD) and mode of anisotropy (MO) values of DTI in the corticospinal tract (CST) positively correlated with the SHI. However, there were no significant correlations between the SHI and the fraction anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) scalars. In addition, patients having ALS with bilateral split-hand phenomenon showed reduced AD values in the left CST and reduced MO values in the bilateral CST compared with those without the split-hand phenomenon. However, there were no significant differences in FA, MD, and RD scalars. Our findings suggest that the split-hand phenomenon is associated with degenerative brain changes, particularly in the CST.}, }
@article {pmid40216746, year = {2025}, author = {Rezaei, A and Kocsis-Jutka, V and Gunes, ZI and Zeng, Q and Kislinger, G and Bauernschmitt, F and Isilgan, HB and Parisi, LR and Kaya, T and Franzenburg, S and Koppenbrink, J and Knogler, J and Arzberger, T and Farny, D and Nuscher, B and Katona, E and Dhingra, A and Yang, C and Gouna, G and LaClair, KD and Janjic, A and Enard, W and Zhou, Q and Hagan, N and Ofengeim, D and Beltrán, E and Gokce, O and Simons, M and Liebscher, S and Edbauer, D}, title = {Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {3442}, pmid = {40216746}, issn = {2041-1723}, support = {390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 407495230//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 423957469//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 390857198//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 101057649//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 101117710//EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)/ ; }, mesh = {Animals ; Female ; Mice ; *Oligodendroglia/metabolism/drug effects ; *Lipid Metabolism/drug effects/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/drug therapy/pathology ; *C9orf72 Protein/genetics/metabolism ; Disease Models, Animal ; Male ; Cholesterol/metabolism ; Humans ; *2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Mice, Transgenic ; Myelin Sheath/metabolism ; Spinal Cord/metabolism/pathology ; Longevity/drug effects/genetics ; }, abstract = {Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.}, }
@article {pmid40216201, year = {2025}, author = {Cagalinec, M and Adnan, M and Borecka, S and Bultynck, G and Choubey, V and Yanovsky-Dagan, S and Ezer, S and Gasperikova, D and Harel, T and Jurkovicova, D and Kaasik, A and Liévens, JC and Maurice, T and Peviani, M and Richard, EM and Skoda, J and Skopkova, M and Tarot, P and Van Gorp, R and Zvejniece, L and Delprat, B}, title = {Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {}, number = {}, pages = {119954}, doi = {10.1016/j.bbamcr.2025.119954}, pmid = {40216201}, issn = {1879-2596}, abstract = {Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca[2+] signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca[2+], reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca[2+]-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.}, }
@article {pmid40215589, year = {2025}, author = {Yaguchi, H and Miyagawa, S and Nakada, R and Yamamoto, S and Sakuta, K}, title = {Speech-swallow dissociation in velopharyngeal closure for differentiating amyotrophic lateral sclerosis and myasthenia gravis.}, journal = {Auris, nasus, larynx}, volume = {52}, number = {3}, pages = {239-242}, doi = {10.1016/j.anl.2025.03.003}, pmid = {40215589}, issn = {1879-1476}, abstract = {OBJECTIVE: Speech-swallow dissociation (SSD) in velopharyngeal closure on laryngoscopy is a sign of pseudobulbar palsy. We hypothesized that this finding could differentiate amyotrophic lateral sclerosis (ALS) from myasthenia gravis (MG). This study aimed to identify laryngoscopic findings useful in differentiating these two diseases.<br><br>METHODS: ALS and MG patients with bulbar symptoms who underwent fiberoptic laryngoscopy in our hospital were retrospectively examined. The following laryngoscopic items were evaluated: velopharyngeal incompetence (VPI) in phonation and swallowing, pharyngeal constriction, vocal cord movement, and salivary status.<br><br>RESULTS: One hundred seven patients (70 with ALS and 37 with MG) were included for analysis. The prevalence of VPI in phonation was significantly higher in the ALS group (40 % vs. 19 %; P = 0.027). The prevalence of SSD in velopharyngeal closure was also significantly higher in the ALS group (33 % vs. 3 %; P < 0.001). The other laryngoscopic findings did not differ between the groups. Multivariate logistic regression showed that SSD in velopharyngeal closure was independently associated with ALS (odds ratio, 26.64; 95 % confidence interval, 2.24-317.58; P = 0.009).<br><br>CONCLUSION: SSD in velopharyngeal closure is useful for differentiating ALS from MG.}, }
@article {pmid40214652, year = {2025}, author = {Yu, G and Liu, X and Huang, W and Wang, S and Zhan, J and Ma, L and Li, H and Lin, X and Liu, T and Amine, K and Li, H}, title = {Ferromagnetic Atomic d-p Orbital Hybridization for Promoting Al-S Batteries.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e2418784}, doi = {10.1002/adma.202418784}, pmid = {40214652}, issn = {1521-4095}, support = {tsqn202211118//Taishan Scholar Program of Shandong Province/ ; ZR2023YQ008//Excellent Youth Science Fund Project of Shandong China/ ; 2021KJ020//Outstanding Youth Innovation Team of Universities in Shandong Province/ ; 51804173//National Natural Science Foundation (NSFC) of China/ ; DE-SC0012704//Brookhaven National Laboratory under contract/ ; }, abstract = {Rechargeable aluminum-sulfur batteries (Al-S) are emerging as a promising alternative energy storage system beyond lithium-ion batteries due to their high energy density, abundant material resources, and economic efficiency. However, their practical application remains challenged by sluggish conversion kinetics, polysulfide shuttling, and low sulfur cathode utilization. While extensive studies have focused on enhancing polysulfide adsorption through catalytic strategies, the roles of electronic structure in dictating catalytic performance remain underexplored. Here, this work unveils the critical effect of unpaired electronic structure on the catalytic performance of single atom ferromagnetic transition metals through a systematic evaluation of three typical atomically dispersed ferromagnetic single atoms-Fe, Co, and Ni-supported on porous carbon (denoted as PC-SAFAs). Comprehensive characterizations and density functional theory (DFT) calculations reveal that the PC-SAFe catalysts, exhibiting the highest spin polarization arising from unpaired electrons, demonstrate the strongest interactions with polysulfide, thereby facilitating rapid and reversible polysulfide conversion reactions. Consequently, Al-S batteries incorporating the optimized PC-SAFe cathode achieve an impressive specific capacity of 508.8 mAh g[-1] at 1.0 A g[-1] after 500 cycles, along with much improved rate capability. This work provides a deeper understanding of the role of electronic structure in catalytic chemistry, and offers new insights for developing high-performance Al-S batteries.}, }
@article {pmid40214138, year = {2025}, author = {Reus, LM and Willemse, SW and de Boer, SCM and De Houwer, J and Hartog, WL and Mol, MO and van Rooij, JGJ and Tesi, N and Donker Kaat, L and Hulsman, M and Vijverberg, EGB and Holstege, H and van Rheenen, W and Veldink, JH and van den Berg, LH and van Swieten, JC and Seelaar, H and van der Lee, SJ and van Es, MA and Pijnenburg, YAL}, title = {UNC13A Polymorphism Influences Survival in Patients with Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27245}, pmid = {40214138}, issn = {1531-8249}, abstract = {UNC13A (rs12608932-CC) is associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and shortens survival in ALS. We aim to describe the association for UNC13A and survival in FTD. We included 626 patients with FTD from Dutch memory clinics, including a subcohort of 150 patients with TDP-43 pathology. Survival analyses were performed using Cox proportional hazard models in a recessive manner. Homozygosity for rs12608932-C in UNC13A was associated with a shorter survival compared with other genotypes (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.02-1.60, p = 0.033), which has implications for patient counselling and trial design. ANN NEUROL 2025.}, }
@article {pmid40213728, year = {2025}, author = {Grigore, A and Goebel, LJ}, title = {Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: A Case Report and Clinical Insights.}, journal = {Cureus}, volume = {17}, number = {3}, pages = {e80329}, pmid = {40213728}, issn = {2168-8184}, abstract = {Primary care providers are often the first contact for patients with neurodegenerative illnesses, however, they may not be aware of the relationship of certain diseases that may have an impact on their patients' longevity. This case report reminds clinicians of the association between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Physicians should be aware of the association, because FTD commonly occurs first and may prepare clinicians to be alert to the signs of ALS in these patients, leading to earlier detection of ALS and the prescription of disease-modifying medication that may extend the lifespan of people with these diseases. We describe the case of a 61-year-old female patient initially presenting with cognitive decline most likely due to FTD who subsequently developed ALS.}, }
@article {pmid40213632, year = {2025}, author = {Dezawa, M}, title = {Macrophage- and pluripotent-like reparative Muse cells are unique endogenous stem cells distinct from other somatic stem cells.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1553382}, pmid = {40213632}, issn = {2296-4185}, abstract = {Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of ∼1.5 × 10[7] donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.}, }
@article {pmid40212206, year = {2025}, author = {Basnet, P and Singh, PR and Pudasaini, KR and Shrestha, S and Kc, A}, title = {A rare case of symmetric quadriplegia in a patient with Japanese encephalitis: a case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {4}, pages = {2430-2433}, pmid = {40212206}, issn = {2049-0801}, abstract = {INTRODUCTION AND IMPORTANCE: Acute flaccid paralysis is a rare neurological complication of Japanese encephalitis (JE) infection, which may involve one or multiple limbs. Symmetric involvement of upper and lower limbs such as in this case is rarely reported.<br><br>PRESENTATION OF CASE: We present a case of a 30-year-old male from Terai region of Nepal who presented with fever, altered level of consciousness, and symmetrical quadriplegia. Based on these clinical findings, cerebrospinal fluid (CSF) analysis was done which came back negative. And based on results, polymerase chain reaction for herpes simplex virus types I and II was done which came out negative. Other neurological conditions such as amyotrophic lateral sclerosis and spinal dystrophy were ruled out because of the presence of fever and altered mental status. He was eventually diagnosed with JE based on his CSF analysis and positive result for JE serology/IgM Antibody Capture Enzyme-Linked Immunosorbent Assay test.<br><br>CLINICAL DISCUSSION: The patient presented with fever, altered mental status, and symmetrical flaccid paralysis of the bilateral upper and lower limb. Symmetrical involvement of the upper and the lower limbs is unusual in most cases of JE.<br><br>CONCLUSION: This case highlights the importance of awareness on the part of the clinician about the possibilities of atypical presentation in JE. It also emphasizes that Japanese encephalitis should be a part of the differential in patients with atypical neurological presentation in endemic areas.}, }
@article {pmid40212027, year = {2025}, author = {Menezes, AT and Nagasse, HY and Lopes, HRM and Coltri, PP}, title = {Design of a GFP reporter for splicing analysis in mammalian cells.}, journal = {Biotechnology reports (Amsterdam, Netherlands)}, volume = {46}, number = {}, pages = {e00887}, pmid = {40212027}, issn = {2215-017X}, abstract = {Eukaryotic genes are formed by exons and introns. Pre-mRNA splicing promotes exon ligation and intron removal and is performed by a specialized macromolecular machinery named spliceosome, composed of five small ribonucleoprotein particles (snRNPs) and more than one hundred proteins. The activity of this complex is highly accurate due to the coordinated activity of its components. Altered splicing has been related to the development of several diseases, including neurodegenerative disorders, such as amyotrophic lateral sclerosis, and different types of cancer. Detailed understanding of splicing regulation in eukaryotic cells can be achieved using splicing reporter systems. We designed a reporter plasmid suitable for splicing analysis in cultured mammalian cells. Our reporter is based on GFP expression, and the splicing outcome can be easily visualized by fluorescence microscopy. We quantified splicing activity in two human cell lines, HEK-293T and MDA-MB-231, confirming its suitability for use in live cells in culture.}, }
@article {pmid40139318, year = {2025}, author = {Lai, IC and Wei, JC}, title = {Comment on Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study.".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.12.054}, pmid = {40139318}, issn = {1097-6787}, }
@article {pmid40210846, year = {2025}, author = {Joyce, EE and Yin, W and Löf, M and Wirdefeldt, K and Sandin, S and Fang, F}, title = {Mediterranean dietary pattern and risk of neurodegenerative diseases in a cohort of Swedish women.}, journal = {NPJ Parkinson's disease}, volume = {11}, number = {1}, pages = {71}, pmid = {40210846}, issn = {2373-8057}, support = {802091/ERC_/European Research Council/International ; R01TS000324-01-00/CC/CDC HHS/United States ; 2019-01088//Vetenskapsr&#xe5;det/ ; }, abstract = {Mediterranean dietary patterns (MDP) may be neuroprotective. Using a large population-based cohort of 42,582 Swedish women, this study examined the association between MDP adherence and the risk of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). During 1991-1992, women in the Women's Lifestyle and Health Study reported dietary intake, and MDP adherence was calculated. Incident neurodegenerative diseases were identified using the Swedish National Patient Register through 2022. Women who reported high MDP adherence had a lower risk of PD (HR: 0.69, 95% CI: 0.49-0.95), primarily over age 60 (HR: 0.68, 95% CI: 0.47-0.97). A moderate-high MDP adherence was associated with a lower risk of ALS before age 60 (HR: 0.44, 95% CI: 0.19-0.99), but not overall. We observed no association between MDP adherence and AD. Our findings suggest higher adherence to a MDP may be protective against PD above age 60, and ALS before age 60.}, }
@article {pmid40210682, year = {2025}, author = {Perciballi, E and Bovio, F and Ferro, S and Forcella, M and Rosati, J and Carletti, RM and D'Anzi, A and Gelati, M and La Bella, V and Innocenti, M and Spataro, R and Pecoraro, M and Lombardi, I and Vulcano, E and Ruotolo, G and Mercurio, S and Sabatelli, M and Lattante, S and Malm, T and Ohtonen, S and Vescovi, AL and Fusi, P and Ferrari, D}, title = {Mitochondrial and energy metabolism dysfunctions are hallmarks of TDP-43[G376D] fibroblasts from members of an Amyotrophic Lateral Sclerosis family.}, journal = {Cell death &amp; disease}, volume = {16}, number = {1}, pages = {272}, pmid = {40210682}, issn = {2041-4889}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Fibroblasts/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; *Mitochondria/metabolism/pathology/genetics ; *Energy Metabolism/genetics ; Male ; Female ; Middle Aged ; Mutation/genetics ; Glycolysis ; Pedigree ; Adult ; Cell Proliferation ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease, causing degeneration of motor neurons, paralysis, and death. About 5-10% of cases are associated with gene mutations inherited from a family member (fALS). Among them, mutations in the transactive-response (TAR)-DNA-binding protein (TARDBP), which encodes for the TAR DNA binding protein 43 (TDP-43) are responsible for 4-5% of fALS but the molecular mechanisms that initiate and sustain the neurodegenerative process are largely unknown. Metabolic impairments might be involved in the pathogenesis of ALS and are currently under investigation. In order to correlate biochemical and metabolic alterations with disease progression, here, we established the metabolic fingerprint of dermal fibroblasts derived from symptomatic and asymptomatic members of a family with fALS cases carrying to the p.G376D mutation in TDP-43. We found that increased proliferation, unbalanced oxidative homeostasis and higher ATP production rate coupled with enhanced metabolic activity are underlying traits of this family. Fibroblasts from carrier individuals deploy several mechanisms to increase mitochondrial respiration to meet increasing energy demands. This is accompanied by an upregulation of glycolysis corresponding to a metabolic reprograming towards a glycolytic phenotype for ATP production during ALS progression, particularly in late disease stages. In summary, we uncover alterations in energy metabolism in TDP43[G376D] patient-derived primary fibroblasts that may be used as risk biomarkers and/or to monitor ALS progression.}, }
@article {pmid40209696, year = {2025}, author = {Hawas, Y and Hamad, AA and Meshref, M and Elbehary, M and Mohamed, RG and Elshahat, A and Mabrouk, MA and Nashwan, AJ and Fouda, BH}, title = {Clinical Features, Diagnostic Implications, And Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review.}, journal = {Medical principles and practice : international journal of the Kuwait University, Health Science Centre}, volume = {}, number = {}, pages = {1-18}, doi = {10.1159/000545806}, pmid = {40209696}, issn = {1423-0151}, abstract = {OBJECTIVE: This review aims to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.<br><br>METHODS: Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.<br><br>RESULTS: 42 cases were categorized into four groups as follows: The first group had 26 cases with MG onset (range 26-82 years) preceding ALS (range 46-83 years). The second group had 9 cases with ALS (range 34-89) preceding MG (range 40-89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.<br><br>CONCLUSION: The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.}, }
@article {pmid40209306, year = {2025}, author = {Meanti, R and Bresciani, E and Rizzi, L and Molteni, L and Coco, S and Omeljaniuk, RJ and Torsello, A}, title = {Cannabinoid Receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {186}, number = {}, pages = {118044}, doi = {10.1016/j.biopha.2025.118044}, pmid = {40209306}, issn = {1950-6007}, abstract = {The endocannabinoid system (ECS) is a ubiquitous physiological system that plays a crucial role in maintaining CNS homeostasis and regulating its functions. It includes cannabinoid receptors (CBRs), endogenous cannabinoids (eCBs), and the enzymes responsible for their synthesis and degradation. In recent years, growing evidence has highlighted the therapeutic potential of the ECS and CBRs, in a wide range of severe diseases and pathological conditions, including Alzheimer's and Parkinson's diseases, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington's Disease, HIV-1 associated neurocognitive disorders, neuropathic pain and migraine. Targeting the cannabinoid type 2 receptor (CB2R) has gained attention due to its ability to (i) mitigate neuroinflammatory responses, (ii) regulate mitochondrial function and (iii) provide trophic support, all without eliciting the psychotropic actions associated with CB1R activation. This review aims to explore the potential of CB2R modulation as a strategy for the prevention and treatment of neurologic disorders, exploring both preclinical and clinical findings.}, }
@article {pmid40207633, year = {2025}, author = {Luteijn, MJ and Bhaskar, V and Trojer, D and Schürz, M and Mahboubi, H and Handl, C and Pizzato, N and Pfeifer, M and Dafinca, R and Voshol, H and Giorgetti, E and Manneville, C and Garnier, IPM and Müller, M and Zeng, F and Buntin, K and Markwalder, R and Schröder, H and Weiler, J and Khar, D and Schuhmann, T and Groot-Kormelink, PJ and Keller, CG and Farmer, P and MacKay, A and Beibel, M and Roma, G and D'Ario, G and Merkl, C and Schebesta, M and Hild, M and Elwood, F and Vahsen, BF and Ripin, N and Clery, A and Allain, F and Labow, M and Gabriel, D and Chao, JA and Talbot, K and Nash, M and Hunziker, J and Meisner-Kober, NC}, title = {High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.}, journal = {Nucleic acids research}, volume = {53}, number = {7}, pages = {}, doi = {10.1093/nar/gkaf253}, pmid = {40207633}, issn = {1362-4962}, support = {EFRE/IWB 20102-F1900731-KZP//European Funds for Regional Development/ ; WISS2025 F2200397-KZP//Salzburger Landesregierung/ ; }, mesh = {Humans ; *Spliceosomes/drug effects/metabolism/genetics ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Protein Biosynthesis/drug effects ; Active Transport, Cell Nucleus/drug effects ; Serine-Arginine Splicing Factors/metabolism ; *Neurons/metabolism/drug effects ; High-Throughput Screening Assays ; *Small Molecule Libraries/pharmacology ; DNA Repeat Expansion ; RNA/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Cell Nucleus/metabolism ; }, abstract = {An intronic G4C2 repeat expansion in the C9ORF72 gene is the major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence for both, loss of function and pathological gain of function disease mechanisms. We screened 96 200 small molecules in C9ORF72 patient iPS neurons for modulation of nuclear G4C2 RNA foci and identified 82 validated hits, including the Brd4 inhibitor JQ1 as well as novel analogs of Spliceostatin-A, a known modulator of SF3B1, the branch point binding protein of the U2-snRNP. Spliceosome modulation by these SF3B1 targeted compounds recruits SRSF1 to nuclear G4C2 RNA, mobilizing it from RNA foci into nucleocytoplasmic export. This leads to increased repeat-associated non-canonical (RAN) translation and ultimately, enhanced cell toxicity. Our data (i) provide a new pharmacological entry point with novel as well as known, publicly available tool compounds for dissection of C9ORF72 pathobiology in C9ORF72 ALS models, (ii) allowing to differentially modulate RNA foci versus RAN translation, and (iii) suggest that therapeutic RNA foci elimination strategies warrant caution due to a potential storage function, counteracting translation into toxic dipeptide repeat polyproteins. Instead, our data support modulation of nuclear export via SRSF1 or SR protein kinases as possible targets for future pharmacological drug discovery.}, }
@article {pmid40205152, year = {2025}, author = {Mohan, M and Mannan, A and Singh, TG}, title = {Unravelling the role of protein kinase R (PKR) in neurodegenerative disease: a review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {377}, pmid = {40205152}, issn = {1573-4978}, mesh = {Humans ; *eIF-2 Kinase/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Parkinson Disease/metabolism/genetics ; Huntington Disease/genetics/metabolism ; Alzheimer Disease/metabolism/genetics ; Mitochondria/metabolism ; }, abstract = {Protein Kinase R is an essential regulator of many cell activities and belongs to one of the largest and most functionally complex gene families. These are found all over the body, and by adding phosphate groups to the substrate proteins, they regulate their activity and coordinate the action of almost all cellular processes. Recent research has illuminated the involvement of PKR in the pathogenesis of neurodegenerative disorders (NDs), thereby expanding our understanding of intricate molecular mechanisms underlying disease progression. Through their inhibition or activation, they hold potential therapeutic targets for the pathogenesis or protection of NDs. In the case of AD (AD), PKR contributes to the protection or elevation of Aβ accumulation, neuroinflammation, synaptic plasticity alterations, and neuronal excitability. Similarly, in Parkinson's disease (PD), PKR again has a dual role in dopaminergic neuronal loss, gene mutations, and mitochondrial dysfunction via various pathways. Notably, neuronal excitotoxicity, as well as genetic mutations, have been linked to ALS. In Huntington's disease (HD), PKR is associated with decreased or increased mutated genes, striatal neuron degeneration, neuroinflammation, and excitotoxicity. This review emphasizes strategies that target PKR for the treatment of neurodegenerative disorders. Doing so offers valuable insights that can guide future research endeavors and the development of innovative therapeutic approaches.}, }
@article {pmid40204975, year = {2025}, author = {Wolmer, PS and de Borba, FC and de Rezende, TJR and González-Salazar, C and Pedroso, JL and Barsottini, OGP and Kleinerova, J and Bede, P and Marques, W and França, MC}, title = {Distinct patterns of cerebral and spinal pathology along the spectrum of ATXN2-related disorders.}, journal = {Journal of neurology}, volume = {272}, number = {5}, pages = {330}, pmid = {40204975}, issn = {1432-1459}, support = {2013/07559-3//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; }, mesh = {Humans ; Male ; *Ataxin-2/genetics ; Female ; Middle Aged ; *Spinocerebellar Ataxias/pathology/genetics/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/pathology/genetics/diagnostic imaging ; Adult ; Magnetic Resonance Imaging ; Aged ; *Spinal Cord/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Neuroimaging ; }, abstract = {BACKGROUND: The ATXN2 gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27-34 repeats pose a risk for ALS (ATXN2-ALS), and > 34 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two ATXN2-related conditions are not yet fully understood.<br><br>OBJECTIVE: To characterize and compare the distinguishing radiological signatures of ATXN2-ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques.<br><br>METHODS: Four groups were defined: healthy controls (n&#x2009;= 34), sALS (n&#x2009;= 17), ATXN2-ALS (n&#x2009;= 16), and SCA2 (n&#x2009;= 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral ATXN2 expression maps from the Allen Human Brain Atlas.<br><br>RESULTS: Study groups were age and sex-matched. sALS, ATXN2-ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the ATXN2-ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain ATXN2 expression correlated with the structural signature of SCA2, but not with that of ATXN2-ALS.<br><br>CONCLUSIONS: Neuroimaging signatures differ in ATXN2-ALS and SCA2, indicating distinct mechanisms of ATXN2-mediated neurodegeneration. sALS and ATXN2-ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.}, }
@article {pmid40204667, year = {2025}, author = {Parajuli, S and McDonald, MR and Adhikari, L and Wolyn, DJ}, title = {Genetic architecture of anthocyanin pigment traits and purple spot (Stemphylium vesicarium) resistance in an F1 pseudo-testcross population of asparagus.}, journal = {The plant genome}, volume = {18}, number = {2}, pages = {e70028}, doi = {10.1002/tpg2.70028}, pmid = {40204667}, issn = {1940-3372}, support = {ASC-18/19//Canadian Agri-Science Cluster for Horticulture 3/ ; //Asparagus Farmers of Ontario/ ; //Agriculture and Agri-Food Canada/ ; UofGT2-2019-27360//Ontario Ministry of Agriculture Food and Rural Affairs/ ; }, mesh = {*Anthocyanins/genetics/metabolism ; Quantitative Trait Loci ; *Plant Diseases/microbiology/genetics ; *Disease Resistance/genetics ; *Asparagus Plant/genetics/microbiology/metabolism ; *Ascomycota/pathogenicity/physiology ; Phenotype ; Crosses, Genetic ; Plant Leaves/genetics/microbiology ; }, abstract = {Stemphylium vesicarium (Wallr.) Simmons is a plant pathogenic fungus causing purple spot in both fern and spears of asparagus (Asparagus officinalis L.). Although the fern can be sprayed with fungicides to control the disease, pesticide applications during spear harvest are restricted. Infected spears can develop prominent pigmentation at lesion sites, reducing marketable yield. Breeding resistant asparagus cultivars with decreased lesion numbers and reduced purpling at the site of infection is considered the most economical and sustainable approach to combat this disease. The objectives of this study were to determine the genetic architectures of, and relationships among, anthocyanin pigment expression in spear scale leaves (ALS) and spear lesions (APS) and purple spot levels in spears (NPS) and fern (PSF). Traits were phenotyped over 2 years under natural conditions in an F1 pseudo-testcross population, and quantitative trait loci (QTL) were mapped. ALS, APS, NPS, and PSF were not correlated, suggesting independent regulation of the anthocyanin pathway in scale leaves and lesions and no relationship between pigment and disease. Segregation, 3 red:1 purple and 3 red:13 purple, was observed in scale leaves and lesions, respectively. Two stable QTL for each of ASL, APS, and NPS, one tentative QTL for ASL, four tentative QTL for APS, two tentative QTL for NPS, and three tentative QTL for PSF were identified. Candidate genes were found for four loci. This study advances the genetic understanding of anthocyanin pigmentation at a tissue-specific level, and purple spot disease severity in spears and fern, supporting future breeding efforts.}, }
@article {pmid40203833, year = {2025}, author = {Shen, D and Vincent, A and Udine, E and Buhidma, Y and Anoar, S and Tsintzas, E and Maeland, M and Xu, D and Carcolé, M and Osumi-Sutherland, D and Aleyakpo, B and Hull, A and Martínez Corrales, G and Woodling, N and Rademakers, R and Isaacs, AM and Frigerio, C and van Blitterswijk, M and Lashley, T and Niccoli, T}, title = {Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1-induced endoplasmic reticulum-associated degradation.}, journal = {Cell reports}, volume = {}, number = {}, pages = {115459}, doi = {10.1016/j.celrep.2025.115459}, pmid = {40203833}, issn = {2211-1247}, abstract = {Neurodegenerative diseases are characterized by the localized loss of neurons. Why cell death is triggered only in specific neuronal populations and whether it is the response to toxic insults or the initial cellular state that determines their vulnerability is unknown. To understand individual cell responses to disease, we profiled their transcriptional signatures throughout disease development in a Drosophila model of C9orf72 (G4C2) repeat expansion (C9), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. We identified neuronal populations specifically vulnerable or resistant to C9 expression and found an upregulation of protein homeostasis pathways in resistant neurons at baseline. Overexpression of Xbp1s, a key regulator of the unfolded protein response and a central node in the resistance network, rescues C9 toxicity. This study shows that neuronal vulnerability depends on the intrinsic transcriptional state of neurons and that leveraging resistant neurons' properties can boost resistance in vulnerable neurons.}, }
@article {pmid40203806, year = {2025}, author = {Johnson, AM and Lukens, JR}, title = {Glia get RIPped in ALS.}, journal = {Immunity}, volume = {58}, number = {4}, pages = {778-780}, doi = {10.1016/j.immuni.2025.03.013}, pmid = {40203806}, issn = {1097-4180}, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology/metabolism ; Humans ; Animals ; *Neuroglia/immunology/metabolism ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/immunology ; *Microglia/immunology/metabolism ; *Astrocytes/immunology/metabolism ; Mice ; Neuroinflammatory Diseases/immunology ; Disease Models, Animal ; }, abstract = {While neuroinflammatory responses driven by microglia and astrocytes have been extensively linked to neurodegenerative disease progression in amyotrophic lateral sclerosis (ALS), the specific pathways that coordinate glial cell-dependent neuroinflammation in ALS remain poorly defined. In this issue of Immunity, Zelic et al.[1] identified RIPK1 as a pivotal regulator of glial cell-driven neuroinflammation in multiple ALS models.}, }
@article {pmid40202986, year = {2025}, author = {Askarova, A and Yaa, RM and Marzi, SJ and Nott, A}, title = {Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways.}, journal = {PLoS genetics}, volume = {21}, number = {4}, pages = {e1011407}, doi = {10.1371/journal.pgen.1011407}, pmid = {40202986}, issn = {1553-7404}, abstract = {Genome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites, while schizophrenia heritability is predominantly enriched at chromatin contact sites in neurons followed by oligodendrocytes. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA), we identified disease risk genes for Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions and within neurons for schizophrenia. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.}, }
@article {pmid40202704, year = {2025}, author = {Oyovwi, MO and Chijiokwu, EA and Ben-Azu, B and Atere, AD and Joseph, UG and Ogbutor, UG and Udi, OA}, title = {Potential Roles of Natural Antioxidants in Modulating Neurodegenerative Disease Pathways.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40202704}, issn = {1559-1182}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are increasingly prevalent among aging populations. Oxidative stress contributes to these diseases, leading to cellular damage and neuronal death. Natural antioxidants are being explored as preventive measures. This study aims to assess the effectiveness of natural antioxidants in delaying the onset or progression of neurodegenerative diseases by identifying their specific mechanisms of action. A comprehensive review of existing literature was conducted, focusing on studies that examine the role of natural antioxidants in neuroprotection. Key natural antioxidants, including flavonoids, polyphenls, vitamins C and E, and omega-3 fatty acids, were reviewed and analyzed for their bioavailability, mechanisms of action, and outcomes in both in vitro and in vivo studies. Additionally, clinical trials involving human subjects were considered to provide insights into the translational implications of antioxidant consumption. The findings suggest that several natural antioxidants exhibit neuroprotective properties by modulating oxidative stress, reducing inflammation, and promoting neuronal survival. For instance, flavonoids such as quercetin and resveratrol have shown promise in enhancing cognitive function and mitigating the pathophysiological alterations associated with neurodegeneration. In clinical studies, higher intakes of dietary antioxidants were correlated with a reduced risk of developing neurodegenerative disorders. Natural antioxidants offer potential for preventing neurodegenerative diseases by counteracting oxidative stress and maintaining cellular integrity. Overall, our report recommends that further research is needed to optimize dosages and understand their long-term benefits.}, }
@article {pmid40202498, year = {2025}, author = {Gu, J and Yang, M and Zhang, L and Liu, Y and Yan, R and Pan, D and Qian, X and Hu, H and Chu, D and Hu, C and Liu, F and Cui, H}, title = {Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination.}, journal = {The Journal of cell biology}, volume = {224}, number = {5}, pages = {}, doi = {10.1083/jcb.202405142}, pmid = {40202498}, issn = {1540-8140}, support = {32171258//National Natural Science Foundation of China/ ; BK20211329//Natural Science Foundation of Jiangsu Province/ ; //Co-Innovation Center of Neuroregeneration/ ; //Nantong University/ ; }, mesh = {Animals ; *ARNTL Transcription Factors/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Ubiquitination ; *Circadian Rhythm/genetics ; Humans ; Mice ; *RNA Splicing/genetics ; *Ubiquitin-Specific Proteases/genetics/metabolism ; Mice, Inbred C57BL ; Male ; HEK293 Cells ; }, abstract = {Circadian rhythm disorders are common characteristics of neurodegenerative diseases. The pathological aggregation of transactive response DNA-binding protein 43 (TDP-43) is associated with multiple neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the relationship between TDP-43 and circadian rhythm remains unknown. Here, we found that TDP-43 is rhythmically expressed both in vivo and in vitro. TDP-43 knockdown affected the expression of circadian genes, including BMAL1, CLOCK, CRY1, and PER2, and impaired autonomous circadian wheel behavior, cognitive functions, and balance abilities in mice. Furthermore, TDP-43 knockdown induced aberrant splicing of ubiquitin-specific peptidase 13 (USP13) and blocked USP13 rhythmic expression, enhancing the ubiquitination of BMAL1. Meanwhile, TDP-43 knockdown altered the rhythmic expression of phospho-AMPKα (Thr172) and platelet-type phosphofructokinase (PFKP), which may change cellular glucose uptake and ATP production. Our findings further the understanding of the role of TDP-43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidence supporting the interaction between circadian rhythm disruption and neurodegeneration.}, }
@article {pmid40200760, year = {2025}, author = {Herrmann, C and Uzelac, Z and Michels, S and Weber, A and Richter, L and Elmas, Z and Jagodzinski, L and Wurster, C and Schuster, J and Dreyhaupt, J and Dorst, J}, title = {Alterations of Fat and Ketone Body Metabolism in ALS and SMA-A Prospective Observational Study.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70132}, doi = {10.1111/ene.70132}, pmid = {40200760}, issn = {1468-1331}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism ; *Ketone Bodies/metabolism ; Male ; Female ; Middle Aged ; Prospective Studies ; *Muscular Atrophy, Spinal/metabolism ; Aged ; Adult ; Energy Metabolism/physiology ; *Adipose Tissue/metabolism ; Fatty Acids, Nonesterified/metabolism/blood ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerdosis (ALS) and spinal muscular atrophy (SMA) are motor neuron diseases associated with distinct metabolic alterations. ALS patients feature an increased resting energy expenditure (REE) causing weight loss and cachexia. In SMA, a disturbed utilization of free fatty acids has been described. These metabolic alterations negatively affect prognosis in both diseases. The objective of this study was to further characterize these changes to identify potential therapeutic targets.<br><br>METHODS: Between 11/2020 and 08/2022, 112 ALS patients, 77 SMA patients, and 50 controls were recruited in the Department of Neurology of Ulm University. Standardized blood and urinary samples were collected to analyze fat and ketone metabolism.<br><br>RESULTS: Ketone body levels were higher in ALS and SMA compared to controls. In both diseases, patients with higher BMI featured higher ketone bodies and free fatty acids compared to those with lower BMI, while in controls we found the opposite phenomenon. In SMA, more severe disease types were associated with higher ketone body levels. Compared to ALS, SMA patients featured higher ketone body and free fatty acid levels.<br><br>CONCLUSIONS: Our data suggest that already during early disease stages, ALS patients produce ketone bodies to compensate for the energy deficit. In SMA, on the other hand, the persistence of ketogenesis may indicate an upregulation of all available metabolic pathways for energy production due to the disturbance of fatty acid utilization. Therefore, the application of additional sources of energy, such as ketone bodies, might constitute a promising therapeutic option in both diseases.}, }
@article {pmid40200577, year = {2025}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Perez, KD and Li, D and Cheung, VG and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100435}, doi = {10.1016/j.xhgg.2025.100435}, pmid = {40200577}, issn = {2666-2477}, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.}, }
@article {pmid40200520, year = {2025}, author = {Nikiema, SLW and Barro, SG and Kantagba, YMK and Kouraogo, BAJ and Staccini, P}, title = {Design and Development of a Virtual Reality Tool for Adult Basic Life Support Training.}, journal = {Studies in health technology and informatics}, volume = {323}, number = {}, pages = {414-418}, doi = {10.3233/SHTI250123}, pmid = {40200520}, issn = {1879-8365}, mesh = {*Virtual Reality ; Humans ; *Cardiopulmonary Resuscitation/education/instrumentation ; Adult ; *User-Computer Interface ; }, abstract = {The research introduces a Virtual Reality (VR) instrument for Adult Basic Life Support (ABLS) training, employing Blender for 3D modeling, Unity3D for VR environment creation, XChart for data visualization, and the Oculus Quest 2 as the principal VR headset. The device replicates authentic emergency situations, offering immediate feedback on CPR execution. Preliminary findings indicate enhancements in technical proficiency and user engagement; nonetheless, issues like as motion sickness and scalability remain unresolved. Future improvements will concentrate on sophisticated haptic feedback and ALS scenarios.}, }
@article {pmid40200352, year = {2025}, author = {Li, J and Tang, S and Li, J and Huang, X and Liu, Y and Zeng, J and Fan, Y}, title = {Incidence and health burden of 20 rare neurological diseases in South China from 2016 to 2022: a hospital-based observational study.}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {163}, pmid = {40200352}, issn = {1750-1172}, support = {202007030010//Guangzhou Science and Technology Program Key Projects/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; }, mesh = {Humans ; China/epidemiology ; Male ; Female ; *Nervous System Diseases/epidemiology ; Incidence ; Adult ; Middle Aged ; *Rare Diseases/epidemiology ; Adolescent ; Child ; Aged ; Young Adult ; Hospitals ; }, abstract = {BACKGROUND: Rare neurological diseases (RNDs) result in severe health burdens worldwide. Data from China are limited. We aimed to investigate the health burden of 20 RNDs in Guangdong Province (GD), which contains two-thirds of the population of South China.<br><br>METHODS: The hospitalization data of 20 RNDs were described using hospital-based front sheet data from 3,037 hospitals of GD from 2016 to 2022. The 20 RNDs included amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, congenital myotonia, congenital myasthenic syndrome, Dravet syndrome, Fabry disease, hereditary spastic paraplegia, Huntington disease, Leber hereditary optic neuropathy, mitochondrial encephalopathy (ME), multi-focal motor neuropathy, myotonic dystrophy, primary hereditary dystonia, progressive muscular dystrophy (PMD), spinal and bulbar muscular atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, Wilson disease (WD) and X-linked adrenoleukodystrophy. Age were presented as mean and standard deviation while length of hospital stay as median and interquartile range (25th and 75th percentiles). The other variables were described as number and percentage. The data were analyzed by Joinpoint regression.<br><br>RESULTS: There were 9,351 cases, including 330 ICU and 155 death cases. The average age was 33.7&#x2009;&#xb1;&#x2009;22.0 y, and 63.8% of patients were male. From 2016 to 2022, the number of RND (and juvenile RND) cases were 1034 (184), 1174 (293), 1443 (374), 1422 (320), 1331 (337), 1432 (409) to 1515 (515). ICU (and juvenile ICU) cases rose from 28 (3), 34 (6), 24 (4), 38 (11), 46 (13), 54 (24) to 106 (56). Joinpoint regression showed significant upward trend in percentages of juvenile and juvenile ICU cases (APC&#x2009;=&#x2009;8.13, P< 0.05; APC&#x2009;=&#x2009;28.42, P< 0.05). The fop five RNDs were WD, ASL, PMD, ME, and SMA, which accounted for 79.7% of all, 99.1% of ICU, and 94.8% of death cases.<br><br>CONCLUSIONS: We demonstrated that the increase in health burden of RNDs was mainly evident in juveniles in South China from 2016 to 2022. The top 5 RNDs accounted for majority of the critical patients.}, }
@article {pmid40199586, year = {2025}, author = {Fyrberg, E and Learnard, H and Lee, S and Jun, YW and Gao, FB}, title = {New Mouse Lines that Drive Tetracycline-Controlled Gene Expression in a Small Subset of Spinal Cord Dorsal Horn Neurons.}, journal = {eNeuro}, volume = {}, number = {}, pages = {}, doi = {10.1523/ENEURO.0441-24.2025}, pmid = {40199586}, issn = {2373-2822}, abstract = {Mouse lines with tetracycline-controlled gene expression in specific neuronal populations provide valuable tools for studying their development, function, connectivity and pathology in vivo. Our initial goal was to generate a mouse model that could express amyotrophic lateral sclerosis (ALS)-associated genes specifically in spinal cord motor neurons under the control of the HB9 promoter. However, HB9-tTA mice unexpectedly direct target gene expression in a small subset of dorsal horn neurons. These mice represent a new tool for scientists who are interested in studying these spinal cord neurons.Significance Statement We have generated new mouse lines that can manipulate gene expression in a small subset of dorsal horn neurons in the spinal cord. These new tools will be useful for scientists who are interested in studying the development, function, and connectivity of this small subset of spinal neurons in vivo.}, }
@article {pmid40198794, year = {2025}, author = {Corucci, G and Vadukul, DM and Paracini, N and Laux, V and Batchu, KC and Aprile, FA and Pastore, A}, title = {Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.5c00594}, pmid = {40198794}, issn = {1520-5126}, abstract = {TDP-43 protein is an RNA-binding protein linked to amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer disease. While normally a protein that shuttles between the nucleus and cytoplasm, TDP-43 has recently been found also in extracellular vesicles. These are an important medium for cell-cell communication that allows the transfer of lipids, proteins, and genetic material among cells. An increasing concern in neurodegenerative diseases, however, is the possibility that extracellular vesicles can also provide an effective way to spread misfolded proteins that could "infect" other cells according to a "prion-like" mechanism. To characterize the interaction of TDP-43 with lipid membranes, we carried out a systematic biophysical study using a TDP-43 fragment lacking the first 84 N-terminal residues, called M85, and synthetic model phospholipid membranes. We utilized standard techniques, such as fluorescence and microscopy, complemented by neutron reflectivity measurements. Our results show that lipid charge affects the modality by which M85 interacts with membranes: a higher negative charge induces the protein to bind to the bilayer surface, promoting protein aggregation and decreasing lipid bilayer damage that this interaction causes. Thus, we speculate that the M85-lipid membrane interaction could play an important and previously undefined role in TDP-43-related neurodegenerative diseases.}, }
@article {pmid40198473, year = {2025}, author = {Seok, HY}, title = {Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40198473}, issn = {1590-3478}, abstract = {Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.}, }
@article {pmid40196899, year = {2025}, author = {Li, S and Pandat, T and Chi, B and Moon, D and Mas, M}, title = {Management Approaches to Spastic Gait Disorders.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28402}, pmid = {40196899}, issn = {1097-4598}, abstract = {Spastic gait presents clinically as the net mechanical consequence of neurological impairments of spasticity, weakness, and abnormal synergies and their interactions with the ground reaction force in patients with upper motor neuron syndromes and with some neuromuscular diseases. It is critical to differentiate whether the primary problem is weakness or spasticity, thus better understanding different phenotypes of spastic gait disorders. Pelvic girdle abnormality plays a pivotal role in determining the clinical presentation of gait disorders, since it determines the body vector and compensatory kinetic chain reactions in the knee and ankle joints. Knee joint abnormality can be a mechanical compensation for hip and/or ankle and foot abnormality. Diagnostic nerve blocks and instrumented gait analysis may be needed for diagnosing the underlying problems and developing an individualized plan of care. A wide spectrum of treatment options has been used to manage spastic gait disorders. Some are in early and investigational stages, such as neuromodulation modalities, while others are well-developed, such as therapeutic exercise, ankle-foot orthoses, botulinum toxin treatment, and surgical interventions. Physicians and other healthcare providers who manage spastic gait disorders should be familiar with these treatment options and should employ appropriate interventions concurrently rather than serially. The most effective treatments can be selected based on careful evaluation, inputs from patients, family, and therapists, along with appropriate goal setting. Treatment plans need to be re-evaluated for effectiveness, relevance, and in concordance with disease progress. This is particularly important for patients with progressive neuromuscular diseases such as amyotrophic lateral sclerosis.}, }
@article {pmid40196659, year = {2025}, author = {Ramesh, N and Evans, A and Wojta, K and Yang, Z and Boks, MM and Kahn, RS and de Boer, SCM and van der Lee, SJ and Pijnenburg, YAL and Reus, LM and Ophoff, RA}, title = {Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.20.643775}, pmid = {40196659}, issn = {2692-8205}, abstract = {The hexanucleotide (G 4 C 2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm Least Absolute Shrinkage and Selection Operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in an independent cohort of 2,548 subjects with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result not only illustrates the accuracy of the DNAm predictor of C9orf72 repeat expansion carriers but also suggests that repeat expansion carriers may be more prevalent than expected. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.}, }
@article {pmid40196013, year = {2025}, author = {Viteri, JA and Kerr, NR and Brennan, CD and Kick, GR and Wang, M and Ketabforoush, A and Snyder, HK and Moore, PJ and Darvishi, FB and Dashtmian, AR and Ayyagari, SN and Rich, K and Zhu, Y and Arnold, WD}, title = {Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43Q331K mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-6081213/v1}, pmid = {40196013}, issn = {2693-5015}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging in ALS. This promotes senescent cell accumulation-marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation-disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&amp;Q) in TDP-43 [Q331K] ALS mice. D&amp;Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy. *Jose A. Viteriab, Nathan R. Kerrab, and Charles D. Brennana are co-first authors.}, }
@article {pmid40192904, year = {2025}, author = {Kodirov, SA}, title = {Comparison of Superoxide Dismutase Activity at the Cell, Organ, and Whole-Body Levels.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {40192904}, issn = {1559-0283}, abstract = {Superoxide dismutase (SOD) can be considered an antitoxic metalloenzyme that facilitates the production of oxygen and hydrogen peroxide from superoxide anions. Four classes have been identified depending on selective binding of metals, namely Cu,Zn-SOD, Fe-SOD, Mn-SOD, and Ni-SOD. The established isoforms are SOD1, SOD2, and SOD3 in various cells and tissues of eukaryotes. The relatively newer type Ni-SOD binds nickel and is observed in bacteria, including the genus Streptomyces. The Fe-SOD and Mn-SOD are also present in bacteria. Cu,Zn superoxide dismutase (SOD1) activity correlates with various pathophysiological states of organs. SOD2 binds manganese (Mn) and is located in the mitochondria. The SOD3, similar to the SOD1, binds copper and zinc, which are also expressed in the brain. The assay relies on several methods, including the enzyme activities, expression, field potential, and patch-clamp electrophysiology. The effects of SOD activity are emphasized at organ and whole-body levels depending on animal models. The antioxidant properties and behavior of SOD are compared based on responses among females and males to diet and toxic substances. However, in humans with amyotrophic lateral sclerosis (ALS), the mean SOD activity in both erythrocytes and muscles was comparable to controls. The detailed comparisons between the catalase and SOD activities are one of the aspects of this review. Also, modulation of excitability and synaptic plasticity in neurons by SOD is highlighted.}, }
@article {pmid40192272, year = {2025}, author = {Kurashige, T and Murao, T and Kanaya, Y and Dodo, Y and Sugiura, T and Kuraoka, K and Ohshita, T}, title = {Intramuscular Nerve Bundles Reflect TDP-43 Pathology in the Medulla and Spinal Cord of ALS Patients.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70016}, pmid = {40192272}, issn = {1365-2990}, support = {//SENSHIN Medical Research Foundation/ ; //ALS foundation by Japan ALS Association/ ; //Tsuchiya Foundation/ ; //Takeda Science Foundation/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Kato Memorial Trust for Nanbyo Research/ ; //Kurozumi Medical Foundation/ ; //Okinaka Memorial Institute for Medical Research/ ; //Takeda Science Foundation, and Tsuchiya Foundation/ ; }, }
@article {pmid40189941, year = {2025}, author = {Padigos, J and Murray, L and Bredhauer, O and Jaspers, J and Bethune, S}, title = {Extending the interval for changing flushing solutions for central venous and arterial line systems in the intensive care unit: An evidence-based quality improvement project.}, journal = {Nursing in critical care}, volume = {30}, number = {3}, pages = {e70034}, pmid = {40189941}, issn = {1478-5153}, mesh = {Humans ; *Quality Improvement ; *Intensive Care Units/organization &amp; administration ; Queensland ; *Catheterization, Central Venous/methods ; Time Factors ; Catheter-Related Infections/prevention &amp; control ; }, abstract = {BACKGROUND: Central venous lines (CVLs) and arterial lines (ALs) are commonly used for patients in the intensive care units (ICUs) to facilitate the administration of medications and haemodynamic monitoring. In an ICU in Queensland, Australia (AU), saline (sodium chloride 0.9%) flush bags used for these lines were routinely changed every 24 h following organizational policy that all intravenous fluid bags are to be changed within a 24-h period.<br><br>AIM: This quality improvement (QI) project aimed to evaluate current practice guided by the Plan-Do-Study-Act (PDSA) model of QI and implementation science. Benchmarking practices with other ICUs was conducted.<br><br>STUDY DESIGN: A narrative literature review focused on evaluating the safe interval for changing flush solutions every 24&#x2009;h was performed using EBSCO Medline, CINAHL, Cochrane Library, Embase and Google Scholar databases for citations up to November 2022. Bloodstream infection rates attributed to CVLs and/or ALs were monitored. Economic analysis was performed. End-user feedback was sought. A change of practice was implemented for a 1-year study period (March 2023 - March 2024) to extend dwell times of flushing solutions for CVLs and ALs from every 24&#x2009;h to every 96&#x2009;h.<br><br>RESULTS: One-year post-implementation, no bloodstream infections were linked to CVLs or ALs. A simplified economic analysis was performed based on costs of 0.9% sodium chloride 500-mL fluid bags, which revealed that changing the fluid bags once every 96&#x2009;h resulted in a per patient saving of AU$3.21 for any individual AL or CVL and up to AU$6.42 per patient where both an AL and CVL are in situ, based on fluid bag cost at AU$1.07 per bag. This saving excludes potential savings from reduced nursing time, infection-related costs and recycling costs.<br><br>CONCLUSION: A sustainable practice change based on evidence was implemented in the local ICU. The use of the PDSA model of the QI process and the principles of implementation science strengthened the buy-in and implementation of the project.<br><br>This practice change was examined through lenses of evidence-based practice, environmental sustainability (minimizing environmental footprint by limiting plastic bag usage), patient safety, cost minimization, and reduced nursing workload.}, }
@article {pmid40189519, year = {2025}, author = {Tseng, PT and Zeng, BY and Hsu, CW and Hung, CM and Carvalho, AF and Stubbs, B and Chen, YW and Chen, TY and Lei, WT and Chen, JJ and Su, KP and Shiue, YL and Liang, CS}, title = {The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis.}, journal = {BMC medicine}, volume = {23}, number = {1}, pages = {197}, pmid = {40189519}, issn = {1741-7015}, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/prevention &amp; control/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; Network Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; Hypoglycemic Agents/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.<br><br>METHODS: We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.<br><br>RESULTS: Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8&#xa0;years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio&#x2009;=&#x2009;0.28, 95%&#xa0;confidence intervals&#x2009;=&#x2009;0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.<br><br>CONCLUSIONS: This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.<br><br>TRIAL REGISTRATION: PROSPERO CRD42021252381.}, }
@article {pmid40188980, year = {2025}, author = {Chong, ZZ and Souayah, N}, title = {Pathogenic TDP-43 in amyotrophic lateral sclerosis.}, journal = {Drug discovery today}, volume = {}, number = {}, pages = {104351}, doi = {10.1016/j.drudis.2025.104351}, pmid = {40188980}, issn = {1878-5832}, abstract = {The aberrant expression of the trans-active response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.}, }
@article {pmid40188806, year = {2025}, author = {Saller, R and Schwabl, H and Rostock, M and Dal Cero, M}, title = {[Vom Spezifischen zum Systemischen - am Beispiel Tormentill / Blutwurz, der Heilpflanze des Jahres 2024].}, journal = {Complementary medicine research}, volume = {}, number = {}, pages = {1-8}, doi = {10.1159/000545128}, pmid = {40188806}, issn = {2504-2106}, abstract = {Am Beispiel des in verschiedenen lokalen Traditionen genutzten Blutwurz, Tormentill (Potentilla erecta) wird exemplarisch eine offensichtliche Kluft zwischen üblichen indikationsgetriebenen Zulassungsverfahren und der empirischen Realität sowie dem Potential vieler Heilpflanzen aufgezeigt. Für Tormentillae rhizoma ist ein breites Spektrum an Inhaltsstoffen und das mit dem Vielstoffgemisch einhergehende Wirkprofil einer u.a. vielfältig antiinflammatorisch wirkenden, systemischen Droge experimentell belegt. Die traditionelle Empirie der dämpfenden Effekte im Entzündungsgeschehen wird dadurch plausibilisiert. Die moderne Forschung liefert also Daten für einen sinnvollen Einsatz einer gut verträglichen Heilpflanze mit vielfältigen Anwendungsmöglichkeiten für Haut und Schleimhaut (innerlich und äusserlich). Auf dem Markt gibt es aber, abgesehen von vereinzelten topischen Spezialitäten und Arzneitees, kaum Zubereitungen als zugelassene Arzneispezialität. Denn die derzeitige Praxis der Arzneimittelzulassung bevorzugt die spezifischen und organbezogenen Wirkungen und übersieht dabei das systemische Potential, die Modulationsfähigkeit dieser natürlichen Stoffgemische, wie sie durch traditionelle und empirische Belege angezeigt wird. Systemische Wirkungen zeigen ihre Stärke gerade im Zusammenspiel mit anderen Therapien insbesondere beim additiven Einsatz mit Spezifika, indem sie bestimmte Wirkungen verstärken bzw. abschwächen oder die Verträglichkeit der Spezifika erhöhen bzw. deren Nebenwirkungen abmildern. Die Kombination von spezifisch wirkenden Arzneimitteln mit solchen Systemmitteln (wie z.B. Blutwurz, Tormentill) stellt damit eine weitere Therapieoption dar, die als sinnvolle Ergänzung, wenn nicht sogar als Grundlage bei Prävention, Therapie und Lebensgestaltung zu werten ist.}, }
@article {pmid40188740, year = {2025}, author = {Kuo, YC and Yang, CC and Tsai, LK}, title = {Exploring CSF biomarkers in amyotrophic lateral sclerosis: Highlighting the significance of TDP-43.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123479}, doi = {10.1016/j.jns.2025.123479}, pmid = {40188740}, issn = {1878-5883}, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the existence of the TAR DNA-binding protein 43 (TDP-43) aggregates in motor neurons. This study investigated specific cerebrospinal fluid (CSF) biomarkers, including TDP-43, as diagnostic or prognostic biomarkers for ALS.<br><br>METHODS: The study included a hospital-based cohort of sporadic ALS patients (N&#xa0;=&#xa0;30) and age-matched controls (N&#xa0;=&#xa0;19). Using immunomagnetic reduction technology, CSF levels of TDP-43, neurofilament light chain (NfL), phosphorylated tau 181 (p-tau181), and total tau (t-tau) were assessed. Plasma levels of TDP-43 were also measured. The association of the different biomarkers with disease severity was investigated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and compound muscle action potential (CMAP) amplitudes. The rate of disease progression was evaluated by measuring decline in ALSFRS-R over time.<br><br>RESULTS: ALS patients had higher CSF NfL and lower ratio of p-tau181/t-tau than control subjects. No significant difference between groups was observed in CSF TDP-43. In ALS patients, CSF levels of any biomarker, including TDP-43, were not associated with ALSFRS-R scores, FVC, or mean CMAP amplitudes. However, CSF TDP-43 positively correlated with the rate of decline in ALSFRS-R (p&#xa0;=&#xa0;0.042). ALS patients with high CSF TDP-43 levels (>5&#xa0;pg/mL) showed larger decline in ALSFRS-R (14.0&#xa0;&#xb1;&#xa0;11.90 vs. 8.8&#xa0;&#xb1;&#xa0;5.48 per year; p&#xa0;=&#xa0;0.045) than those with lower TDP-43. Plasma TDP-43 levels did not correlate with CSF TDP-43 or any clinical parameter.<br><br>CONCLUSION: CSF TDP-43 is associated with the rate of disease progression and may be a prognostic biomarker in patients with sporadic ALS.}, }
@article {pmid40188375, year = {2025}, author = {Prajapati, JL and Dhurandhar, Y and Singh, AP and Gupta, DK and Baghel, VS and Kushwaha, U and Namdeo, KP}, title = {Redox chemical delivery system: an innovative strategy for the treatment of neurodegenerative diseases.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.1080/17425247.2025.2489558}, pmid = {40188375}, issn = {1744-7593}, abstract = {INTRODUCTION: It is anticipated that the prevalence of illnesses affecting the central nervous system (CNS) will rise significantly due to longer lifespans and changing demography. Age-related decline in brain function and neuronal death are features of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, which provide formidable treatment challenges. Because most therapeutic drugs cannot pass across the blood-brain barrier (BBB) to reach the brain, there are still few treatment alternatives available despite a great deal of research.<br><br>AREAS COVERED: This study explores the role of redox chemical delivery systems in CNS drug delivery and addresses challenges associated with neurodegenerative disease (ND). Redox Chemical Delivery System offers a promising approach to enhancing leveraging redox reactions that facilitate the transport of therapeutic agents across the BBB. Through the optimization of medication delivery pathways to the brain, this technology has the potential to greatly improve the treatment of ND.<br><br>EXPERT OPINION: As our understanding of the biological underpinnings of ND deepens, the potential for effective interventions increases. Refining drug delivery strategies, such as RCDS, is essential for advancing CNS therapies from research to clinical practice. These advancements could transform the management of ND, improving both treatment efficacy and patient outcomes.}, }
@article {pmid40187044, year = {2025}, author = {Fu, Y and Zhang, J and Qin, R and Ren, Y and Zhou, T and Han, B and Liu, B}, title = {Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.}, journal = {Pharmacological reviews}, volume = {77}, number = {3}, pages = {100053}, doi = {10.1016/j.pharmr.2025.100053}, pmid = {40187044}, issn = {1521-0081}, abstract = {Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.}, }
@article {pmid40186067, year = {2025}, author = {Maranzano, A and Gentile, F and Passaretti, M and Doretti, A and Colombo, E and Wall, AK and Treddenti, M and Patisso, V and De Lorenzo, A and Gendarini, C and Cocuzza, A and Maio, AD and Pierro, S and Poletti, B and Cinnante, CM and Morelli, C and Messina, S and Pereira, JB and Hardiman, O and Silani, V and Verde, F and Ticozzi, N}, title = {Rate of change in upper and lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {315}, pmid = {40186067}, issn = {1432-1459}, support = {2022-12375731//Ministero della Salute/ ; E3-2022-23683266//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/pathology/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Motor Neurons/pathology ; Retrospective Studies ; Aged ; Disease Progression ; Adult ; Severity of Illness Index ; Cohort Studies ; ROC Curve ; }, abstract = {BACKGROUND: We hypothesize that the rate of change in upper (ΔUMN) and lower (ΔLMN) motor neuron signs from symptom onset to first clinical assessment represent best predictors of survival and disease progression in amyotrophic lateral sclerosis (ALS) compared to singular quantification of UMN and LMN involvement.<br><br>METHODS: A retrospective inpatient cohort of 1000 ALS patients was evaluated. The burden of UMN and LMN signs was assessed using the Penn Upper Motor Neuron Score and Lower Motor Neuron Score, respectively. For 421 patients, we compute the ENCALS survival model. Univariate and regularized Cox regressions were conducted to estimate the effect of the aforementioned variables on survival. The ROC curve analysis was then employed to a training sub-cohort to identify a &#x394;LMN cut-off value discriminating ALS patients with prolonged vs short survival. This cut-off value was then cross validated on a test sub-cohort. A multinomial regression model was used to compare different &#x394;UMN and &#x394;LMN scores among ENCALS groups.<br><br>RESULTS: &#x394;UMN and &#x394;LMN showed a negative association with survival (&#x394;UMN: HR&#x2009;=&#x2009;1.30; &#x394;LMN: HR&#x2009;=&#x2009;4.22). A cut-off value of 0.22 for &#x394;LMN was identified to predict patients with estimated short vs prolonged survival. ENCALS groups characterized by shorter survival presented significantly higher &#x394;UMN and &#x394;LMN scores compared to those with longer survival. No significant association of PUMNS or LMNS gross scores with the above-mentioned variables was observed.<br><br>CONCLUSION: By reflecting the progressing degeneration of the two distinct motor neuron subpopulations, &#x394;UMN and &#x394;LMN might represent reliable and easily measurable clinical indexes to estimate survival in ALS.}, }
@article {pmid40185982, year = {2025}, author = {Cummings, JL and Teunissen, CE and Fiske, BK and Le Ber, I and Wildsmith, KR and Schöll, M and Dunn, B and Scheltens, P}, title = {Biomarker-guided decision making in clinical drug development for neurodegenerative disorders.}, journal = {Nature reviews. Drug discovery}, volume = {}, number = {}, pages = {}, pmid = {40185982}, issn = {1474-1784}, abstract = {Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.}, }
@article {pmid40185700, year = {2025}, author = {Yang, T and Pang, D and Huang, J and Xiao, Y and Li, C and Wei, Q and Ou, R and Cheng, Y and Lin, J and Che, N and Fu, J and Jiang, Q and Wang, S and Liu, J and Zhang, S and Shang, H}, title = {Association between sleep and ALS-FTSD: A Prospective Cohort Study based on 396,918 UK biobank participants.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {123}, pmid = {40185700}, issn = {2158-3188}, support = {82371430//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; United Kingdom/epidemiology ; Prospective Studies ; *Amyotrophic Lateral Sclerosis/epidemiology ; *Sleep Wake Disorders/epidemiology/complications ; Aged ; Risk Factors ; Biological Specimen Banks ; *Sleep/physiology ; Incidence ; Adult ; Proportional Hazards Models ; *Frontotemporal Dementia/epidemiology ; UK Biobank ; }, abstract = {Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is a fatal neurodegenerative condition, and identifying its modifiable risk factors is a critical public health issue. This large-scale prospective cohort study investigated the role of sleep-related factors in ALS-FTSD risk using data from 396,918 UK Biobank participants. Eight sleep-related exposures were assessed, and Cox proportional hazards regression was employed to evaluate their associations with ALS-FTSD incidence. Subgroup and sensitivity analyses were conducted to validate the robustness of our findings. At baseline, participants had a mean age of 56.31 ± 8.12 years, with 47.5% being male. In the fully adjusted Cox model, organic sleep disorders (G47) (HR: 1.81, 95% CI: 1.21, 2.72, P = 0.004), hypersomnia (G47.1) (HR: 36.53, 95% CI: 9.04, 147.55, P < 0.001), and extreme short sleep (<5 h per day) (HR: 2.09, 95% CI: 1.09, 3.99, P = 0.046) were significantly associated with increased ALS-FTSD risk. In conclusions, these findings revealed the relationship between sleep and the risk of ALS-FTSD, identifying new modifiable risk factors and potential preventive possibilities for ALS-FTSD. Further research is warranted to elucidate the mechanistic links between sleep disturbances and ALS-FTSD pathogenesis.}, }
@article {pmid40185615, year = {2025}, author = {Dawson, M}, title = {Marxism on Musk: reflections on Baum et al's 'Twenty-First Century Alienation and Health'.}, journal = {Journal of epidemiology and community health}, volume = {}, number = {}, pages = {}, doi = {10.1136/jech-2025-223762}, pmid = {40185615}, issn = {1470-2738}, }
@article {pmid40185536, year = {2025}, author = {Uzgiris, AJ and Ladic, LA and Pfister, SX}, title = {Advances in neurofilament light chain analysis.}, journal = {Advances in clinical chemistry}, volume = {126}, number = {}, pages = {31-71}, doi = {10.1016/bs.acc.2025.01.006}, pmid = {40185536}, issn = {2162-9471}, mesh = {*Neurofilament Proteins/analysis ; Humans ; Biomarkers/analysis ; *Nervous System Diseases/diagnosis/metabolism ; }, abstract = {This chapter provides a comprehensive summary of clinical laboratory testing for neurofilament light chain (NfL) in neurologic disease. A primer on the NfL structure and function is presented with its potential use as a biomarker. The most widely utilized methods for NfL in biologic samples are highlighted and examined. Limitations of current knowledge are considered, as are outstanding questions related to dissemination and standardization of testing. Herein we focus on methods available today and those in development for clinical use. In the final section, a broad vision is presented of how NfL may be utilized in the future to improve diagnosis and treatment of neurologic diseases as well as for maintaining health.}, }
@article {pmid40185386, year = {2025}, author = {Lei, S and Liu, Y}, title = {Identifying blood mitochondrial DNA copy number as a biomarker for development of neurodegenerative diseases: Evidence from Mendelian randomization analysis.}, journal = {Neuroscience}, volume = {573}, number = {}, pages = {421-429}, doi = {10.1016/j.neuroscience.2025.04.003}, pmid = {40185386}, issn = {1873-7544}, abstract = {Mitochondrial dysfunction has been associated with neurodegenerative diseases (NDDs). This study aimed to explore the association between blood mitochondrial DNA copy number (mtDNA-CN) and development of NDDs. This study was based on two-sample Mendelian randomization (MR) analysis. The genome wide association study (GWAS) data of NDDs including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), multiple sclerosis (MS), Parkinson's disease (PD), primary open-angle glaucoma (POAG), and vascular dementia (VD) was obtained from FinnGen consortium. Inverse-variance weighted (IVW) was applied as the primary approach for MR estimation. MR results revealed that blood mtDNA-CN exhibited a significant relationship with the incidence of AD (IVW-P = 0.011, odds ratio [OR] = 0.65) and AMD (IVW-P = 0.038, OR = 0.64). However, there was no significant association observed between blood mtDNA-CN and other NDDs (IVW-P > 0.05). Our findings supported the relationship between mitochondrial dysfunction and development of AD and AMD, and that blood mtDNA-CN may serve as a potential biomarker for the incidence of these two NDDs.}, }
@article {pmid40185066, year = {2025}, author = {Fujii, T and Honda, H and Yoshidomi, S and Kashu, KY and Yamasaki, R and Yoshimura, M and Sasagasako, N and Iwaki, T and Isobe, N}, title = {Plexin D1 accumulation in the spinal motor neurons of patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {472}, number = {}, pages = {123483}, doi = {10.1016/j.jns.2025.123483}, pmid = {40185066}, issn = {1878-5883}, abstract = {BACKGROUND: Plexin D1 in endothelial cells (ECs) in the spinal cord (SC) has emerged as a key protein in spinal motor neuron (MN) maturation. Here, we pathologically investigated plexin D1 expression in the SCs of patients with sporadic amyotrophic lateral sclerosis (sALS) to clarify the association between plexin D1 expression in ECs and MN degeneration.<br><br>METHODS: We measured plexin D1 expression in the ECs of lumbar SC tissue samples from 11 patients with sALS and 8 age- and sex-matched patients with other non-inflammatory neurological diseases (OND) by immunohistochemistry. Additionally, the number and percentage of plexin D1-positive MNs in lumbar MNs were assessed in each case. We also evaluated the immunoreactivity of TAR DNA binding protein (TARDBP) in plexin D1-positive MNs.<br><br>RESULTS: Immunohistochemistry showed that there was no obvious difference in plexin D1 expression in ECs between sALS and OND cases. Unexpectedly, plexin D1 accumulation was greater in MNs of patients with sALS compared with those with OND. The number and percentage of plexin D1-positive MNs in patients with sALS were significantly greater than in patients with OND (median [interquartile range], 6 (Brown and Al-Chalabi, 2017; Mackenzie et al., 2007; Suk and Rousseaux, n.d.; Vieira et al., 2022; Oda et al., 1995; Tateno et al., 2009; Brandon et al., 2003; Brooks et al., 2000; Fujii et al., 2018; Honda et al., 2015; Oiwa et al., 2023 [1-3, 5-12]) vs. 1 [0-3.3], p&#xa0;=&#xa0;0.0349; and 12.9&#xa0;% [5.5-15.5] vs. 1.1&#xa0;% [0-3.5], p&#xa0;=&#xa0;0.0032, respectively). Plexin D1-positive MNs showed TARDBP cytoplasmic mislocalization and aggregation.<br><br>CONCLUSIONS: Plexin D1 was similarly expressed in ECs between sALS and OND cases, but accumulated in the degenerated MNs of patients with sALS. Plexin D1 accumulation in MNs may provide new insights into the mechanism of MN degeneration in ALS.}, }
@article {pmid40184864, year = {2025}, author = {Deloncle, R and Guillard, O and Pineau, A}, title = {Copper in human health: From COVID 19 to neurodegenerative diseases.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {89}, number = {}, pages = {127636}, doi = {10.1016/j.jtemb.2025.127636}, pmid = {40184864}, issn = {1878-3252}, abstract = {Copper (Cu) exists in two oxidation states Cu+I and Cu+II yielding formation of enzymes involved in biological processes. In higher concentrations, by oxidative process and ROS production, Cu is toxic towards plants, humans and animals livers as observed in Wilson disease or sheep scrapie. Fighting according to the Fenton reaction against bacteria and viruses, has been proposed as a mean of combatting nosocomial diseases and complementary to COVID19 vaccination. In humans, Cu is stocked in liver, muscle or bound to brain protein as ß-APP, tau-protein, α-synuclein, ubiquitin or prion which present antioxidant properties when Cu-bonded. In abnormal ß-sheet conformation, they can trigger neurodegenerative diseases such as Alzheimer(AD), Parkinson(PD) and ALS. In these diseases, blood copper increase correlated with brain copper decrease has been described. In AD, abnormal D-serine has been detected in blood and cerebrospinal fluid. D-glutamate and D-alanine blood levels have been found in AD and could also be controlled with Cu and ceruloplasmin in a possible disease screening test. This abnormal D-conformation might result from epimerization of physiologically L-conformation brain peptides into protease-resistant D-enantiomers. This has previously been experimentally demonstrated for Bovine Spongiform Encephalopathy in a free Cu reductive medium with UV-induced free radicals. The Cu brain protective effect against free radicals was restored with cupric addition in oxidizing medium. Cupric supplementation in the brain, might restore Cu protection and slow down neurodegenerative processes. To lower side effects, Cu amino-acid complexes able to cross the blood brain barrier might be suggested for a Cu transfer to the brain.}, }
@article {pmid40184012, year = {2025}, author = {Chowdhury, MR and Reddy, RVS and Nampoothiri, NK and Erva, RR and Vijaykumar, SD}, title = {Exploring bioactive natural products for treating neurodegenerative diseases: a computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {4}, pages = {169}, doi = {10.1007/s11011-025-01585-y}, pmid = {40184012}, issn = {1573-7365}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Parkinson Disease/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; Computational Biology/methods ; *Estrogens/metabolism ; *Biological Products/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Gene Regulatory Networks/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share overlapping molecular mechanisms, including estrogen signaling dysregulation, oxidative stress, and neuroinflammation. Standard treatments often lead to adverse effects due to unintended cross-talk with the estrogen signaling pathway. Identifying key regulatory genes and bioactive plant-derived compounds that modulate estrogen signaling without interfering with standard therapies offers a promising neuroprotective strategy. A network medicine and systems biology approach was used, beginning with the screening of 29 medicinal plants for ALS and 49 for PD, identifying 12 shared plants with neuroprotective potential. Bioactive compounds were screened for gene, protein, and pathway interactions, leading to target prediction (846 ALS-related and 690 PD-related targets) and disease association mining, which identified 93 overlapping genes (OGs). Protein-protein interaction (PPI) network analysis and MCODE clustering revealed ESR1, EGFR, and SRC as key hub-bottleneck (HB) genes, further validated via differential gene expression analysis. Gene ontology (GO) and pathway enrichment analyses revealed significant enrichment in estrogen signaling confirming the involvement of HB genes in neurodegenerative disease progression. Differential expression analysis confirmed ESR1 upregulation in ALS but downregulation in PD, suggesting a converse disease-specific regulatory pattern. Gene regulatory network (GRN) analysis identified hsa-miR-145-5p (ALS) and hsa-miR-181a-5p (PD) as key regulators, while FOXC1, GATA2, and TP53 emerged as crucial transcription factors (TFs) influencing disease progression. Molecular docking and MD simulations validated strong and stable interactions of Eupalitin (CYP19A1, -9.0 kcal/mol), Hesperetin (ESR1, -8.1 kcal/mol), and Sumatrol (PIK3CA, -8.9 kcal/mol). These phytochemicals, derived from Rosmarinus officinalis, Artemisia scoparia, Ocimum tenuiflorum, and Indigofera tinctoria, maintained stable hydrogen bonding and hydrophobic interactions for over 30% of a 25 ns simulation, supporting their therapeutic potential. The identification of ESR1, EGFR, and SRC as key targets, alongside estrogen signaling involvement, highlights the need for targeted nutraceutical interventions. These findings pave the way for safer, plant-based therapies that mitigate neurodegeneration while preserving estrogen signaling integrity, offering a promising adjuvant strategy alongside existing treatments.}, }
@article {pmid40183526, year = {2025}, author = {Dorst, J and Dreyhaupt, J and Wernecke, D and Weiland, U and Parlak, &#xd6; and Wiesenfarth, M and Elmas, Z and Herrmann, C and Bäzner, H and Boertlein, A and Dempewolf, S and Foerch, C and Hecht, M and Kohler, A and Opherk, C and Althaus, K and Clauer-Bredt, M and Lindner, A and Ruf, W and Brenner, D and Witzel, S and Peter, RS and Schuster, J and Ludolph, AC and Rosenbohm, A and Nagel, G}, title = {Population-Based Versus Hospital-Based Data in Amyotrophic Lateral Sclerosis-A Factor to Consider?.}, journal = {European journal of neurology}, volume = {32}, number = {4}, pages = {e70137}, pmid = {40183526}, issn = {1468-1331}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/therapy ; Male ; Female ; Middle Aged ; Aged ; *Registries ; Selection Bias ; *Hospitals/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Over the past years, some studies in amyotrophic lateral sclerosis (ALS) have provided heterogeneous findings regarding demographic and clinical data as well as the impact of various prognostic factors. It is well known that these inconsistencies might be caused by a selection bias in hospital-based data sets. In this study, we sought to further characterize this selection bias.<br><br>METHODS: We compared hospital-based data from the ALS center at Ulm University (UC; n&#x2009;=&#x2009;3833; 1997-2021) with the population-based ALS registry Swabia (SR; n&#x2009;=&#x2009;852; 2010-2020).<br><br>RESULTS: Patients from UC were younger (age of onset 60.9 [IQR 52.4-68.9] vs. 65.0 [57.0-72.7]), had a higher share of males (60.5% vs. 56.3%), a longer diagnostic delay (10.5 [IQR 6.4-18.4] months vs. 6.9 [IQR 3.4-12.1] months), a higher prevalence of the "definite" category according to El Escorial diagnostic criteria (60.9% vs. 11.2%), a higher share of familial cases (12.9% vs. 6.3%), a slower progression rate (points of ALS functional rating scale revised lost per month -0.54 [IQR -1.02 to -0.28] vs. -0.79 [IQR -1.47 to -0.43]), and (among all deceased patients) a higher share of percutaneous endoscopic gastrostomy (26.7% vs. 17.7%) and non-invasive ventilation (34.3% vs. 25.3%).<br><br>CONCLUSIONS: The observed differences likely indicate a selection bias in hospital-based data, which may be attributed, among others, to the willingness to travel large distances to a specialized center, the desire to participate in clinical studies, and the attitude toward life-prolonging measures. These differences must be considered when interpreting and generalizing study results from hospital-based populations.}, }
@article {pmid40183433, year = {2025}, author = {Jiang, J and Li, X and Mi, Y and Wang, Y and Heng, Y and Li, Z and Deng, M}, title = {Real-world evidence of riluzole on survival and ALSFRS change in a Chinese ALS cohort.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/17582024.2025.2488235}, pmid = {40183433}, issn = {1758-2032}, abstract = {AIMS: This study aimed to evaluate the effects of riluzole on survival and changes in ALS Functional Rating Scale (ALSFRS) among Chinese patients with Amyotrophic Lateral Sclerosis (ALS).<br><br>PATIENTS &amp; METHODS: Propensity score matching was used to balance baseline variables between the riluzole group (n&#x2009;=&#x2009;238) and control group (n&#x2009;=&#x2009;454). Survival was analyzed using Kaplan - Meier curves and Cox regression, while multivariable linear regression assessed ALSFRS changes at 6 and 12&#x2009;months. Subgroup analyses were conducted to identify potential responders.<br><br>RESULTS: Riluzole did not significantly improve survival (p&#x2009;=&#x2009;0.478) or ALSFRS changes at 6&#x2009;months (p = 0.380) or 12&#x2009;months (p&#x2009;=&#x2009;0.175). Subgroup analyses revealed no survival benefit in any subgroup, and further stratification showed inconsistent adverse effects on ALSFRS scores.<br><br>CONCLUSIONS: Riluzole neither prolonged survival nor slowed functional decline in Chinese ALS patients, with no subgroup demonstrating a better response.}, }
@article {pmid40183173, year = {2025}, author = {Zulueta, A and Piras, R and Azzolino, D and Mariani, P and Sideri, R and Garrè, C and Federico, G and Lucchi, T and Magni, P and Parati, EA and Lunetta, C}, title = {Neurofilament Light Chain Levels, Skeletal Muscle Loss, and Nutritional Decline: Key Prognostic Factors in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28407}, pmid = {40183173}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Hypermetabolism and weight loss are established negative prognostic factors in amyotrophic lateral sclerosis (ALS). However, the role of individualized body composition parameters in predicting ALS progression has been underexplored. This study aimed to investigate the correlation between nutritional parameters, neurofilament light chain (NfL) levels, and disease progression in ALS patients.<br><br>METHODS: The Global Leadership Initiative on Malnutrition criteria were used to define malnutrition in this study. Nutritional status was assessed using body mass index and bioelectrical impedance analysis. The rate of disease progression was defined by the change in the Revised ALS Functional Rating Scale score (&#x394;FRS). NfL was quantified using single molecule array technology. Spearman's analyses were used to assess correlations.<br><br>RESULTS: Sixty of 110 ALS patients were classified as malnourished. There was a strong positive correlation between NfL and &#x394;FRS (r&#x2009;=&#x2009;0.71), and a moderate negative correlation with disease duration (r&#x2009;=&#x2009;-0.55). The correlations between NfL and body composition parameters were statistically significant, although weak. NfL levels were significantly higher in fast progressors (p&#x2009;<&#x2009;0.0001 compared to slow progressors) and in malnourished patients (p&#x2009;=&#x2009;0.0001). Of the 34 fast progressor patients, 28 (82%) exhibited some degree of malnutrition.<br><br>DISCUSSION: Our findings indicate that poor nutritional status, particularly reduced skeletal muscle mass-both independently and in combination with fat mass loss-is associated with elevated NfL levels and faster ALS progression. NfL, combined with nutritional parameters, could serve as a valuable biomarker for disease severity. Further research is warranted to clarify the role of skeletal muscle abnormalities in ALS progression.}, }
@article {pmid40182859, year = {2025}, author = {Kobayakawa, Y and Ko, S and Tashiro, T and Maimaitijiang, G and Kira, JI and Kishimoto, J and Yamasaki, R and Isobe, N}, title = {FVC-DiP correlates with neurofilament light chain levels in serum and cerebrospinal fluid in patients with ALS.}, journal = {BMJ neurology open}, volume = {7}, number = {1}, pages = {e001012}, pmid = {40182859}, issn = {2632-6140}, abstract = {BACKGROUND: We previously reported a scale to assess the disease progression rate in patients with amyotrophic lateral sclerosis (ALS), the forced vital capacity decline pattern scale (FVC-DiP). In this study, we investigated the association between FVC-DiP scores and neurofilament light chain (NfL) in the serum and cerebrospinal fluid (CSF) in patients with ALS.<br><br>METHODS: We performed a retrospective study to examine the association between NfL levels and the rate of disease progression (N=41). The disease progression rate was assessed using three methods: the FVC-DiP score determined using the percentage of predicted FVC (%FVC) and disease duration at the %FVC measurement, the rate of decline in the ALS Functional Rating Scale Revised (ALSFRS-R) score (&#x394;FS) and the rate of decline in the %FVC (&#x394;%FVC).<br><br>RESULTS: The FVC-DiP scores were significantly correlated with NfL levels in both the serum and CSF (serum, R[2]=0.274, p<0.001; CSF, R[2]=0.274, p=0.001). Patients assessed as rapidly progressing by the FVC-DiP had high NfL levels, and patients assessed as slowly progressing had low NfL levels. In the group with a low &#x394;FS and/or &#x394;%FVC, although the disease progression rate assessed by the FVC-DiP may have differed from the assessments obtained using the ALSFRS-R and/or %FVC, the correlation between FVC-DiP scores and serum NfL levels remained consistent.<br><br>CONCLUSIONS: The FVC-DiP was significantly associated with NfL levels in the serum and CSF, suggesting that the FVC-DiP is a reasonable scale to assess the rate of ALS progression.}, }
@article {pmid40181571, year = {2025}, author = {Yoganathan, K and Dharmadasa, T and Northall, A and Talbot, K and Thompson, AG and Turner, MR}, title = {Asymmetry in amyotrophic lateral sclerosis: clinical, neuroimaging and histological observations.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf121}, pmid = {40181571}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralised onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.}, }
@article {pmid40181198, year = {2025}, author = {Manolopoulos, A and Yao, PJ and Kapogiannis, D}, title = {Extracellular vesicles: translational research and applications in neurology.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {40181198}, issn = {1759-4766}, abstract = {Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.}, }
@article {pmid40180875, year = {2025}, author = {Li, H and Cheng, M and Zhang, N and Wang, S and Ye, C and Li, H and Wang, S and Wang, Z and Yang, X and Liu, Z and Zhang, X and Xu, J and Xu, Q and Wang, J}, title = {The role of serum vitamins in mediating the effect of neurodegenerative diseases on subcortical brain volume.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100155}, doi = {10.1016/j.tjpad.2025.100155}, pmid = {40180875}, issn = {2426-0266}, abstract = {BACKGROUND: Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process.<br><br>METHODS: Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms.<br><br>RESULTS: Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (&#x3b2; = -0.09; p = 5.13 &#xd7; 10[-5]), amygdala (&#x3b2; = -0.07; p = 8.44 &#xd7; 10[-4]), and hippocampus (&#x3b2; = -0.07; p = 0.001), as well as with low serum vitamin D level (&#x3b2; = -0.02; p = 6.84 &#xd7; 10[-6]). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 &#xd7; 10[-5]) and 3.97 % (95 % CI: -0.007 to -2.94 &#xd7; 10[-4]) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of &#x3b2;-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet.<br><br>CONCLUSIONS: These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.}, }
@article {pmid40180687, year = {2025}, author = {Ms, S and Banerjee, S and D'Mello, SR and Dastidar, SG}, title = {Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40180687}, issn = {1559-1182}, support = {SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; SAN No: 102/IFD/SAN/2549/2019-20//DBT RLS/ ; CRG/2022/005004//Science and Engineering Research Board/ ; CRG/2022/005004//Science and Engineering Research Board/ ; LBRN//Louisiana Biomedical Research Network/ ; IIRPIG-2023-0001508//Indian Council of Medical Research/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper and lower motor neurons. Whereas most ALS cases are caused by a combination of environmental factors and genetic susceptibility, in a relatively small proportion of cases, the disorder results from mutations in genes that are inherited. Defects in several different cellular mechanisms and processes contribute to the selective loss of motor neurons (MNs) in ALS. Prominent among these is the accumulation of aggregates of misfolded proteins or peptides which are toxic to motor neurons. These accumulating aggregates stress the ability of the endoplasmic reticulum (ER) to function normally, cause defects in the transport of proteins between the ER and Golgi, and impair the transport of RNA, proteins, and organelles, such as mitochondria, within axons and dendrites, all of which contribute to the degeneration of MNs. Although dysfunction of a variety of cellular processes combines towards the pathogenesis of ALS, in this review, we focus on recent advances concerning the involvement of defective ER stress, vesicular transport between the ER and Golgi, and axonal transport.}, }
@article {pmid40180646, year = {2025}, author = {Temiz, K and Gul, A and Gov, E}, title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {24}, pmid = {40180646}, issn = {1559-1174}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.}, }
@article {pmid40179811, year = {2025}, author = {Li, B and Mu, H and Shan, D and Yang, Y and Wang, Y and Li, J and Wang, H and Sun, X and Ji, X and Zhan, Z and Jiao, Y and Tang, Y and Kong, B and Gao, B and Wang, Y and Sun, P and Liu, F}, title = {Generation of an induced pluripotent stem cell (iPSC) line (INNDSUi009-A) from a patient with amyotrophic lateral sclerosis due to SOD1 mutation.}, journal = {Stem cell research}, volume = {85}, number = {}, pages = {103704}, doi = {10.1016/j.scr.2025.103704}, pmid = {40179811}, issn = {1876-7753}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of nerve cells in the spinal cord and brain. We generated and characterized a human induced pluripotent stem cell (iPSC) line from skin fibroblasts of a patient with ALS due to SOD1 Mutation. The pluripotency of these iPSCs was verified by the expression of several pluripotency markers at both RNA and protein levels, as well as their capability to differentiate into all three germ layers.}, }
@article {pmid40179249, year = {2025}, author = {Traynor, BJ}, title = {The interneuron hypothesis of amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1045-1046}, pmid = {40179249}, issn = {1460-2156}, support = {/NH/NIH HHS/United States ; 1ZIAAG000933/AG/NIA NIH HHS/United States ; }, }
@article {pmid40178484, year = {2025}, author = {Gao, Y and Lu, Y and Chen, R and Zhao, S and Liu, J and Zhang, S and Bai, X and Zhang, J}, title = {Skin pathology in ALS: Diagnostic implications and biomarker potential.}, journal = {Biomolecules &amp; biomedicine}, volume = {}, number = {}, pages = {}, doi = {10.17305/bb.2025.12100}, pmid = {40178484}, issn = {2831-090X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain, resulting in motor deficits and muscle atrophy. Approximately 5-10% of ALS patients are familial (fALS), while the rest are sporadic (sALS). Currently, early diagnosis of ALS cannot be achieved based on clinical manifestations and electromyography due to the lack of effective and easily available biomarkers. The skin and central nervous system (CNS) share the same embryonic origin. Several skin biomarkers have been found in many neurodegenerative diseases, such as abnormal deposition of pathological α-synuclein (α-Syn) in Parkinson's disease. Thus, molecular changes in the skin associated with ALS-specific pathological events could readily be detected and become biomarkers for ALS through skin testing. Here, we summarize the literature on pathological changes in the skin of ALS patients and animal models, including structural abnormalities of the skin, reduced density of skin nerve fibers, abnormal protein aggregation, altered mitochondrial morphology and function, and dysregulation of skin inflammation, which may be useful for early diagnosis and monitoring of ALS progression.}, }
@article {pmid40178078, year = {2025}, author = {Castro, J and de Carvalho, M}, title = {Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {133}, number = {4}, pages = {1146-1147}, doi = {10.1152/jn.00582.2024}, pmid = {40178078}, issn = {1522-1598}, }
@article {pmid40177728, year = {2025}, author = {Liu, S and Lun, J and Zhan, Y and Li, Z and Tian, J and Zhang, C and Pan, L}, title = {CRISPR/Cas12a Combined with RAA for On-Site Detection of ALS W574L Mutation in Three Alopecurus Species: A Visual Approach for Herbicide Resistance Monitoring.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.5c02188}, pmid = {40177728}, issn = {1520-5118}, abstract = {The genus Alopecurus encompasses several weed species, including Alopecurus japonicus, Alopecurus aequalis, and Alopecurus myosuroides, which represent significant threats to agricultural productivity, particularly in wheat and oilseed rape fields. ALS-inhibiting herbicides have been extensively used for controlling Alopecurus weeds. However, the widespread use of these herbicides has led to the rapid emergence of resistance in Alopecurus populations with the Trp-574-Leu (W574L) mutation in the ALS gene being one of the most common resistance mechanisms. This study aims to develop a novel molecular detection method combining recombinase-aided amplification (RAA) with CRISPR/Cas12a technology to detect the W574L mutation in Alopecurus species. The method was optimized for key parameters, balancing efficiency with experimental costs, and was evaluated for specificity, sensitivity, and field applicability. This approach offers a rapid, accurate, and visual tool for identifying W574L target-site resistance in A. japonicus, A. aequalis, and A. myosuroides, with significant potential for monitoring resistance and enhancing weed management strategies.}, }
@article {pmid40176466, year = {2025}, author = {Zhang, Y and Robinson, K and Xia, Y and Sun, J}, title = {Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut-Neuron Axis.}, journal = {Comprehensive Physiology}, volume = {15}, number = {2}, pages = {e70009}, pmid = {40176466}, issn = {2040-4603}, support = {R01DK114126/NH/NIH HHS/United States ; R01DK105118/NH/NIH HHS/United States ; R01DK134343/NH/NIH HHS/United States ; I01BX004824-06//U.S. Department of Veterans Affairs/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Mice ; *Butyric Acid/pharmacology/therapeutic use ; Disease Progression ; *Neuroprotective Agents/pharmacology ; Male ; Mice, Transgenic ; Drug Synergism ; Disease Models, Animal ; *Neurons/drug effects ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Emerging evidence has shown that gut-brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA-approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h-SOD1[G93A], restores the gut-brain barrier function, and delays ALS progression. SOD1[G93A] mice (9-10-week-old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate-only treatment. More reduction of h-SOD1[G93A] aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate-only treatment. Tight junction proteins (ZO-1 and Claudin-5) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h-SOD1[G93A] aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate-only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate-only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut-brain axis for ALS.}, }
@article {pmid40174325, year = {2025}, author = {Farndale, L and Insall, R and Yuan, K}, title = {TriDeNT : Triple deep network training for privileged knowledge distillation in histopathology.}, journal = {Medical image analysis}, volume = {102}, number = {}, pages = {103479}, doi = {10.1016/j.media.2025.103479}, pmid = {40174325}, issn = {1361-8423}, abstract = {Computational pathology models rarely utilise data that will not be available for inference. This means most models cannot learn from highly informative data such as additional immunohistochemical (IHC) stains and spatial transcriptomics. We present TriDeNT , a novel self-supervised method for utilising privileged data that is not available during inference to improve performance. We demonstrate the efficacy of this method for a range of different paired data including immunohistochemistry, spatial transcriptomics and expert nuclei annotations. In all settings, TriDeNT outperforms other state-of-the-art methods in downstream tasks, with observed improvements of up to 101%. Furthermore, we provide qualitative and quantitative measurements of the features learned by these models and how they differ from baselines. TriDeNT offers a novel method to distil knowledge from scarce or costly data during training, to create significantly better models for routine inputs.}, }
@article {pmid40172690, year = {2025}, author = {Mathis, S and Beauvais, D and Duval, F and Barnay, M and Strub, V and Géfard-Gontier, E and Solé, G and Le Masson, G}, title = {When neuromuscular disorders become stars.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {305}, pmid = {40172690}, issn = {1432-1459}, mesh = {Humans ; *Neuromuscular Diseases/diagnosis ; Retrospective Studies ; History, 20th Century ; Motion Pictures ; Television ; }, abstract = {This retrospective study identified 125 audio-visual works from cinema and television, including films, TV series, and documentaries, depicting neuromuscular disorders since 1910. Motor neuron disorders, including amyotrophic lateral sclerosis (ALS), had the highest representation (69.3%), followed by myopathies (20%). The predominant genre was documentary (48%), which offered more factual representation than fictional works. ALS was overrepresented due to its dramatic nature and association with notable figures, including the American baseball player Lou Gehrig and British theoretical physicist Stephen Hawking; other neuromuscular disorders, such as Duchenne muscular dystrophy, were depicted less frequently. Despite inaccuracies in some portrayals, these works raise public awareness and contribute to a greater understanding of rare diseases, such as neuromuscular disorders, among the general public.}, }
@article {pmid40171862, year = {2025}, author = {Bierowski, AE and Comber, PC and Kuc, A and Shah, A and Carroll, G}, title = {The Effect of Prehospital Protocol Modification during COVID-19 on First-Pass Intubation Success Rates.}, journal = {Prehospital and disaster medicine}, volume = {}, number = {}, pages = {1-4}, doi = {10.1017/S1049023X25000238}, pmid = {40171862}, issn = {1945-1938}, abstract = {INTRODUCTION: Many Emergency Medical Services (EMS) agencies modified their protocols during the height of the COVID-19 pandemic, particularly those involving procedures that lead to an increased risk of airborne exposure, such as intubation. In 2020, local Advanced Life Support (ALS) providers' first-line airway management device was the supraglottic airway (SGA), and tracheal intubations (TIs) were rarely performed.<br><br>OBJECTIVE: This study's aim was to investigate the potential clinical effect of this pandemic-related protocol change on first-pass TI success rates and on overall initial advanced airway placement success.<br><br>METHODS: This study was a retrospective prehospital chart review for all ALS encounters from a single urban EMS agency that resulted in the out-of-hospital placement of at least one advanced airway per encounter from January 1, 2019 through June 30, 2021 (n = 452). Descriptive statistics and chi square tests were used to evaluate data. Statistical significance was defined at P < .05.<br><br>RESULTS: Significantly fewer TIs were attempted in 2020 (n = 16) compared to 2019 (n = 80; P < .001), and first-pass TI success rates significantly decreased in 2021 (n = 22; 61.1%) compared to 2019 (n = 63; 78.8%; P = .047). Also, SGA placement constituted 91.2% of all initial airway management attempts in 2020 (n = 165), more than both 2019 (n = 114; 58.8%; P < .001) and 2021 (n = 87; 70.7%; P < .001). Overall first-attempt advanced airway placement success, encompassing both supraglottic and TI, increased from 2019 (n = 169; 87.1%) to 2020 (n = 170; 93.9%; P = .025). Conversely, overall first attempt advanced airway placement success decreased from 2020 to 2021 (n = 104; 84.6%; P = .0072).<br><br>CONCLUSIONS: Lack of exposure to TI during the COVID-19 pandemic likely contributed to this local agency's decreased first-pass TI success in 2021. Moving forward, agencies should utilize simulation labs and other continuing education efforts to help maintain prehospital providers' proficiency in performing this critical procedure, particularly when protocol changes temporarily hinder or prohibit field-based psychomotor skill development.}, }
@article {pmid40171534, year = {2025}, author = {Burg, T and Tzeplaeff, L and Cassel, R and Lingor, P}, title = {Editorial: Innovative approaches to catalyze preclinical and clinical research on amyotrophic lateral sclerosis (ALS) and related disorders.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1582539}, pmid = {40171534}, issn = {1662-4548}, }
@article {pmid40171495, year = {2024}, author = {Oviedo, BJ and Arroyo-Hernandez, J and Gutiérrez-Bolaños, MJ and Alvarado-Pérez, H and Mora-Monestel, E and Rojas-Alvarado, A and Álvarez-Valverde, V and Jiménez-Bonilla, P}, title = {Assesment of chemometric analysis utilizing Multivariate Curve Resolution Alternating Least Squares (MCRALS) for examination of thermal and photodegradation of fern extracts.}, journal = {BioInspired Processing (BIP), IEEE International Conference on}, volume = {2024}, number = {}, pages = {}, pmid = {40171495}, support = {D43 TW011403/TW/FIC NIH HHS/United States ; }, abstract = {This study focuses on refining Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) for chromatographic profiling to analyze chemical changes in Serpocaulon sessilifolium extracts from the Costa Rican rainforest. High-Performance Liquid Chromatography (HPLC) with a diode array detector (DAD) and Mass Detector were employed, where traditional analyses often discard valuable spectral data beyond the maximum absorption wavelength. To optimize the analysis, Principal Component Analysis (PCA) were used to select the optimal number of components for MCR-ALS. Fern extracts, stored under varying conditions -refrigeration, warm temperatures, and UV light exposure- are analyzed over time to study their chemical stability. The decomposition identifies key chemical constituents, revealing that warmer conditions and UV exposure accelerate degradation, with significant shifts in chemical composition observed over time. MCR-ALS analysis allows detailed tracking of chemical changes, showing emerging peaks and shifts in concentration, particularly in the more reactive compounds, enhancing resolution and overcoming challenges such as peak interference and co-elution. The study highlights the differences between UV-absorption data and mass spectrometry, where mass spectrometry offers more detailed resolution but requiring greater computational resources. The use of both methods provides a comprehensive understanding of the chemical dynamics of the extracts. This research demonstrates the potential of MCR-ALS, combined with advanced statistical tools, for improving chromatographic analysis and contributing to botanical and natural product research.}, }
@article {pmid40171058, year = {2025}, author = {Husted, C and Tubman, G}, title = {Case Study: The Benefits of the Neubie Direct Current Electrical Stimulation Device for Pain, Spasticity, and Movement in Amyotrophic Lateral Sclerosis.}, journal = {Integrative medicine (Encinitas, Calif.)}, volume = {24}, number = {2}, pages = {25-29}, pmid = {40171058}, issn = {1546-993X}, abstract = {This case study reports the impact of the Neubie direct current electrical stimulation device in helping restore nerve conduction and function in a 65-year-old woman with sporadic ALS. Use of the Neubie began 12 months after her sudden onset of symptoms. By then, she could not move her fingers or toes, had drop foot, had lost considerable weight and muscle mass, and was in pain. After her first Neubie session, she could wiggle her toes and that movement persisted. After two months she had no hip pain and was moving her fingers, toes, hands, and feet. The Master Reset protocol was used to facilitate the calming of the nervous system and required a sequential increase of settings. She then developed tight, painful shoulders from being in a wheelchair and Neubie treatments on her shoulders ultimately allowed her to become pain-free and regain some range of motion to increase her shoulder flexibility. Her voice then became soft due to a weak diaphragm. After two months she could feel the Neubie treatments increase the innervation of her diaphragm. At the time of this data collection and work, she was pain-free, had increased movement and range of motion, and had more energy. She showed improvements in muscle activation and strength in her legs and was able to stand with assistance. The results of this case study support the need to further study the impact of the Neubie in ALS, especially early in the course of the disease.}, }
@article {pmid40170896, year = {2025}, author = {Wang, Y and Mi, Y and Wang, H and Jiang, J and Mao, L and Heng, Y and Li, X and Deng, M}, title = {Combined impact of CHCHD10 p.Gly66Val and three other variants suggests oligogenic contributions to ALS.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1438207}, pmid = {40170896}, issn = {1664-2295}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Genetic factors are known to play important roles in ALS and concomitant presence of rare variants in ALS patients have been increasingly reported.<br><br>METHODS: In order to explore the genetic variants in ALS patients within the context of oligogenic inheritance and to elucidate the clinical heterogeneity observed in these patients, we conducted whole-genome sequencing on 34 familial ALS (FALS) probands.<br><br>RESULTS: In one proband, we identified a CHCHD10 p.Gly66Val variant, along with three additional variants: UNC13A p.Leu1034Val, SUSD1 p.Trp704Ser, and SQSTM1 p.His359del. This patient exhibited a slow disease progression and a prolonged survival duration, consistent with the clinical features of ALS patients with CHCHD10 variants. This suggests that the CHCHD10 p.Gly66Val variant may play a predominant role in shaping the patient's phenotype, while the other variants may primarily contribute to ALS occurrence.<br><br>DISCUSSION: Variants in CHCHD10 have been found in ALS and other neurodegenerative diseases, exhibiting significant clinical variability. However, the combinatorial effect of CHCHD10 and other ALS-related gene variants has not been fully studied. Our findings suggest that the combined impact of these four variants contributes to this patient's ALS phenotype, distinguishing it from other, less severe neuromuscular disorders associated with CHCHD10 mutations. Overall, this study further supports the oligogenic pathogenic basis of ALS and offers new insights into understanding the intricate clinical presentations associated with CHCHD10 variants.}, }
@article {pmid40170672, year = {2025}, author = {Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Arcila-Londono, X and Lunetta, C and Wymer, J and Olney, N and Gwathmey, K and Ajroud-Driss, S and Hayat, G and Heiman-Patterson, T and Cerri, F and Fournier, C and Glass, J and Sherman, A and Fiecas, M and Walk, D}, title = {Time-to-event prediction in ALS using a landmark modeling approach, using the ALS Natural History Consortium dataset.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2482943}, pmid = {40170672}, issn = {2167-9223}, abstract = {BACKGROUND AND OBJECTIVES: Times to clinically relevant events are a valuable outcome in observational and interventional studies, complementing linear outcomes such as functional rating scales and biomarkers. In ALS, there are several clinically relevant events. We developed dynamic prediction models for several of these times to events that can be used for clinical trial modeling and personal planning.<br><br>METHODS: Landmark time-to-event analysis was implemented to determine the effect of patient characteristics on disease progression. Longitudinal data from 1557 participants in the ALS Natural History Consortium dataset were used. Five outcomes in the ALS disease progression were considered: loss of ambulation, loss of speech, gastrostomy, noninvasive ventilation (NIV) use, and continuous NIV use. Covariates in our models include age at diagnosis, sex, onset location, riluzole use, diagnostic delay, ALSFRS-R scores at the landmark time, and ALSFRS-R rates of change from baseline. Internal and external validation techniques were used.<br><br>RESULTS: For each of our models and landmark times, we present risk prediction intervals for random sets of patient characteristics. We demonstrate our models' application for an individual's personal predicted time-to-event. Our internal and external validation metrics indicate good concordance and overall performance. The time to loss of speech models perform the best for each metric in terms of both internal and external validation.<br><br>DISCUSSION: Landmarking is an efficient, individualized risk prediction model that is intuitive for both clinicians and patients. Importantly, landmarking can be used for clinical trial modeling, personal planning, and development of real-world evidence of the impacts of treatment interventions.}, }
@article {pmid40169784, year = {2025}, author = {Simonini, C and Zucchi, E and Martinelli, I and Gianferrari, G and Lunetta, C and Sorarù, G and Trojsi, F and Pepe, R and Piras, R and Giacchino, M and Banchelli, F and Mandrioli, J}, title = {Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11034}, pmid = {40169784}, issn = {2045-2322}, support = {Ricerca Corrente funding scheme of the Italian Ministry of Health//Ministero della Salute/ ; Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project)//Universit&#xe0; Degli Studi di Modena e Reggio Emila/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy/cerebrospinal fluid ; Middle Aged ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; *Superoxide Dismutase-1 ; *alpha 1-Antitrypsin/blood ; Disease Progression ; Aged ; Adult ; Chitinase-3-Like Protein 1/blood/cerebrospinal fluid ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {The initiation of tofersen, a new specific antisense oligonucleotide (ASO) for SOD1 pathology, marked a significant turning point for SOD1-ALS patients. While clinical trials and early access program studies reported a significant reduction in plasma and cerebrospinal fluid (CSF) neurofilament levels, neuroinflammation following prolonged treatment was never assessed. In this multicenter study, we evaluated a cohort of 18 SOD1-ALS patients treated with tofersen, analyzing correlations between biomarkers of neurodegeneration/neuroinflammation and clinical variables indicative of disease progression. NfL, NfH, CHI3L1, and Serpina1 levels in serum and CSF were determined by semi-automated immunoassays (Ella™ technology). Generalized linear mixed models were employed to investigate longitudinal trends of these biomarkers. Our data highlighted a progressive decrease in CSF neurofilament levels during tofersen treatment (MR = 0.97, 95% CI 0.94-0.99, p = 0.006 and MR = 0.98, 95% CI 0.95-1.00, p = 0.076 for NfL and NfH in CSF, respectively). Conversely, CSF levels of SerpinA1 and CHI3L1 increased over time (MR = 1.12, 95% CI 1.08-1.16, p < 0.0001 and MR = 1.039, 95% CI 1.015-1.062, p = 0.001 for SerpinA1 and CHI3L1 in CSF, respectively), but these modifications were most apparent after six and twelve months of therapy, respectively. Disease progression rate did not correlate with these biomarker trends. We observed a significant decrease in neurofilament levels during Tofersen treatment, alongside an increase in neuroinflammatory markers, potentially linked to an immune response triggered by ASO treatment. Given the limited data on tofersen's long-term efficacy in ALS due to its recent introduction, identifying biomarkers that predict clinical outcomes such as diminished therapeutic response or adverse effects is crucial. These biomarkers may help to better understand the underlying pathomechanisms of ALS and tofersen's role in modulating disease progression.}, }
@article {pmid40169635, year = {2025}, author = {D'Amico, A and Cucunato, R and Salemi, G and Bella, V and Aridon, P}, title = {A population based study to analyse amyotrophic lateral sclerosis as a multi-step process.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {11189}, pmid = {40169635}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Humans ; Female ; Male ; Middle Aged ; Aged ; Disease Progression ; Adult ; Sicily/epidemiology ; Incidence ; Aged, 80 and over ; }, abstract = {Recent studies suggest that Amyotrophic Lateral Sclerosis (ALS) follows a multistep process. We evaluated this hypothesis in a well-defined ALS population in Palermo, Sicily, almost entirely followed by our ALS Clinical Center. Incident data from the ALS Center (2014-2023) were analyzed, including both sporadic and familial ALS forms of the disease. To evaluate the multistep process, we regressed the natural log of age-specific incidence against the natural log of patient age We identified 216 ALS patients. We obtained a slope of 5 (r[2] = 0.93); the 95% CI ranged from 2.51 to 7.60, remaining relatively wide due to the small sample size, with a p-value of 0.008. The slope estimate was consistent with a 6-step process. In the Palermo ALS population, the multistep analysis confirms a process consistent with a 6-step model. This data, obtained in a relatively homogeneous population, further highlights the probability of strict interaction between environmental and genetic variables in the disease. Our data offer insights into the complexity of the mechanisms involved in the pathogenesis of the disease, particularly during its asymptomatic phase. This study supports the hypothesis that a single therapeutic silver bullet would probably be insufficient to arrest or slow the disease's progression.}, }
@article {pmid40169538, year = {2025}, author = {Iyer, KA and Tenchov, R and Sasso, JM and Ralhan, K and Jotshi, J and Polshakov, D and Maind, A and Zhou, QA}, title = {Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.}, journal = {Biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.biochem.4c00722}, pmid = {40169538}, issn = {1520-4995}, abstract = {Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.}, }
@article {pmid40169452, year = {2025}, author = {Hou, X and Jiang, J and Deng, M}, title = {Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {304}, pmid = {40169452}, issn = {1432-1459}, support = {82273915//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *Epigenesis, Genetic ; *Biomarkers/metabolism ; DNA Methylation ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. Whole-genome sequencing has identified many novel ALS-associated genes, but genetics alone cannot fully explain the onset of ALS and an effective treatment is still lacking. Moreover, we need more biomarkers for accurate diagnosis and assessment of disease prognosis. Epigenetics, which includes DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs, influences gene transcription and expression by affecting chromatin accessibility and transcription factor binding without altering genetic information. These processes play a role in the onset and progression of ALS. Epigenetic targets can serve as potential biomarkers and more importantly, the reversibility of epigenetic changes supports their potential role as versatile therapeutic targets in ALS. This review summarized the alterations in different epigenetic modulations in ALS. Additionally, given the close association between aberrant metabolic profiles characterized by hypoxia and high glycolytic metabolism in ALS and epigenetic changes, we also integrate epigenetics with metabolomics. Finally, we discuss the application of therapies based on epigenetic mechanisms in ALS. Our data integration helps to identify potential diagnostic and prognostic biomarkers and support the development of new effective therapies.}, }
@article {pmid40167598, year = {2025}, author = {Shi, Y and Wan, Y and Wang, Y and Fang, K and Yang, J and Lu, Y and Xie, X and Pan, J and Gao, D and Wang, H and Qu, H}, title = {Quantitative [1]H NMR optimization for high-throughput metabolite analysis in industrial bioprocess monitoring.}, journal = {Analytical and bioanalytical chemistry}, volume = {}, number = {}, pages = {}, pmid = {40167598}, issn = {1618-2650}, support = {2023C03116//Key Research and Development Program of Zhejiang Province/ ; }, abstract = {Quantitative [1]H NMR ([1]H qNMR) is an ideal tool for bioprocess monitoring because it can comprehensively detect and quantify diverse metabolites that significantly influence bioprocess performance. However, the long experiment time associated with the [1]H qNMR, due to the long longitudinal relaxation time (T1) of some metabolites, does not meet the requirements for high-throughput analysis. We developed a high-throughput [1]H qNMR method for bioprocess analysis using a short relaxation delay (D1) to reduce analytical time and a correction factor (k) to compensate for incomplete relaxation. A total of 27 metabolites were quantified using spectral deconvolution via a peak fitting algorithm and MCR-ALS. Methodological validation results indicated that the precision and accuracy of the developed qNMR method were consistently high across different D1 values, with LOQs ranging from 0.008 to 0.13 mM and LODs ranging from 0.024 to 0.38 mM. Notably, a longer D1 value generally resulted in lower LODs and LOQs for most metabolites. A D1 value of 4 s was optimal for balancing analysis time and performance. The method is broadly applicable for bioprocess monitoring and control, offering valuable guidance for optimizing CHO cell culture processes and improving yield.}, }
@article {pmid40166719, year = {2025}, author = {Xiong, J and Chen, X and Huang, K and Pan, Y}, title = {Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.}, journal = {Clinical, cosmetic and investigational dermatology}, volume = {18}, number = {}, pages = {735-741}, pmid = {40166719}, issn = {1178-7015}, abstract = {Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.}, }
@article {pmid40166606, year = {2025}, author = {de-Winton Cummings, PJ and Gonzalez Bravo, C and Dukes, KC and Wilks, AD and Ahlers, CD and Casado Castillo, FE and Courtney, A and Elliott-Wherry, AN and Knobbe, JE and Pineiro-Falcon, NM and Schaeffer, SE and Tillinghast, S and Tovar, EF and Villa, AT and Carvour, ML}, title = {Modifiable social and structural factors influence COVID-19 vaccine intention among frontline workers in the Midwestern USA: a community-engaged survey study.}, journal = {BMJ public health}, volume = {3}, number = {1}, pages = {e000859}, pmid = {40166606}, issn = {2753-4294}, abstract = {INTRODUCTION: COVID-19 vaccines have been a crucial measure in the pandemic response, yet vaccine uptake has been variable across the population. We sought to identify social and structural factors associated with COVID-19 vaccine intention among adults in the Midwestern USA who worked in one or more frontline industries during the COVID-19 pandemic.<br><br>METHODS: A community-engaged, cross-sectional online survey study was conducted between May and July 2022 among 889 workers. Guided by Thomas and Penchasky's 5As theory of access and Thomson et al's 5As taxonomy of vaccine uptake, we assessed modifiable social and structural factors related to access (transportation and convenient locations), affordability (time and incentives), activation (reminders), acceptability (experiences in a healthcare setting, political confidence and vaccine confidence) and accommodation (language inclusion and flexible appointments). Multinomial logistic regression was used to identify potentially modifiable factors that may influence vaccine intention among more than 200 surveyed workers who had not yet been vaccinated.<br><br>RESULTS: Workers who intended not to receive the vaccine were at least three times more likely to report transportation challenges, limited time off work and inflexible vaccine appointments compared with those who intended to vaccinate. Interest in financial incentives was strongly endorsed among workers who did not intend to vaccinate and among those who were undecided. Concerns about vaccine safety or side effects did not influence intention, whereas concerns about vaccine effectiveness were more common among workers who did not intend to vaccinate. Mistrust in government leaders was associated with positive vaccine intention.<br><br>CONCLUSIONS: Vaccine intention among frontline workers is strongly influenced by social and structural factors and not solely by hesitancy about the vaccine itself.}, }
@article {pmid40166559, year = {2025}, author = {Lorincz-Comi, N and Cheng, F}, title = {Bayesian estimation of shared polygenicity identifies drug targets and repurposable medicines for human complex diseases.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.03.17.25324106}, pmid = {40166559}, abstract = {BACKGROUND: Complex diseases may share portions of their polygenic architectures which can be leveraged to identify drug targets with low off-target potential or repurposable candidates. However, the literature lacks methods which can make these inferences at scale using publicly available data.<br><br>METHODS: We introduce a Bayesian model to estimate the polygenic structure of a trait using only gene-based association test statistics from GWAS summary data and returns gene-level posterior risk probabilities (PRPs). PRPs were used to infer shared polygenicity between 496 trait pairs and we introduce measures that can prioritize drug targets with low off-target effects or drug repurposing potential.<br><br>RESULTS: Across 32 traits, we estimated that 69.5 to 97.5% of disease-associated genes are shared between multiple traits, and the estimated number of druggable genes that were only associated with a single disease ranged from 1 (multiple sclerosis) to 59 (schizophrenia). Estimating the shared genetic architecture of ALS with all other traits identified the KIT gene as a potentially harmful drug target because of its deleterious association with triglycerides, but also identified TBK1 and SCN11B as putatively safer because of their non-association with any of the other 31 traits. We additionally found 21 genes which are candidate repourposable targets for Alzheimer's disease (AD) (e.g., PLEKHA1, PPIB) and 5 for ALS (e.g., GAK, DGKQ).<br><br>CONCLUSIONS: The sets of candidate drug targets which have limited off-target potential are generally smaller compared to the sets of pleiotropic and putatively repurposable drug targets, but both represent promising directions for future experimental studies.}, }
@article {pmid40165742, year = {2025}, author = {Fernández Soberón, S and Gómez Escobar, T and Caravaca Puchades, A and Andrés-Benito, P and Vázquez-Costa, JF and Mora Pardina, J and Juntas Morales, R and Povedano, M}, title = {Yentl syndrome, a real phenomenon in amyotrophic lateral sclerosis (ALS)?.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2432030}, pmid = {40165742}, issn = {2167-9223}, abstract = {Introduction: ALS, a neurodegenerative disorder, exhibits variable incidence and prevalence across various databases consulted. Among these, PRO-ACT stands out as the most extensive publicly accessible repository of aggregated ALS clinical trial information. The estimated male-female ratio is greater for men at younger ages, which tends to equalize with aging. If specific measures are not taken to address this, this higher male prevalence could result in a higher inclusion of men in clinical trials, which could lead to biases in the observed results, preventing the proper assessment of differences between sexes. Our aim was to describe the demographic dates of the population included in ALS clinical trials in the last 8 years at Spanish national reference centers, with special interest in female participation. Methodology: Retrospective and descriptive observational study using databases of national reference centers. Results: We analyzed the databases of 4 neurological Spanish reference centers during a period of 8 years. A total number of 426 subjects were included. A greater participation of the male sex was evident in all the studies evaluated, representing 64.55% of the subjects included. This predominance has not varied significantly over the last 8 years. Our results correlate with the data published in PRO-ACT to date, where men represent 60% of the total number of participants. Conclusion: The predominance of the male sex in ALS clinical trials is a consistent and invariable finding and is known as Yentl's syndrome. This phenomenon prevents the principle of neutrality of medicine, allowing for purely partial knowledge.}, }
@article {pmid40164574, year = {2025}, author = {Gómez-Gálvez, P and Navarro, V and Castro, AM and Paradas, C and Escudero, LM}, title = {Computational Analysis of SOD1-G93A Mouse Muscle Biomarkers for Comprehensive Assessment of ALS Progression.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70014}, doi = {10.1111/nan.70014}, pmid = {40164574}, issn = {1365-2990}, support = {//Margarita Salas Fellowship - NextGenerationEU/ ; CB18/05/00028//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; PI13/01347//National Institute of Health Carlos III/ ; PI23/01892//National Institute of Health Carlos III/ ; FORT23/00008//National Institute of Health Carlos III/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics ; Animals ; *Disease Progression ; *Muscle, Skeletal/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *Biomarkers/metabolism ; Superoxide Dismutase-1/genetics ; }, abstract = {AIMS: To identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1[G93A] mouse and wild-type (WT) controls at distinct stages of disease progression.<br><br>METHODS: Using the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1[G93A] and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages.<br><br>RESULTS: Our findings demonstrate that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages.<br><br>CONCLUSIONS: Our assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease is phenotypically imperceptible.}, }
@article {pmid40163151, year = {2025}, author = {Wadan, AS and Shaaban, AH and El-Sadek, MZ and Mostafa, SA and Moshref, AS and El-Hussein, A and Ellakwa, DE and Mehanny, SS}, title = {Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40163151}, issn = {1432-1912}, abstract = {Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.}, }
@article {pmid40162390, year = {2025}, author = {Xie, Y and Xie, H and Wang, RL}, title = {Enhancing palliative care in malignant obstructive jaundice: A critical care perspective on endoscopic biliary stenting.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {3}, pages = {103431}, pmid = {40162390}, issn = {1948-9366}, abstract = {This letter responds to Wang et al's recent publication on endoscopic biliary stenting for malignant obstructive jaundice (MOJ) by offering constructive feedback and suggestions for future research. We commend the authors for their comprehensive study design and execution, which included a clear delineation of study groups and a robust set of outcome measures. We suggest that future studies incorporate additional biomarkers, such as serum levels of liver enzymes and bilirubin, to provide a more nuanced understanding of liver function changes post-intervention. The study's focus on short-term survival rates is appreciated, but we recommend exploring longer-term follow-up periods to capture the full spectrum of survival outcomes. Additionally, the inclusion of quality of life assessments using validated instruments could offer a more holistic view of patient outcomes. From a critical care perspective, we advocate for the integration of advanced imaging techniques to better characterize biliary anatomy and potentially predict treatment response or complications. We believe that incorporating these suggestions could enhance the understanding of endoscopic biliary stenting's role in MOJ management and its impact on patient outcomes, influencing future clinical guidelines and practice.}, }
@article {pmid40161216, year = {2025}, author = {Scarcella, S and Brambilla, L and Quetti, L and Rizzuti, M and Melzi, V and Galli, N and Sali, L and Costamagna, G and Comi, GP and Corti, S and Gagliardi, D}, title = {Unveiling amyotrophic lateral sclerosis complexity: insights from proteomics, metabolomics and microbiomics.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf114}, pmid = {40161216}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is the most common motor neuron disease and manifests as a clinically and genetically heterogeneous neurodegenerative disorder mainly affecting the motor systems. To date, despite promising results and accumulating knowledge on the pathomechanisms of amyotrophic lateral sclerosis, a specific disease-modifying treatment is still not available. In vitro and in vivo disease models coupled with multiomics techniques have helped elucidate the pathomechanisms underlying this disease. In particular, omics approaches are powerful tools for identifying new potential disease biomarkers that may be particularly useful for diagnosis, prognosis and assessment of treatment response. In turn, these findings could support physicians in stratifying patients into clinically relevant subgroups for the identification of the best therapeutic targets. Here, we provide a comprehensive review of the most relevant literature highlighting the importance of proteomics approaches in determining the role of pathogenic misfolded/aggregated proteins and the molecular mechanisms involved in the pathogenesis and progression of amyotrophic lateral sclerosis. In addition, we explored new findings arising from metabolomic and lipidomic studies, which can aid to elucidate the intricate metabolic alterations underlying amyotrophic lateral sclerosis pathology. Moreover, we integrated these insights with microbiomics data, providing a thorough understanding of the interplay between metabolic dysregulation and microbial dynamics in disease progression. Indeed, a greater integration of these multiomics data could lead to a deeper understanding of disease mechanisms, supporting the development of specific therapies for amyotrophic lateral sclerosis.}, }
@article {pmid40159068, year = {2025}, author = {Wang, HF and Wang, HR and Lin, YC and Bai, JM and Li, M and Huang, XS}, title = {[Analysis of serum 25-hydroxyvitamin D3 levels and prognosis in patients with amyotrophic lateral sclerosis].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {4}, pages = {325-332}, doi = {10.3760/cma.j.cn112138-20240728-00481}, pmid = {40159068}, issn = {0578-1426}, support = {2023124//Tianjin Municipal Health and Health Commission Traditional Chinese Medicine and Integrative Medicine Research Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Prognosis ; Prospective Studies ; *Calcifediol/blood ; Cross-Sectional Studies ; Risk Factors ; Male ; Biomarkers/blood ; Female ; Middle Aged ; }, abstract = {Objective: To evaluate serum 25-hydroxyvitamin D3 [25(OH)D3] as a potential biomarker for amyotrophic lateral sclerosis (ALS) severity and to identify risk factors influencing ALS prognosis. Methods: This study included 217 ALS patients hospitalized at the Department of Neurology, First Medical Center, Chinese PLA General Hospital, between October 2018 and October 2021, who met the revised El Escorial diagnostic criteria. A cross-sectional analysis assessed differences in clinical indicators-including the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity percentage (FVC%)-across different serum 25(OH)D3 levels. The correlation between 25(OH)D3 levels and individual ALSFRS-R components was also examined. Conduct a prospective cohort study to identify independent risk factors affecting the survival time of ALS patients. Results: Among three groups categorized by serum 25(OH)D3 levels, there were significant differences in the proportion of males (χ[2]=10.51, P<0.05). Serum 25(OH)D3 levels correlated positively with lower limb function scores in the ALSFRS-R (r=0.05, P<0.05), but they were not identified as an independent risk factor for survival (HR=0.98, 95%CI 0.93-1.04, P>0.05). In contrast, delayed diagnosis(HR=0.94, 95%CI 0.89-0.99, P<0.05) and reduced FVC%(HR=0.94, 95%CI 0.97-0.99, P<0.05) were independent predictors of shorter survival. Conclusion: Serum 25(OH)D3 levels differ by gender distribution and may be linked to better lower limb function in ALS patients. However, their role in prolonging survival remains uncertain.}, }
@article {pmid40157939, year = {2025}, author = {Rossi, S and Milani, M and Della Valle, I and Bisegna, S and Durante, V and Addesse, M and D'Avorio, E and Di Salvio, M and Serafino, A and Cestra, G and Apolloni, S and D'Ambrosi, N and Cozzolino, M}, title = {Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS.}, journal = {Cell death &amp; disease}, volume = {16}, number = {1}, pages = {219}, pmid = {40157939}, issn = {2041-4889}, support = {Nutrage, IFT DBA.AD005.225//Consiglio Nazionale delle Ricerche (National Research Council)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SpliceALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; SwitchALS//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (Italian Research Foundation for ALS)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism/genetics ; *RNA-Binding Protein FUS/metabolism/genetics ; Mice ; *Disease Models, Animal ; *Cytoplasm/metabolism ; *Alternative Splicing/genetics ; *Motor Neurons/metabolism/pathology ; Humans ; Exons/genetics ; Mice, Transgenic ; }, abstract = {Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RNA binding proteins (RBPs) such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.}, }
@article {pmid40157684, year = {2025}, author = {Yu, T and Li, M and Li, M and Zhang, Q and Zhang, H and Jiang, Z and Wang, S and Mao, H and Li, D and Fan, L and Hu, C and Xu, X}, title = {Zebrafish TDP43 positively regulates p65-mediated apoptotic pathway.}, journal = {International journal of biological macromolecules}, volume = {308}, number = {Pt 3}, pages = {142599}, doi = {10.1016/j.ijbiomac.2025.142599}, pmid = {40157684}, issn = {1879-0003}, abstract = {TAR DNA-binding protein 43 (TDP43) is a multifunctional RNA/DNA binding protein that serves as a hallmark of neurodegeneration in amyotrophic lateral sclerosis (ALS) and is associated with the inflammatory response related to nuclear factor κB (NF-κB) pathway. However, the relationship between TDP43 and NF-κB is not well known. In this study, zebrafish TDP43 (DrTDP43) can be induced by grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV). DrTDP43 enhances the nuclear factor-kappaB (NF-κB) activity and the expression of p65 and TNFα, as well as promotes the phosphorylation of p65 in response to stimulation of GCRV and SVCV. Further assays indicate that DrTDP43 primarily resides in the nucleus and interacts with p65 via its RRM1. DrTDP43 is required for p65 to induce pro-inflammatory cytokine production (IL-6, IL-10, TNFα, IL-1β). It disrupts mitochondrial membrane potential and exacerbates apoptosis via downregulating Bcl2 and upregulating Bax, caspase3, and eIF2α. Moreover, knockdown of TDP43 decreases the content of reactive oxygen species (ROS) and the number of apoptotic cells in zebrafish larvae, which is attributed to the lower lever of p65 phosphorylation and expression of TNFα, Bax and cleaved-caspase3. In a word, these results establish TDP43 as a critical activator of the NF-κB-mediated apoptotic pathway during antiviral responses, which reveals a previously unrecognized host defense mechanism.}, }
@article {pmid40157434, year = {2025}, author = {Pu, L and Steele, JR and Phillips, CR and Violi, JP and Rodgers, KJ}, title = {The cyanobacterial toxins BMAA and 2,4-DAB perturb the l-serine biosynthesis pathway and induce systemic changes in energy metabolism in human neuroblastoma cells: A proteomic study.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {106}, number = {}, pages = {106058}, doi = {10.1016/j.tiv.2025.106058}, pmid = {40157434}, issn = {1879-3177}, abstract = {Blue-green algae (cyanobacteria), an ancient phylum of bacteria, produce a wide array of secondary metabolites that are toxic to humans. Rapid growth of cyanobacteria in an aquatic environment can result in algal blooms capable of turning waterways green and increasing toxin levels in the environment. Cyanobacterial toxins were first linked to the high incidence of a complex neurodegenerative disorder reported on the island of Guam in the 1940s but more recently have been linked to clusters of sporadic amyotrophic lateral sclerosis (sALS) worldwide. The non-protein amino acid β-N-methylamino-L-alanine (BMAA) and its isomer L-2,4-diaminobutyric acid (2,4-DAB) are produced concurrently by most cyanobacterial species. We carried out proteomic analysis on human neuroblastoma cells treated with BMAA and 2,4-DAB to determine the underlying mechanisms of toxicity resulting from exposure to these cyanotoxins and identified significant changes in the l-serine biosynthesis pathway as well as pathways associated with energy production in the cell such as fatty acid ß-oxidation and glycolysis. The impact on the serine biosynthetic pathway was supported by demonstrating a significant decrease in both mRNA and protein levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH) the first committed step in serine biosynthesis. PHGDH uses 3-phospho-D-glycerate (3PG) an intermediate in the glycolytic pathway as a substrate, and co-incubation of cells with l-serine restored expression levels of PHGDH as did cell pre-treatment with the glycolytic product pyruvate. This is the first study to link exposure to BMAA and 2,4-DAB to impairments in the l-serine biosynthesis pathway and broad disturbances in energy metabolism.}, }
@article {pmid40157356, year = {2025}, author = {Rummens, J and Khalil, B and Yıldırım, G and Silva, P and Zorzini, V and Peredo, N and Wojno, M and Ramakers, M and Van Den Bosch, L and Van Damme, P and Davie, K and Hendrix, J and Rousseau, F and Schymkowitz, J and Da Cruz, S}, title = {TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.03.004}, pmid = {40157356}, issn = {1097-4199}, abstract = {Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.}, }
@article {pmid40157355, year = {2025}, author = {Scialò, C and Zhong, W and Jagannath, S and Wilkins, O and Caredio, D and Hruska-Plochan, M and Lurati, F and Peter, M and De Cecco, E and Celauro, L and Aguzzi, A and Legname, G and Fratta, P and Polymenidou, M}, title = {Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.03.008}, pmid = {40157355}, issn = {1097-4199}, abstract = {Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.}, }
@article {pmid40157354, year = {2025}, author = {Klickstein, JA and Johnson, MA and Antonoudiou, P and Maguire, J and Paulo, JA and Gygi, SP and Weihl, C and Raman, M}, title = {ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.}, journal = {Stem cell reports}, volume = {}, number = {}, pages = {102478}, doi = {10.1016/j.stemcr.2025.102478}, pmid = {40157354}, issn = {2213-6711}, }
@article {pmid40156516, year = {2025}, author = {Gorgich, EA and Heidari, Z and Mahmoudzadeh-Sagheb, H and Rustamzadeh, A and Shabani, A and Amirzadeh, A and Haghi Ashtiani, B}, title = {Brain Metabolite Profiles are Associated with Selective Neuronal Vulnerability and Underlying Mechanisms in Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.4c00593}, pmid = {40156516}, issn = {1948-7193}, abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy ([1]H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel [1]H-MRS. [1]H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between [1]H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (p < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (p < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (p > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (p = 0.001, r = 0.71), FVC (p = 0.03, r = 0.58), and ΔFS (p = 0.01, r = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (p = 0.02, r = 0.41). In the INC, tCho concentrations (p = 0.04, r = -0.54) and mIns/tNAA ratio (p = 0.02, r = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (p = 0.01, r = 0.33) and (p = 0.001, r = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.}, }
@article {pmid40155688, year = {2025}, author = {Fan, X and Zeng, Y and Zhang, F and Xu, Y and Duan, Q and Long, S and Lin, Y and Wang, K and Jiang, L}, title = {Genetic effects of circulating hormone and proteome on amyotrophic lateral sclerosis identified by Mendelian randomization.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10782}, pmid = {40155688}, issn = {2045-2322}, support = {82201242//National Natural Science Foundation of China/ ; 82470903//National Natural Science Foundation of China/ ; LY24C110001//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; *Mendelian Randomization Analysis ; *Proteome ; Testosterone/blood ; Sex Hormone-Binding Globulin/metabolism/genetics ; Proteomics/methods ; Risk Factors ; Polymorphism, Single Nucleotide ; Insulin-Like Growth Factor I/metabolism/genetics ; Male ; Biomarkers/blood ; Female ; Genetic Predisposition to Disease ; Hormones/blood ; }, abstract = {Altered circulating hormones in ALS patients have been widely reported by previous observational studies, but whether these relationships are causal is unclear. Moreover, the potential therapeutic targets for ALS and the effects of plasma protein fluctuation on ALS progression are not fully understood. Therefore, we conducted a Mendelian randomization (MR) study to evaluate the causal role of 5 hormonal risk factors (insulin-like growth factor-1, IGF-1; sex hormone-binding globulin, SHBG; free testosterone, FT; total testosterone, TT; and estradiol) in ALS risk. Furthermore, we screened up to 90 circulating proteins including cytokines, chemokines, growth factors, and interferons, to identify potential therapeutic targets for ALS. Our MR analysis found genetically predicted higher level of FT was associated with a 23% lowered risk of ALS. Further screening of proteomic traits found that 12 plasma proteins were causally associated with ALS. These findings suggest that higher FT potentially exerts a protective effect on ALS risk. Several proteins may act as potential circulating biomarkers and therapeutic targets for ALS. In the future, high-throughput proteomic analyses and experimental explorations are likely needed to clarify the regulated role and mechanistic pathways.}, }
@article {pmid40155564, year = {2025}, author = {Tang, J and Zhao, Y and Chen, Y and Yang, Y and Gong, Z and Li, Z and Zhang, M and Zhang, J}, title = {White matter integrity mediated the effect of plasma uric acid levels on cognitive function in ALS patients.}, journal = {Brain imaging and behavior}, volume = {}, number = {}, pages = {}, pmid = {40155564}, issn = {1931-7565}, support = {82271478//National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, abstract = {OBJECTIVE: To investigate the association between plasma uric acid levels and white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) patients and to explore the potential mediating role of white matter microstructural alterations in the protective effect of plasma uric acid on cognitive function in ALS patients.<br><br>METHODS: 73 right-handed ALS patients were recruited for this study. Plasma uric acid levels were measured, diffusion tensor imaging scans were performed to assess white matter integrity, and cognition was evaluated using the Edinburgh Cognitive and Behavioral Screen. The relationships among plasma uric acid, white matter integrity, and cognitive function were examined through multivariate linear regression analysis. Additionally, mediation analysis was performed to investigate whether white matter integrity mediated the relationship between uric acid levels and cognitive function.<br><br>RESULTS: The findings revealed a positive correlation between plasma uric acid levels and extensive preservation of white matter microstructure in various regions, including the fornix, cerebellar, internal capsule, frontotemporal and frontooccipital lobe bundles among ALS patients. Mediation analysis indicated that fractional anisotropy in the hippocampal portion of the cingulum fully mediated the effects of plasma uric acid levels on executive function in ALS patients.<br><br>INTERPRETATION: Our results suggested that elevated plasma uric acid may preserve the integrity of white matter microstructure in ALS patients. Furthermore, we have identified evidence supporting the mediating influence of the hippocampal portion of the cingulum in linking plasma uric acid levels to cognitive function among ALS patients.}, }
@article {pmid40153582, year = {2025}, author = {Norata, D and Capone, F and Motolese, F and Marano, M and Rossi, M and Calandrelli, R and Sacchetti, M and Mantelli, F and Di Lazzaro, V and Pilato, F}, title = {1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.0573}, pmid = {40153582}, issn = {2152-5250}, abstract = {Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.}, }
@article {pmid40152938, year = {2025}, author = {Yu, L and Yang, Z and Ming, Z and Zhou, Q and Zeng, S}, title = {Impaired Aortic Biomechanical Properties in Patients With Severe Obstructive Sleep Apnea Syndrome.}, journal = {Echocardiography (Mount Kisco, N.Y.)}, volume = {42}, number = {4}, pages = {e70135}, doi = {10.1111/echo.70135}, pmid = {40152938}, issn = {1540-8175}, support = {kq2208343//Natural Science Foundation of Changsha City/ ; 2024JJ8122//Natural Science Foundation of Hunan Province/ ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/physiopathology/complications ; Male ; Female ; Middle Aged ; *Aorta/physiopathology/diagnostic imaging ; Biomechanical Phenomena ; Severity of Illness Index ; Adult ; Echocardiography/methods ; }, abstract = {PURPOSE: Evaluating the biomechanical properties of the aorta is crucial for assessing cardiovascular risk and preventing disease progression. The aim of this study was to evaluate the biomechanical properties of the ascending aorta (AA) in severe obstructive sleep apnea syndrome (OSAS) patients with or without hypertension (HT) via velocity vector imaging (VVI).<br><br>METHODS: A total of 68 patients with severe OSAS were selected, 35 of whom were included in the simple OSAS group and 33 of whom were included in the OSAS&#xa0;+&#xa0;HT group, and 40 volunteers without these two disorders who were taken as the control group. AA biomechanical properties, that is, AA longitudinal strain (ALS), AA circumferential strain (ACS), and fractional area change (FAC), were evaluated via VVI. Pulsed Doppler early transmitral peak flow velocity (E), early diastolic mitral annular velocity (e'), left ventricular (LV) global longitudinal strain (GLS), and the AA dimension (AD) were also measured.<br><br>RESULTS: ALS (mean&#xa0;&#xb1;&#xa0;SD; 32.8%&#xa0;&#xb1;&#xa0;11.9% and 19.7%&#xa0;&#xb1;&#xa0;7.6%&#xa0;vs. 40.6%&#xa0;&#xb1;&#xa0;15.6%, p = 0.006), ACS (mean&#xa0;&#xb1;&#xa0;SD; 11.8%&#xa0;&#xb1;&#xa0;3.5% and 8.6%&#xa0;&#xb1;&#xa0;2.7%&#xa0;vs. 16.5%&#xa0;&#xb1;&#xa0;5.8%, p = 0.02), and FAC (mean&#xa0;&#xb1;&#xa0;SD; 21.0%&#xa0;&#xb1;&#xa0;5.3% and 12.4%&#xa0;&#xb1;&#xa0;3.8%&#xa0;vs. 32.8%&#xa0;&#xb1;&#xa0;9.7%, p = 0.004) were significantly lower in the patient groups (OSAS and OSAS&#xa0;+&#xa0;HT, respectively) than in the control group. LV systolic and diastolic functions were also impaired in the patient groups. Compared with volunteers without OSAS and HT, these patients had a greater AD and E/e' ratio and a lower GLS (p&#xa0;<&#xa0;0.01). The aortic biomechanical properties were strongly correlated with the LV function and sleep parameters.<br><br>CONCLUSION: AA biomechanical properties are impaired in patients with severe OSAS, especially those with HT. Impairments in these aortic biomechanical properties are associated with diminished LV function and abnormal sleep parameters. This discovery may help clinicians identify and manage potential cardiovascular risks in OSAS patients. Further large-scale longitudinal studies are needed to confirm the potential predictive value of aortic events (e.g., aortic aneurysm or dissection) in patients with OSAS.}, }
@article {pmid40152605, year = {2025}, author = {Yuan, C and Dong, H and Wu, C and Liu, J and Wang, Z and Wang, X and Ren, H and Wang, Z and Lu, Q}, title = {EPG-5 regulates TGFB/TGF-β and WNT signalling by modulating retrograde endocytic trafficking.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/15548627.2025.2485420}, pmid = {40152605}, issn = {1554-8635}, abstract = {The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-β signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-β: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.}, }
@article {pmid40152389, year = {2025}, author = {Belosludtseva, NV and Ilzorkina, AI and Dubinin, MV and Mikheeva, IB and Belosludtsev, KN}, title = {Comparative Study of Structural and Functional Rearrangements in Skeletal Muscle Mitochondria of SOD1-G93A Transgenic Mice at Pre-, Early-, and Late-Symptomatic Stages of ALS Progression.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {30}, number = {3}, pages = {28260}, doi = {10.31083/FBL28260}, pmid = {40152389}, issn = {2768-6698}, support = {23-25-00286//Russian Science Foundation/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology/pathology ; *Mice, Transgenic ; *Disease Progression ; Male ; *Mitochondria, Muscle/metabolism/ultrastructure/pathology ; Mice ; Muscle, Skeletal/metabolism/ultrastructure/pathology/physiopathology ; Disease Models, Animal ; Superoxide Dismutase/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Lipid Peroxidation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive multisystem disease characterized by limb and trunk muscle weakness that is attributed, in part, to abnormalities in mitochondrial ultrastructure and impaired mitochondrial functions. This study investigated the time course of structural and functional rearrangements in skeletal muscle mitochondria in combination with motor impairments in Tg (copper-zinc superoxide dismutase enzyme (SOD1) G93A) dl1/GurJ (referred to as SOD1-G93A/low) male mice, a familial ALS model, as compared with non-transgenic littermates.<br><br>METHODS: The neurological status and motor functions were assessed weekly using the paw grip endurance method and the grid suspension test with two-limb and four-limb suspension tasks. Transmission electron microscopy followed by quantitative analysis was performed to study ultrastructural alterations in the quadriceps femoris. Functional analysis of skeletal muscle mitochondria was performed using high-resolution Oxygraph-2k (O2K) respirometry and methods for assessing the calcium retention capacity index and the content of lipid peroxidation products in freshly isolated preparations.<br><br>RESULTS: Based on the behavioral phenotyping data, specific age groups were identified: postnatal day 56 (P56) (n = 10-11), 84 (P84) (n = 10-11), and 156 (P154) (n = 10-12), representing the pre-symptomatic, early-symptomatic and late-symptomatic stages of ALS progression in SOD1-G93A/low mice, respectively. Electron microscopy showed mosaic destructive changes in subsarcolemmal mitochondria in fibers of the quadriceps femoris from 84-day-old SOD1-G93A/low mice. Morphometric analysis revealed an elevation in the mean size of the mitochondria in SOD1-G93A mice at P84 and P154. In addition, the P154 transgenic group demonstrated a decrease in sarcomere width and the number of mitochondria per unit area. At the symptomatic stage, SOD1-G93A mice exhibited a decreased respiratory control ratio, ADP-stimulated, and uncoupled respiration rates of mitochondria isolated from the quadriceps femoris muscle, as measured by high-resolution respirometry. In parallel, the mitochondria showed lower calcium retention capacity and increased levels of lipid peroxidation products compared with the control.<br><br>CONCLUSIONS: Taken together, these results indicate stage-dependent changes in skeletal muscle mitochondrial ultrastructure and functions associated with defective oxidative phosphorylation, impaired calcium homeostasis, and oxidative damage in the SOD1-G93A/low mouse model, which appears to be a promising direction for the development of combination therapies for ALS.}, }
@article {pmid40151753, year = {2025}, author = {Carqueja, I and Montenegro Sá, F and Monteiro, S}, title = {Ventricular Arrhythmias Caused by Left Main Coronary Artery Vasospasm: A Diagnostic Challenge in a Cardiac Arrest Victim.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79554}, pmid = {40151753}, issn = {2168-8184}, abstract = {Sudden cardiac death (SCD) is a common cause of cardiovascular deaths. It may be caused by primary electrical diseases, cardiomyopathies, myocarditis, valvular heart diseases, or coronary artery disease (including acute coronary syndrome). Coronary artery vasospasm is defined as a transient total or subtotal coronary artery obstruction, associated with angina symptoms and ischemic findings on electrocardiogram (ECG). It is a cause of myocardial infarction, life-threatening arrhythmias, atrioventricular block, and SCD. A 55-year-old man presented to the hospital after an out-of-hospital cardiac arrest (OHCA). He had a previous history of cardiovascular risk factors, excessive alcohol intake, non-obstructive coronary artery disease, and paroxysmic atrial fibrillation. On the day of the OHCA, he had a sudden collapse while exercising, with ventricular fibrillation and return of spontaneous circulation (ROSC) after advanced life support (ALS). No ECG or echocardiographic anomalies were identified on hospital admission. The patient suffered three more episodes of cardiac arrest during the hospital stay, with atypical arrhythmic presentations. No ECG or echocardiographic abnormalities were observed after ROSC. The fourth cardiac arrest had concomitant segmental ST changes and de novoechocardiographic segmental motility abnormalities suggestive of left main coronary artery occlusion. These findings were transient, with a normal ECG and echocardiogram obtained one hour after ROSC. No electrolyte abnormalities or other causes of cardiac arrest were identified. The hypothesis of left main coronary vasospasm was raised as the likely diagnosis. Coronary artery vasospasm is a possible cause of major cardiac events. Diagnosis can be challenging due to the transient findings and varied manifestations, often in patients with normal coronary arteries. The correct diagnosis and treatment of coronary artery vasospasm can have a determinant effect on prognosis and mortality, as appropriate treatment can lead to prolonged event-free survival. Provocative coronary vasospasm tests performed in patients with atypical cardiovascular manifestations can allow for the timely diagnosis of vasospasm and avoid critical events. The authors aim to raise awareness of the different clinical presentations of coronary artery vasospasm and its consequences. The performance of provocative tests in selected patients should be considered to promote early diagnosis and potentially avoid major events.}, }
@article {pmid40151693, year = {2025}, author = {Tariq, D and Madhusudan, R and Guntupalli, Y and Karumanchi Anantha Venkata Sai, S and Vejandla, B and Lnu, M}, title = {A Cross-Sectional Study Comparing Patient Information Guides for Amyotrophic Lateral Sclerosis, Myasthenia Gravis, and Guillain-Barré Syndrome Produced by ChatGPT-4 and Google Gemini 1.5.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e79646}, pmid = {40151693}, issn = {2168-8184}, abstract = {INTRODUCTION: Patient education for amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG), and Guillain-Barré syndrome (GBS) is essential for effective symptom management, improving quality of life, and enabling informed care decisions. AI tools enhance healthcare and patient education through personalized care and improved diagnostics.<br><br>METHODS: &#xa0;In this study, ChatGPT (OpenAI, San Francisco, CA, USA) and Google Gemini (Mountain View, CA, USA) generated patient education guides for ALS, MG, and GBS. Variables included word count, sentence count, average words and syllables per sentence, grade level, ease score using the Flesch-Kincaid calculator, similarity score using QuillBot, and reliability using a modified DISCERN score. Statistical analysis was done using R version 4.3.2 (2023; R Foundation for Statistical Computing, Vienna, Austria).<br><br>RESULTS: ChatGPT-generated brochures for patient education on ALS, MG, and GBS had a higher grade level and lower ease score compared to those generated by Google Gemini. Although both models had similar reliability and similarity percentages, ChatGPT produced more content with greater complexity and slightly higher reliability.<br><br>CONCLUSION: &#xa0;This study found no significant difference in the average ease, grade, and reliability scores between the two AI tools when generating patient information brochures on ALS, MG and GBS. However, a statistically significant difference was observed in the mean word&#xa0;counts generated by the tools.}, }
@article {pmid40151398, year = {2025}, author = {Roy, SM and Acquarone, E and Argyrousi, EK and Zhang, H and Staniszewski, A and Inoue, A and Ziarek, JJ and Arancio, O and Watterson, DM}, title = {Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.}, journal = {Alzheimer's &amp; dementia (New York, N. Y.)}, volume = {11}, number = {1}, pages = {e70073}, pmid = {40151398}, issn = {2352-8737}, abstract = {INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.<br><br>METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and &#x3b2;-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.<br><br>RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and &#x3b2;-arrestin-1 recruitment.<br><br>DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.<br><br>HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.}, }
@article {pmid40150989, year = {2025}, author = {Matsumoto, S and Tateishi-Karimata, H and Ohyama, T and Sugimoto, N}, title = {Controlling the Local Conformation of RNA G-Quadruplex Results in Reduced RNA/Peptide Cytotoxic Accumulation Associated with C9orf72 ALS/FTD.}, journal = {Small methods}, volume = {}, number = {}, pages = {e2401630}, doi = {10.1002/smtd.202401630}, pmid = {40150989}, issn = {2366-9608}, abstract = {Repeat expansion of d(G4C2) in the noncoding region of the C9orf72 gene contributes to neurodegenerative diseases. The repeat expansion transcript r(G4C2) induces RNA/peptide accumulation, which, in turn, induces cytotoxicity and accelerates the development of neurodegenerative diseases. Such cytotoxic accumulation is triggered by peptide aggregation. Here, a technique is developed to prevent accumulation by regulating RNA interactions, assuming that RNA structure is important for peptide interactions. A screening method is used to identify compounds that suppress RNA accumulation of r(G4C2) repeats. The four compounds are identified with wide π-planes containing hydroxyl, methoxy, and cyclic ether groups that suppressed RNA accumulation. Interestingly, these compounds also suppressed RNA/peptide accumulation in neuroblastoma cells, indicating that RNA accumulation is a key regulator of RNA/peptide cytotoxic aggregate formation. In vitro and in silico physicochemical analyses reveal that these compounds bind to the loop region of the G-quadruplex via hydrogen bonds or CH-π interactions, resulting in an altered loop conformation. Importantly, these conformational changes inhibited RNA G-quadruplex associations. These results show that conformational changes are promising for controlling the interactions between G-quadruplexes and further RNA accumulation. These findings may be useful in the development of therapeutic strategies for the treatment of neurodegenerative diseases.}, }
@article {pmid40149779, year = {2025}, author = {Ginanneschi, F and Casali, S and Cioni, C and Righi, D and Emmanuello, E and Toccaceli, C and Plantone, D and De Stefano, N}, title = {Does Lumbar Puncture Still Have Clinical Value for Patients with Amyotrophic Lateral Sclerosis?.}, journal = {Brain sciences}, volume = {15}, number = {3}, pages = {}, pmid = {40149779}, issn = {2076-3425}, abstract = {Background: The relationship between routine cerebrospinal fluid (CSF) testing and clinical and prognostic data in amyotrophic lateral sclerosis (ALS) remains unclear. Additionally, biochemical data have never been correlated with markers of neurodegeneration. The purpose of this study is to determine whether lumbar puncture may still have clinical utility in ALS. Methods: We collected the CSF profiles of 140 ALS subjects. CSF protein, albumin, IgG, IgG index, albumin quotient (QAlb), t-tau, p-tau, and Aβ42 were analyzed. Results: Approximately one-quarter of ALS patients had elevated levels of protein, albumin, and QAlb in the CSF, but these were not associated with clinical or survival data. Among the neurodegeneration markers, the percentage of patients with abnormal values ranged from 26.3% to 35.4%. The p-tau/t-tau ratio and Aβ42 were correlated with both the ALS progression rate and the time from diagnosis to death. Aβ42 was the prognostic marker most strongly associated with survival. Conclusions: The lack of correlation between biochemical CSF findings and the clinical and/or prognostic status of ALS suggests that these markers have no clinical value. However, neurodegeneration markers that are easily measurable in clinical laboratories, particularly Aβ42, may be useful at the time of diagnosis for predicting ALS survival and progression rate.}, }
@article {pmid40149599, year = {2025}, author = {Yang, W and Xiao, W and Liu, X and Li, H and Huang, T and Fan, D}, title = {Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149599}, issn = {2227-9059}, support = {82071426//National Natural Science Foundation of China/ ; }, abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.}, }
@article {pmid40149536, year = {2025}, author = {Kleinerova, J and Chipika, RH and Tan, EL and Yunusova, Y and Marchand-Pauvert, V and Kassubek, J and Pradat, PF and Bede, P}, title = {Sensory Dysfunction in ALS and Other Motor Neuron Diseases: Clinical Relevance, Histopathology, Neurophysiology, and Insights from Neuroimaging.}, journal = {Biomedicines}, volume = {13}, number = {3}, pages = {}, pmid = {40149536}, issn = {2227-9059}, support = {JPND-Cofund-2-2019-1 &amp; HRB EIA-2017-019//HRB/ ; }, abstract = {Background: The clinical profiles of MNDs are dominated by inexorable motor decline, but subclinical proprioceptive, nociceptive and somatosensory deficits may also exacerbate mobility, dexterity, and bulbar function. While extra-motor pathology and frontotemporal involvement are widely recognised in motor neuron diseases (MNDs), reports of sensory involvement are conflicting. The potential contribution of sensory deficits to clinical disability is not firmly established and the spectrum of sensory manifestations is poorly characterised. Methods: A systematic review was conducted to examine the clinical, neuroimaging, electrophysiology and neuropathology evidence for sensory dysfunction in MND phenotypes. Results: In ALS, paraesthesia, pain, proprioceptive deficits and taste alterations are sporadically reported and there is also compelling electrophysiological, histological and imaging evidence of sensory network alterations. Gait impairment, impaired dexterity, and poor balance in ALS are likely to be multifactorial, with extrapyramidal, cerebellar, proprioceptive and vestibular deficits at play. Human imaging studies and animal models also confirm dorsal column-medial lemniscus pathway involvement as part of the disease process. Sensory symptoms are relatively common in spinal and bulbar muscular atrophy (SBMA) and Hereditary Spastic Paraplegia (HSP), but are inconsistently reported in primary lateral sclerosis (PLS) and in post-poliomyelitis syndrome (PPS). Conclusions: Establishing the prevalence and nature of sensory dysfunction across the spectrum of MNDs has a dual clinical and academic relevance. From a clinical perspective, subtle sensory deficits are likely to impact the disability profile and care needs of patients with MND. From an academic standpoint, sensory networks may be ideally suited to evaluate propagation patterns and the involvement of subcortical grey matter structures. Our review suggests that sensory dysfunction is an important albeit under-recognised facet of MND.}, }
@article {pmid40149460, year = {2025}, author = {Ghezzi, A and Gianferrari, G and Baldassarri, E and Zucchi, E and Martinelli, I and Vacchiano, V and Bonan, L and Zinno, L and Nuredini, A and Canali, E and Gizzi, M and Terlizzi, E and Medici, D and Sette, E and Currò Dossi, M and Morresi, S and Santangelo, M and Patuelli, A and Longoni, M and De Massis, P and Ferro, S and Fini, N and Simonini, C and Carra, S and Zamboni, G and Mandrioli, J}, title = {Phenotypical Characterization of C9ALS Patients from the Emilia Romagna Registry of ALS: A Retrospective Case-Control Study.}, journal = {Genes}, volume = {16}, number = {3}, pages = {}, pmid = {40149460}, issn = {2073-4425}, support = {00000000//Emilia Romagna Regional Health Authority/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/epidemiology ; Male ; Female ; *C9orf72 Protein/genetics ; Middle Aged ; *Registries ; Aged ; *Phenotype ; Case-Control Studies ; Disease Progression ; Retrospective Studies ; Adult ; Prognosis ; }, abstract = {BACKGROUND/OBJECTIVES: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic delay, sourced from the same register.<br><br>METHODS: In total, 67 C9ALS patients were compared to 201 nmALS. Clinical data, phenotype, and prognostic factors were analyzed in the two groups and within the C9ALS group after stratification by sex.<br><br>RESULTS: C9ALS patients displayed a higher disease progression rate and shorter times to gastrostomy and invasive ventilation, despite no differences in overall survival. Female C9ALS had a more severe bulbar and upper motor neuron involvement compared to males. Cognitive and behavioral symptoms were more common in the C9ALS group, and the former was an independent prognostic factor. Prevalences of, autoimmune diseases, and dyslipidemia were significantly higher among C9ALS patients.<br><br>CONCLUSIONS: In our dataset, we show an overall increased disease progression rate in C9ALS patients and hint at sex-specific discrepancies in some phenotypical characteristics. We also suggest a possible clinically relevant involvement of C9ORF72 expansion in metabolism and autoimmunity.}, }
@article {pmid40149017, year = {2025}, author = {Suk, TR and Part, CE and Zhang, JL and Nguyen, TT and Heer, MM and Caballero-Gómez, A and Grybas, VS and McKeever, PM and Nguyen, B and Ali, T and Callaghan, SM and Woulfe, JM and Robertson, J and Rousseaux, MWC}, title = {A stress-dependent TDP-43 SUMOylation program preserves neuronal function.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {38}, pmid = {40149017}, issn = {1750-1326}, support = {PJT-195691//CIHR/ ; }, mesh = {*Sumoylation/physiology ; *DNA-Binding Proteins/metabolism/genetics ; Humans ; Animals ; *Neurons/metabolism ; Mice ; Male ; Female ; Frontotemporal Dementia/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Aging/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.}, }
@article {pmid40148124, year = {2025}, author = {Beckers, D and Kretz, F and Glandorf, K and Abdassalam, S and Amer, M and Breyer, DRH and Kaymak, H and Klabe, K and Beckers, L}, title = {Automated Comprehensive Analysis of Preoperative Biometric Parameters in Cataract Patients: A Retrospective Study of over 6 000 Eyes.}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2541-4942}, pmid = {40148124}, issn = {1439-3999}, abstract = {Cataract surgery is one of the most successful surgical procedures, improving vision and quality of life for millions globally. An accurate preoperative measurement is crucial for predicting outcomes, particularly in minimizing postoperative refractive errors through precise intraocular lens (IOL) selection. This study aimed to analyze preoperative biometric data in cataract patients to identify key parameters relevant for clinical decision-making. The study also sought to understand patient demographics and biometrics in a representative population. An automated retrospective analysis was conducted on the preoperative biometric data of 6 163 eyes from 3 118 patients who underwent cataract or clear lens extraction (CLE) surgery in a German clinic over the past 2 years. All measurements were taken using the IOL Master 700 (Carl Zeiss Meditec, Jena, Germany), and data were automatically transferred for analysis using a dedicated software tool. Biometric parameters assessed included axial length (AL), keratometry values (K, TK), anterior chamber depth (ACD), lens thickness (LT), and vitreous length (VL). The age and gender distribution of the cohort was also considered. The biometric data from this large patient cohort largely aligns with published norms for cataract patients. The majority of eyes exhibited ALs and corneal curvatures within expected ranges, supporting accurate IOL power calculations. The study also confirmed a high prevalence of mild astigmatism, suggesting that toric IOLs could address residual astigmatism for better visual outcomes. This study's large sample size adds valuable insights into preoperative cataract patient data and shows the value of an automated analysis.}, }
@article {pmid40148057, year = {2025}, author = {De Marchi, F and Spinelli, EG and Bendotti, C}, title = {Neuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Handbook of clinical neurology}, volume = {210}, number = {}, pages = {45-67}, doi = {10.1016/B978-0-443-19102-2.00004-1}, pmid = {40148057}, issn = {0072-9752}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Frontotemporal Dementia/pathology ; *Neuroglia/pathology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases sharing significant pathologic and genetic overlap, leading to consider these diseases as a continuum in the spectrum of their pathologic features. Although FTD compromises only specific brain districts, while ALS involves both the nervous system and the skeletal muscles, several neurocentric mechanisms are in common between ALS and FTD. Also, recent research has revealed the significant involvement of nonneuronal cells, particularly glial cells such as astrocytes, oligodendrocytes, microglia, and peripheral immune cells, in disease pathology. This chapter aims to provide an extensive overview of the current understanding of the role of glia in the onset and advancement of ALS and FTD, highlighting the recent implications in terms of prognosis and future treatment options.}, }
@article {pmid40147067, year = {2025}, author = {Jiang, T and Ding, W and Li, X}, title = {Serum creatine kinase dynamics in amyotrophic lateral sclerosis: Predictive role of male sex, limb onset, and intermediate disease duration for stratified monitoring.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {135}, number = {}, pages = {111203}, doi = {10.1016/j.jocn.2025.111203}, pmid = {40147067}, issn = {1532-2653}, abstract = {OBJECTIVE: To investigate serum creatine kinase (CK) levels in amyotrophic lateral sclerosis (ALS) patients and their associations with disease characteristics, exploring its utility as a biomarker for disease progression.<br><br>METHODS: This retrospective study included 81 definitive ALS patients and 99 matched controls. Serum CK levels were analyzed against sex, age, onset site, disease duration, and ALSFRS-R scores using Mann-Whitney U tests, Kruskal-Wallis tests, and multivariate regression.<br><br>RESULTS: ALS patients exhibited significantly elevated CK levels compared to controls (233.92&#xa0;&#xb1;&#xa0;216.91 vs. 101.81&#xa0;&#xb1;&#xa0;34.28&#xa0;IU/L, P&#xa0;<&#xa0;0.05), with 65.43&#xa0;% exceeding gender-specific ranges. Multivariate analysis identified male sex (&#x3b2;&#xa0;=&#xa0;0.32, 95&#xa0;% CI: 0.21-0.43; P&#xa0;<&#xa0;0.05), limb onset (vs. bulbar: &#x3b2;&#xa0;=&#xa0;0.41, 95&#xa0;% CI: 0.29-0.53; P&#xa0;<&#xa0;0.05), and intermediate disease duration (1-3&#xa0;years: &#x3b2;&#xa0;=&#xa0;0.32, P&#xa0;<&#xa0;0.05) as independent predictors. CK levels peaked in limb-onset patients (lower limb: 342.40&#xa0;&#xb1;&#xa0;283.53&#xa0;IU/L vs. bulbar: 96.20&#xa0;&#xb1;&#xa0;49.39&#xa0;IU/L; P&#xa0;<&#xa0;0.05). Higher CK was associated with moderate disease severity (ALSFRS-R 36-40 vs.&#xa0;&#x2264;&#xa0;35: P&#xa0;<&#xa0;0.05).<br><br>CONCLUSION: Serum CK elevation in ALS is strongly linked to male sex, limb onset, and intermediate disease duration (1-3&#xa0;years), though long-duration cases (>3 years) were underrepresented (n&#xa0;=&#xa0;4). These findings highlight CK's potential as a cost-effective biomarker for personalized monitoring, particularly in limb-onset males with moderate functional impairment. Further validation in larger cohorts is warranted.}, }
@article {pmid40145977, year = {2025}, author = {Zhao, W and Liu, Z and Wu, J and Liu, A and Yan, J}, title = {Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01343}, pmid = {40145977}, issn = {1673-5374}, abstract = {For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.}, }
@article {pmid40145976, year = {2025}, author = {Wang, Z and Cao, W and Chen, L and Zhang, S and Tang, L and Cui, W and Kong, M and Yu, L and Fan, D and Zheng, W}, title = {The role of the peripheral immune system in mediating axonal dysfunction in early-stage amyotrophic lateral sclerosis: an age- and sex-based analysis.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01081}, pmid = {40145976}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons. Early-stage axonal dysfunction, rather than central nervous system injury, plays a key role in the disease process. However, the molecular mechanisms underlying this dysfunction remain unclear. To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis, we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024. We collected peripheral immune markers at baseline, including total leukocytes, lymphocytes, monocytes, neutrophils, basophils, eosinophils, and platelets. We also calculated four derived ratios: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and systemic immune inflammation index. Multivariate analysis, adjusted for confounding factors, revealed that higher counts of total leukocytes and neutrophils, as well as higher neutrophil-related ratios, including the neutrophil to lymphocyte ratio and the systemic immune inflammation index, were significantly correlated with higher compound muscle action potential scores. Stratified analyses revealed that these associations varied by age and sex. Furthermore, mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression. These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury, particularly in the early stages of the disease. This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.}, }
@article {pmid40143847, year = {2025}, author = {Meyer, J and Gaur, N and von der Gablentz, J and Friedrich, B and Roediger, A and Grosskreutz, J and Steinbach, R}, title = {Phosphorylated neurofilament heavy chain (pNfH) concentration in cerebrospinal fluid predicts overall disease aggressiveness (D50) in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1536818}, pmid = {40143847}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by tremendous clinical heterogeneity that necessitates reliable biomarkers for the trajectory of the disease. The potential of phosphorylated Neurofilament-Heavy-chain (pNfH) measured in cerebrospinal fluid (CSF) to mirror disease progressiveness has repeatedly been suggested but is not applicable as outcome on an individual patient-level. This potential was probably obfuscated before due to imprecise clinical measures of disease progression that assumed a linear decline of motoric function over time. The primary objective was therefore to study if disease aggressiveness, as quantified via the D50 model, would reveal more stable correlations with pNfH.<br><br>METHODS: ELISA-quantified pNfH CSF levels of 108 patients with ALS were comparatively analyzed in relation to three different measures of disease progression speed via analyses of covariance, linear and non-linear regressions, respectively. These were (a) the D50, depicting a patient's overall disease aggressiveness, (b) cFL, the calculated functional loss-rate as locally derived parameter of progression speed, and (c) DPR, the disease progression-rate as more commonly used linear approximation of points lost per month in the ALS functional rating scale since symptom onset.<br><br>RESULTS: All analyses of covariance showed a significant main impact of the respective disease progression-speed parameter on pNfH, independent of disease phase, presence of frontotemporal dementia, analyzing laboratory, sex or clinical onset type, while only age revealed borderline additional influence. Notably, CSF pNfH concentration was independent of how far the disease had progressed, as neither disease phase nor a direct regression with the quantified disease accumulation at the time of lumbar puncture revealed a significant correlation. However, the parameter D50 quantifying aggressiveness showed the most significant impact on pNfH-levels, as compared to the cFL and even more evident in contrast to the DPR. This superiority of D50 was confirmed in direct linear and most evident in non-linear regressions with pNfH.<br><br>CONCLUSION: Overall disease aggressiveness in ALS, as quantified by D50, most robustly correlated with CSF pNfH-levels, independent of the time of collection during symptomatic disease. This opens perspectives to use CSF pNfH as a prognostic outcome measure for future therapeutic interventions in the sense of precision medicine.}, }
@article {pmid40143800, year = {2025}, author = {Heylen, A and Vermeiren, Y and De Deyn, PP and Van Dam, D}, title = {Monoaminergic Alterations at the Subregional Cervical and Thoracic Spinal Cord Level of Patients Within the FTD-ALS Continuum and Early-Onset AD: Low Thoracic Dopaminergic Activity in ALS.}, journal = {Journal of neurochemistry}, volume = {169}, number = {3}, pages = {e70046}, doi = {10.1111/jnc.70046}, pmid = {40143800}, issn = {1471-4159}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Female ; Male ; *Frontotemporal Dementia/metabolism/pathology ; Aged ; Middle Aged ; *Alzheimer Disease/metabolism/pathology ; *Dopamine/metabolism ; Spinal Cord/metabolism ; Biogenic Monoamines/metabolism ; Thoracic Vertebrae ; Cervical Cord/metabolism ; }, abstract = {Early-onset neurodegeneration leads to cognitive and behavioral symptoms in frontotemporal dementia (FTD) and motor disturbances in amyotrophic lateral sclerosis (ALS). Despite distinct clinical profiles, more than half of FTD patients experience ALS-related symptoms and vice versa. Spinal cord monoamine neurotransmitter alterations were reported in ALS, but not yet in FTD. Therefore, we compared monoaminergic turnover across the FTD-ALS continuum. Reversed-phase, ultra-high-performance liquid chromatography with electrochemical detection was used to measure levels of the monoamines (nor)adrenaline ((N)A), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in five cervical and thoracic spinal cord regions in 10 FTD, 14 ALS, 6 mixed FTD-ALS, 14 early-onset Alzheimer's disease (EOAD), and 7 control (CONTR) individuals. At the cervical level, NA levels were lower in FTD-ALS versus CONTR, whereas the HVA/5-HIAA ratio was higher in ALS versus EOAD in the lateral funiculus. In the dorsal horn-intermediate gray matter, DA levels were decreased in FTD-ALS compared to FTD. At the thoracic level, DOPAC was lower in ALS than in FTD-ALS patients in the ventral and lateral funiculus, ventral horn, and dorsal horn-intermediate gray matter, as was the DOPAC/DA ratio in the lateral funiculus and dorsal horn-intermediate gray matter. Contrarily, HVA/DA turnover was lower in FTD-ALS than in FTD in the dorsal and ventral funiculus. We observed lower NA levels in FTD-ALS than in FTD in the ventral funiculus, and lower MHPG/NA turnover in the dorsal horn-intermediate gray matter. A levels were lower in ALS versus FTD. This study indicates differences in monoaminergic turnover across the FTD-ALS continuum, at the cervical and thoracic levels, with primarily a decrease in dopaminergic activity in ALS. Characterizing disease-specific neurochemical profiles for FTD, ALS, or FTD-ALS could contribute to the identification of novel interesting pharmacological targets.}, }
@article {pmid40143051, year = {2025}, author = {Zou, Y and Zhang, J and Chen, L and Xu, Q and Yao, S and Chen, H}, title = {Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.}, journal = {Pharmaceutics}, volume = {17}, number = {3}, pages = {}, pmid = {40143051}, issn = {1999-4923}, support = {82100892//Hong Chen/ ; 82300929//Jing Zhang/ ; }, abstract = {Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.}, }
@article {pmid40141996, year = {2025}, author = {Kodama, TS and Furuita, K and Kojima, C}, title = {Beyond Static Tethering at Membrane Contact Sites: Structural Dynamics and Functional Implications of VAP Proteins.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141996}, issn = {1420-3049}, support = {JP22H05536, JP22K19184, JP23H02416, and JP23K18030//Ministry of Education, Culture, Sports, Science and Technology/ ; NMR Platform//Ministry of Education, Culture, Sports, Science and Technology/ ; CR-24-05//Institute for Protein Research, Osaka University/ ; JP24ama121001//Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; *Vesicular Transport Proteins/chemistry/metabolism ; Cell Membrane/metabolism/chemistry ; Animals ; Protein Conformation ; Phylogeny ; }, abstract = {The membranes surrounding the eukaryotic cell and its organelles are continuously invaginating, budding, and undergoing membrane fusion-fission events, which enable them to perform functions not found in prokaryotic cells. In addition, organelles come into close contact with each other at membrane contact sites (MCSs), which involve many types of proteins, and which regulate the signaling and transport of various molecules. Vesicle-associated membrane protein (VAMP)-associated protein (VAP) is an important factor involved in the tethering and contact of various organelles at MCSs in almost all eukaryotes and has attracted attention for its association with various diseases, mainly neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the detailed mechanism of its functional expression remains unclear. In this review, we quantitatively discuss the structural dynamics of the entire molecule, including intrinsically disordered regions and intramolecular and intermolecular interactions, focusing on the vertebrate VAP paralogs VAPA and VAPB. Molecular phylogenetic and biophysical considerations are the basis of the work.}, }
@article {pmid40141987, year = {2025}, author = {Russo, A and Putaggio, S and Tellone, E and Calderaro, A and Cirmi, S and Laganà, G and Ficarra, S and Barreca, D and Patanè, GT}, title = {Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {6}, pages = {}, pmid = {40141987}, issn = {1420-3049}, mesh = {*Ferroptosis/drug effects ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/drug therapy/genetics ; *Polyphenols/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Reactive Oxygen Species/metabolism ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Mitochondria/metabolism/drug effects ; Iron/metabolism ; }, abstract = {Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc[-] system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols.}, }
@article {pmid40141149, year = {2025}, author = {Zheng, MY and Luo, LZ}, title = {The Role of IL-17A in Mediating Inflammatory Responses and Progression of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {6}, pages = {}, pmid = {40141149}, issn = {1422-0067}, support = {No. 2023D022//the Fujian Provincial Natural Science Foundation/ ; No. 3502Z202473076//the Science and Technology Program of Xiamen City/ ; No. 2019-WJ-30//the Fujian Province Health Education Joint Research Project/ ; }, mesh = {Humans ; *Interleukin-17/metabolism/immunology ; *Neurodegenerative Diseases/metabolism/immunology/pathology ; Animals ; Inflammation/metabolism/immunology/pathology ; Receptors, Interleukin-17/metabolism ; Signal Transduction ; Disease Progression ; Blood-Brain Barrier/metabolism/immunology ; }, abstract = {IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades; the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.}, }
@article {pmid40140966, year = {2025}, author = {Balaban, E and Köse, TE and Günaçar, DN and Naralan, ME and Gonca, M}, title = {Comparison of methods for detecting mandibular lingula and can antilingula be used in lingula mandibula detection?.}, journal = {BMC oral health}, volume = {25}, number = {1}, pages = {430}, pmid = {40140966}, issn = {1472-6831}, support = {02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; 02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; 02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; 02025001021255//Recep Tayyip Erdo&#x11f;an University Development Foundation/ ; }, mesh = {Humans ; *Cone-Beam Computed Tomography ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Mandible/diagnostic imaging ; Aged ; Adolescent ; Aged, 80 and over ; Young Adult ; Orthognathic Surgical Procedures ; Anatomic Landmarks/diagnostic imaging ; Mandibular Nerve/diagnostic imaging/anatomy &amp; histology ; }, abstract = {OBJECTIVE: The aim of this study is to evaluate the relationship between anatomical reference points used during orthognathic surgery and to minimize the risks of iatrogenic neurovascular damage.<br><br>MATERIALS AND METHODS: This retrospective study included cone-beam computed tomography (CBCT) images involving the mandible from patients who visited Recep Tayyip Erdo&#x11f;an University Faculty of Dentistry between January 2018 and September 2023. The age range of the included individuals was set between 18 and 80 years. Horizontal and vertical distances between mandibular anatomical structures, such as the lingula mandibula (LM), mandibular foramen (MF), antilingula (AL), and surrounding structures were measured using CBCT software. Individuals with intraosseous pathology, insufficient image quality, or a history of surgical/orthodontic treatment were excluded from the study.<br><br>RESULTS: A total of 240 hemimandibles from 120 patients were analyzed (55.83% female, 44.17% male; mean age: 46.78&#x2009;&#xb1;&#x2009;15.30 years). Significant differences were identified in LM positions according to different AL types. The LM was found to be more inferior and posterior relative to hill and ridge type ALs, while it was more anterior relative to plateau type ALs. In 26.25% of mandibular rami, AL was not detected.<br><br>CONCLUSION: The position of the AL can serve as a guide in determining the osteotomy line during inferior vertical ramus osteotomy (IVRO). However, relying solely on AL as a reference point may increase the risk of inferior alveolar nerve (IAN) injury. Preoperative tomographic evaluations to determine the relationships among LM, MF, and AL can provide a safer approach in surgical planning, reduce complications, and help protect neurovascular structures.}, }
@article {pmid40140908, year = {2025}, author = {Wang, KS and Smeyers, J and Eggan, K and Budnik, B and Mordes, DA}, title = {C9ORF72 poly-PR disrupts expression of ALS/FTD-implicated STMN2 through SRSF7.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {67}, pmid = {40140908}, issn = {2051-5960}, support = {K08 NS104270/NS/NINDS NIH HHS/United States ; K08NS104270/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Serine-Arginine Splicing Factors/genetics/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Stathmin/genetics/metabolism ; DNA Repeat Expansion/genetics ; Neurons/metabolism/drug effects ; }, abstract = {A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and combined ALS/FTD. The repeat is transcribed in the sense and the antisense directions to produce several dipeptide repeat proteins (DPRs) that have toxic gain-of-function effects; however, the mechanisms by which DPRs lead to neural dysfunction remain unresolved. Here, we observed that poly-proline-arginine (poly-PR) was sufficient to inhibit axonal regeneration of human induced pluripotent stem cell (iPSC)-derived neurons. Global phospho-proteomics revealed that poly-PR selectively perturbs nuclear RNA binding proteins (RBPs). In neurons, we found that depletion of one of these RBPs, SRSF7 (serine/arginine-rich splicing factor 7), resulted in decreased abundance of STMN2 (stathmin-2), though not TDP-43. STMN2 supports axon maintenance and repair and has been recently implicated in the pathogenesis of ALS/FTD. We observed that depletion of SRSF7 impaired axonal regeneration, a phenotype that could be rescued by exogenous STMN2. We propose that antisense repeat-encoded poly-PR perturbs RBPs, particularly SRSF7, resulting in reduced STMN2 and axonal repair defects in neurons. Hence, we provide a potential link between DPRs gain-of-function effects and STMN2 loss-of-function phenotypes in neurodegeneration.}, }
@article {pmid40140666, year = {2025}, author = {de Bernardo, N and de la Rubia Ortí, JE and Villarón-Casales, C and Privado, J and Maset-Roig, R and Cañabate, M and Sancho-Cantus, D and Sanz, IO and Fernández, RF and Proaño, B and Tvarijonaviciute, A and Rubio, CP and Benlloch, M and Menargues-Ramírez, R and Alarcón-Jiménez, J}, title = {Autonomic nervous system and mediating role of respiratory function in patients with ALS.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10513}, pmid = {40140666}, issn = {2045-2322}, support = {2021-203-003//Universidad Cat&#xf3;lica de Valencia San Vicente M&#xe0;rtir/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Autonomic Nervous System/physiopathology ; Cross-Sectional Studies ; Aged ; Antioxidants/metabolism ; Cognition/physiology ; Respiration ; Oxidative Stress ; Heart Rate/physiology ; Adult ; }, abstract = {Patients with Amyotrophic Lateral Sclerosis (ALS) exhibit altered patterns of respiratory rate and heart rhythm that are directly related to autonomic nervous system (ANS) activity. This study aimed to analyze the role of the ANS in respiratory function, cognition, functionality, and antioxidant capacity in patients with ALS through a predictive model that assesses the mediating activity of respiration. This quantitative, observational, analytical, and cross-sectional clinical study was conducted using a sample of 75 patients diagnosed with ALS. ANS activity, respiratory function, cognition, functionality, and antioxidant capacity were also measured. Using these values, a structural equation model was developed using AMOS V.23 software. The mediational predictive model showed that increased sympathetic nervous system (SNS) activity, in turn, increased respiratory function, whereas the role of the parasympathetic nervous system in respiration was very weak and had the opposite effect. Furthermore, SNS activity increased respiratory function values, which, in turn, improved functional capacity, cognition, and antioxidant power in patients with ALS, with respiratory function playing a mediating role. The mediating effect of respiratory function was observed primarily between ANS and functional disability. For oxidative stress, respiratory function showed a high mediating effect, such that greater respiratory function corresponded to greater antioxidant capacity. Additionally, for cognitive activity, a moderate direct effect of the ANS was observed; however, it was greatly enhanced by respiratory disability. Finally, differences were only found based on sex, with respiratory capacity and antioxidant power being higher in men.}, }
@article {pmid40140608, year = {2025}, author = {Dubey, SK and Bellen, HJ}, title = {A neuroprotective role of polyunsaturated fatty acids in C9orf72-ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {710-712}, pmid = {40140608}, issn = {1546-1726}, }
@article {pmid40140376, year = {2025}, author = {Megat, S and Marques, C and Hernán-Godoy, M and Sellier, C and Stuart-Lopez, G and Dirrig-Grosch, S and Gorin, C and Brunet, A and Fischer, M and Keime, C and Kessler, P and Mendoza-Parra, MA and Zwamborn, RAJ and Veldink, JH and Scholz, SW and Ferrucci, L and Ludolph, A and Traynor, B and Chio, A and Dupuis, L and Rouaux, C}, title = {CREB3 gain of function variants protect against ALS.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2942}, pmid = {40140376}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; Humans ; *Cyclic AMP Response Element-Binding Protein/metabolism/genetics ; Male ; Mice ; *Motor Neurons/metabolism/pathology ; Mice, Transgenic ; Gain of Function Mutation ; Endoplasmic Reticulum Stress/genetics ; Female ; Motor Cortex/metabolism/pathology ; Disease Models, Animal ; Middle Aged ; Superoxide Dismutase-1/genetics/metabolism ; Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal RNA-seq on CSN purified from male Sod1[G86R] mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3[R119G] (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3[R119G] decreases the risk of developing ALS and the motor progression rate of ALS patients.}, }
@article {pmid40139174, year = {2025}, author = {Toraih, EA and Siddiqui, S and Siddiqui, S and Shirini, K and Elfezzani, N and Abdelmaksoud, A and Elshazli, RM and Hussein, MH and Elmorsy, EM and Fawzy, MS}, title = {Thyroid Disorders as a Risk Factor for Neurodegenerative Proteinopathies: A Large-Scale Propensity Score-Matched Analysis.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000545369}, pmid = {40139174}, issn = {1423-0208}, abstract = {INTRODUCTION: The relationship between thyroid disorders and neurodegenerative diseases remains poorly understood. This large-scale retrospective cohort study aimed to investigate the association between thyroid disorders and various neurodegenerative diseases, as well as the potential impact of thyroidectomy.<br><br>METHODS: We analyzed data from 3,719,666 patients with thyroid disorders and 2,945,438 controls from 120 healthcare organizations. After propensity score matching, each group included 2,033,096 patients. We compared the risk of neurodegenerative diseases between these groups and examined the effect of thyroidectomy in a subgroup analysis of 31,753 matched pairs.<br><br>RESULTS: Patients with thyroid disorders showed significantly higher risks of Alzheimer's disease (RR=1.15, 95%CI: 1.110-1.195), Parkinson's disease (RR=1.25, 95%CI: 1.187-1.318), amyotrophic lateral sclerosis (RR=1.35, 95%CI: 1.131-1.622), frontotemporal dementia (RR=1.44, 95%CI: 1.219-1.702), Lewy body dementia (RR=1.15, 95%CI: 1.107-1.186), progressive supranuclear palsy (RR=1.41, 95%CI: 1.095-1.819), vascular dementia (RR=1.32, 95%CI: 1.266-1.369), Niemann-Pick disease type C (RR=1.34, 95%CI: 1.092-1.638), and Wilson's disease (RR=1.26, 95%CI: 1.056-1.507). Interestingly, the risk of multiple sclerosis was lower (RR=0.80, 95%CI: 0.738-0.862). Thyroidectomy was associated with a 44.2% lower risk of Lewy body dementia (RR=0.558, 95%CI: 0.339-0.919, p=0.020).<br><br>CONCLUSION: Thyroid disorders are significantly associated with an increased risk of several neurodegenerative diseases. Thyroidectomy may have a protective effect against Lewy body dementia. These findings suggest a complex relationship between thyroid function and neurodegeneration, emphasizing the need for neurological monitoring in patients with thyroid disorders and further research into thyroid-brain interactions.}, }
@article {pmid40138872, year = {2025}, author = {Liang, T and Jiang, T and Liang, Z and Li, L and Chen, Y and Chen, T and Yang, L and Zhang, N and Dong, B and Xie, X and Gu, B and Wu, Q}, title = {Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China.}, journal = {Microbiological research}, volume = {296}, number = {}, pages = {128145}, doi = {10.1016/j.micres.2025.128145}, pmid = {40138872}, issn = {1618-0623}, mesh = {*Diabetes Mellitus, Type 2/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology ; *Staphylococcus aureus/enzymology/genetics/metabolism ; *Amino Acids, Branched-Chain/biosynthesis ; *Acetolactate Synthase/metabolism/genetics ; Humans ; Animals ; Mice ; China ; Male ; Insulin Resistance ; Female ; Middle Aged ; *Glycemic Control ; Blood Glucose ; Feces/microbiology ; Staphylococcal Infections/microbiology ; Metagenomics ; Prediabetic State/microbiology ; Metabolomics ; Insulin ; }, abstract = {An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.}, }
@article {pmid40138119, year = {2025}, author = {Ali, N and Sayeed, U and Shahid, SMA and Akhtar, S and Khan, MKA}, title = {Molecular mechanisms and biomarkers in neurodegenerative disorders: a comprehensive review.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {337}, pmid = {40138119}, issn = {1573-4978}, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism/cerebrospinal fluid ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; tau Proteins/metabolism/cerebrospinal fluid ; Parkinson Disease/diagnosis/metabolism/genetics/cerebrospinal fluid ; alpha-Synuclein/metabolism ; Alzheimer Disease/diagnosis/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/diagnosis/genetics/cerebrospinal fluid ; Huntington Disease/diagnosis/metabolism/genetics ; Positron-Emission Tomography/methods ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD), are significant global health challenges, owing to their profound impact on cognitive, motor, and behavioral functions. The etiology and progression of these disorders are influenced by a complex interplay of environmental factors and genetic predispositions with specific genetic markers, such as mutations in the APOE and HTT genes, which play pivotal roles. Current therapeutic interventions predominantly focus on symptom management; however, emerging strategies, including gene therapies, anti-amyloid agents, and neuroprotective approaches, are designed to directly target the underlying disease mechanisms. Advances in biomarker discovery and imaging methodologies have emerged as essential tools for early diagnosis and monitoring of therapeutic efficacy in these disorders. In the context of AD, cerebrospinal fluid (CSF) amyloid-beta (Aβ) and tau levels, along with positron emission tomography (PET) imaging, are well-established biomarkers. Similarly, CSF alpha-synuclein and dopamine transporter (DAT) imaging have been employed as diagnostic tools for PD. Moreover, emerging biomarkers, such as blood-based tau and the Aβ42/40 ratio for AD, as well as the neurofilament light chain (NfL) for ALS and PD, hold promise for enhancing early diagnostic accuracy and facilitating the longitudinal assessment of disease progression. This study comprehensively examined the molecular mechanisms underlying these neurodegenerative disorders, focusing on amyloid-beta plaque deposition and tau protein aggregation in AD, alpha-synuclein misfolding in PD, and aberrant protein aggregation in ALS and HD, thereby contributing to a deeper understanding of the pathophysiological basis of these disorders.}, }
@article {pmid40138021, year = {2025}, author = {Vaughan, DP and Real, R and Jensen, MT and Fumi, RG and Hodgson, M and Jabbari, E and Lux, D and Wu, L and ,  and ,  and Warner, TT and Jaunmuktane, Z and Revesz, T and Rowe, JB and Rohrer, J and Morris, HR}, title = {Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {293}, pmid = {40138021}, issn = {1432-1459}, support = {PROSPECT2//Progressive Supranuclear Palsy Association/ ; T033371/1/MRC_/Medical Research Council/United Kingdom ; 220258/WT_/Wellcome Trust/United Kingdom ; MC_UU_00030/14//Cambridge Centre for Parkinson-Plus/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Supranuclear Palsy, Progressive/genetics ; Male ; Female ; Aged ; *Parkinsonian Disorders/genetics ; *DNA Repeat Expansion/genetics ; Middle Aged ; *Corticobasal Degeneration/genetics ; Aged, 80 and over ; Cohort Studies ; Prospective Studies ; }, abstract = {BACKGROUND: Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.<br><br>AIMS: To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and&#xa0;CBD in neuropathologically confirmed cases.<br><br>METHODS: 626 cases, including PSP (n&#x2009;=&#x2009;366), CBS (n&#x2009;=&#x2009;130), and APS (n&#x2009;=&#x2009;53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in C9orf72 using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort.<br><br>RESULTS: There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large C9orf72 repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival.<br><br>CONCLUSIONS: Intermediate expansions in C9orf72 do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.}, }
@article {pmid40137505, year = {2025}, author = {Calderón-Garcidueñas, L and González-Maciel, A and Reynoso-Robles, R and Cejudo-Ruiz, FR and Silva-Pereyra, HG and Gorzalski, A and Torres-Jardón, R}, title = {Alzheimer's, Parkinson's, Frontotemporal Lobar Degeneration, and Amyotrophic Lateral Sclerosis Start in Pediatric Ages: Ultrafine Particulate Matter and Industrial Nanoparticles Are Key in the Early-Onset Neurodegeneration: Time to Invest in Preventive Medicine.}, journal = {Toxics}, volume = {13}, number = {3}, pages = {}, pmid = {40137505}, issn = {2305-6304}, abstract = {Billions of people are exposed to fine particulate matter (PM2.5) levels above the USEPA's annual standard of 9 μg/m[3]. Common emission sources are anthropogenic, producing complex aerosolized toxins. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on the brain, but the USA does not measure UFPM on a routine basis. This review focuses on the development and progression of common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one of the most polluted megacities in the world, with a population of 22 million residents, many of whom are unaware of the brain effects caused by their polluted atmosphere. Fatal neurodegenerative diseases (such as Alzheimer's and Parkinson's) that begin in childhood in populations living in air polluted environments are preventable. We conclude that UFPM/NPs are capable of disrupting neural homeostasis and give rise to relentless neurodegenerative processes throughout the entire life of the highly exposed population in MMC. The paradigm of reaching old age to have neurodegeneration is no longer supported. Neurodegenerative changes start early in pediatric ages and are irreversible. It is time to invest in preventive medicine.}, }
@article {pmid40137226, year = {2025}, author = {Stella, R and Bertoli, A and Lopreiato, R and Peggion, C}, title = {A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {40137226}, issn = {2309-608X}, abstract = {TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.}, }
@article {pmid40136713, year = {2025}, author = {Gao, J and Sikal, A and Hankin, R and Zheng, Y and Sterling, E and Chan, K and Yao, Y}, title = {Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Cells}, volume = {14}, number = {6}, pages = {}, pmid = {40136713}, issn = {2073-4409}, support = {startup//University of Georgia/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Extracellular Vesicles/metabolism/transplantation ; *Muscular Atrophy/pathology/metabolism ; *Muscle, Skeletal/pathology/metabolism ; *Disease Models, Animal ; Mice ; *Regeneration ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Cell Differentiation ; Macrophages/metabolism ; Male ; Myoblasts/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor neuron degeneration and muscle atrophy, with no effective treatments available. Chronic inflammation, which impairs muscle regeneration and promotes proteolysis, is a key contributor to ALS-related muscle atrophy and a promising therapeutic target. Here, we applied extracellular vesicles (EVs) derived from regenerating skeletal muscles 14 days post-acute injury (CTXD14SkM-EVs), which possess a unique anti-inflammatory profile, to target muscle defects in ALS. We found that CTXD14SkM-EVs enhanced myoblast differentiation and fusion in a cellular muscle-wasting model induced by pro-inflammatory cytokine tumor necrosis factor alpha. Intramuscular administration of these EVs into an ALS mouse model mitigated muscle atrophy by promoting muscle regeneration, shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 state, and suppressing the aberrant Nuclear Factor Kappa B (NF-κB) signaling, a key driver of muscle protein degradation. These results underscore the therapeutic potential of regenerating muscle-derived EVs for combating muscle atrophy in ALS.}, }
@article {pmid40136670, year = {2025}, author = {Bond, S and Saxena, S and Sierra-Delgado, JA}, title = {Microglia in ALS: Insights into Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {6}, pages = {}, pmid = {40136670}, issn = {2073-4409}, support = {//Rare Village/ ; //Radala Foundation/ ; //University of Missouri- Columbia, School of Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology/immunology ; Humans ; *Microglia/pathology/metabolism ; Animals ; Motor Neurons/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.}, }
@article {pmid40136528, year = {2025}, author = {Chen, X and Wang, Y and Zhang, Y and Li, X and Zhang, L and Gao, S and Zhang, C}, title = {Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges.}, journal = {Biology}, volume = {14}, number = {3}, pages = {}, pmid = {40136528}, issn = {2079-7737}, support = {C2406001//the Shenzhen Medical Research Fund/ ; 2024TJCR023//the Tongji Hospital High Quality Clinical Research Fund/ ; 32020103007//the Major International (Regional) Joint Research Project/ ; 2022YFA1206000//the National Key Research and Development Program of China/ ; 32371189, 32300984//the National Natural Science Foundation of China/ ; }, abstract = {Neural excitatory/inhibitory (E/I) imbalance plays a pivotal role in the aging process. However, despite its significant impact, the role of E/I imbalance in motor dysfunction and neurodegenerative diseases has not received sufficient attention. This review explores the mechanisms underlying motor aging through the lens of E/I balance, emphasizing genetic and molecular factors that contribute to this imbalance (such as SCN2A, CACNA1C, GABRB3, GRIN2A, SYT, BDNF…). Key regulatory genes, including REST, vps-34, and STXBP1, are examined for their roles in modulating synaptic activity and neuronal function during aging. With insights drawn from ALS, we discuss how disruptions in E/I balance contribute to the pathophysiology of age-related motor dysfunction. The genes discussed above exhibit a certain association with age-related motor neuron diseases (like ALS), a relationship that had not been previously recognized. Innovative genetic therapies, such as gene editing technology and optogenetic manipulation, are emerging as promising tools for restoring E/I balance, offering hope for ameliorating motor deficits in aging. This review explores the potential of these technologies to intervene in aging-related motor diseases, despite challenges in their direct application to human conditions.}, }
@article {pmid40135721, year = {2025}, author = {Fayaz, MU and Wang, Q and Xu, M and Chen, D and Pan, F and Song, C}, title = {Compressive Strain-Induced Uphill Hydrogen Distribution in Strontium Ferrite Films.}, journal = {ACS applied materials &amp; interfaces}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsami.4c21825}, pmid = {40135721}, issn = {1944-8252}, abstract = {Hydrogen incorporation into metal oxides enhances their electrochemical properties, making them highly suitable for various energy conversion applications. The controlled distribution of hydrogen ions in material systems and their conduction at elevated temperatures have garnered significant attention for various energy storage and environmental monitoring applications, including fuel cells, smart windows, and sensor technologies. In this work, cost-effective, high-concentration hydrogen-doped SrFeO3-δ (HSrFeO3-δ) films were prepared under ambient conditions by treating Al(s)|SrFeO3-δ(s) films with KOH(aq), utilizing electron-proton codoping to investigate hydrogen distribution. The uphill hydrogen distributions in SrFeO3-δ films with compressive strain, in contrast to the density gradient behavior under tensile strain, suggest the fundamental role of the strain states in the hydrogen accommodation. Compressively strained films with a rich Al source follow an anomalous uphill feature of hydrogen distribution, highlighting their potential use as electrolyte for fuel cells. The strain significantly influences the structure, chemical lattice coupling, and consequently the ionic transport in SrFeO3-δ. Ionic conductivity measurements reveal that compressively strained HSrFeO3-δ films with uphill hydrogen distributions exhibit a significant ionic conductivity of 0.189 S/cm at 413 K, with an activation energy of approximately 0.29 eV, making them suitable for low-temperature electrochemical applications. These findings provide a promising approach for tuning material properties and valuable insights for building iontronic devices.}, }
@article {pmid40135631, year = {2024}, author = {Novy, C and Tysnes, OB and Busk, &#xd8;L and Jaioun, K and Holmøy, T and Holla, &#xd8;L and Høyer, H}, title = {Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2447922}, pmid = {40135631}, issn = {2167-9223}, abstract = {Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.}, }
@article {pmid40135564, year = {2025}, author = {Liang, W and Zhang, C and Wang, D and Su, X and Tan, X and Yang, Y and Cong, C and Wang, Y and Huo, D and Wang, H and Wang, S and Wang, X and Feng, H}, title = {Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {31}, number = {3}, pages = {e70341}, pmid = {40135564}, issn = {1755-5949}, support = {2023-KYYWF-0195//Innovative Scientific Research Fund of Harbin Medical University/ ; 82271450//National Natural Science Foundation of China/ ; 82301599//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Autophagy/physiology ; Mice ; *Mice, Transgenic ; *Protein Serine-Threonine Kinases/metabolism/genetics ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; Humans ; Mice, Inbred C57BL ; Male ; Nerve Degeneration/pathology/metabolism ; }, abstract = {OBJECTIVES: Autophagic impairment has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Salt-inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK) family widely expressed in the central nervous system, plays critical roles in neuronal survival, neurogenesis, and the regulation of autophagy. This study aims to investigate the effects and underlying mechanisms of SIK2 in the pathogenesis of ALS.<br><br>METHODS: In our work, we used both in&#xa0;vivo and in&#xa0;vitro models of ALS to study the effect of SIK2. Protein and RNA levels were assessed by Western blot, RT-qPCR, immunofluorescence, and immunohistochemistry. Cell viability and apoptosis were evaluated using CCK-8 assay and flow cytometry. Transmission electron microscopy was employed to examine autophagic vacuoles. Additionally, lentivirus particles carrying shRNA targeting SIK2 (sh-SIK2) were injected into the lateral ventricle of ALS mice at 60&#x2009;days of age. Motor performance was evaluated by the rotarod test.<br><br>RESULTS: We observed that increased expression of SIK2 significantly contributed to the degeneration of motor neurons in both the cellular model and the hSOD1[G93A] transgenic mice model of ALS. SIK2 knockdown enhanced neuronal survival and restored mTORC1 activity. Furthermore, SIK2 suppression facilitated the clearance of mutant SOD1 accumulation by activating autophagic flux and enhancing lysosomal acidification. Conversely, SIK2 overexpression impaired mTORC1 activity, exacerbating autophagy dysfunction by inhibiting lysosomal function, and ultimately led to motor neuron degeneration. In&#xa0;vivo, SIK2 deficiency delayed disease onset and extended the lifespan of ALS mice by enhancing autophagy-mediated clearance of mutant SOD1 aggregates.<br><br>CONCLUSIONS: Our findings reveal that SIK2 regulates autophagic flux by modulating lysosomal acidification, thereby influencing the degradation of mutant SOD1 aggregates. SIK2 suppression enhances autophagy-mediated clearance of toxic protein aggregates and protects motor neurons, highlighting its potential as a therapeutic target for ALS.}, }
@article {pmid40135522, year = {2025}, author = {Bai, D and Fang, Y and Tian, J and Liao, Y and Liu, M and Pan, L}, title = {Tribenuron-methyl resistance in Capsella bursa-pastoris: the co-existence of ALS target enzyme mutation (Pro-197-Ser) and overexpression of GSTF12 and ADP/ATP carrier protein.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8794}, pmid = {40135522}, issn = {1526-4998}, support = {//Scientific Research Fund of Hunan Provincial Education Department/ ; //National Natural Science Foundation of China/ ; //National Key Research and Development Program of China/ ; //China Agriculture Research System/ ; //Modern Agricultural Industrial Technology System of Hunan Province/ ; }, abstract = {BACKGROUND: Capsella bursa-pastoris, a prevalent wheat-field weed in China, demonstrates substantial resistance to tribenuron-methyl, a herbicide-targeting acetolactate synthase (ALS). Understanding weed herbicide-resistance mechanisms is crucial for managing resistant weed populations. However, the genes potentially involved in nontarget-site resistance (NTSR) in herbicide-resistant C. bursa-pastoris remain poorly understood and require further investigation. This research aimed to elucidate the resistance level and underlying mechanisms of a field population (R) from Shandong Province, China, to tribenuron-methyl.<br><br>RESULTS: Whole-plant bioassays revealed that the relative resistance index (RI) of the R population was 54-fold greater than that of the tribenuron-methyl-sensitive population (S). Additionally, treatment with the cytochrome P450 (CYP450) inhibitor malathion or the glutathione S-transferase (GST) inhibitor 4-Chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) partially mitigated the resistance of the R population to tribenuron-methyl. Sequencing of the ALS target enzyme identified a substitution of proline (CCT) at position 197 with serine (TCT). RNA sequencing combined with quantitative reverse transcription polymerase chain reaction (qRT-PCR) verification identified upregulation of a candidate GST gene (GSTF12) and an ADP/ATP carrier protein in the R population. Heterologous expression of the two candidate genes in yeast cells demonstrated enhanced growth in the presence of tribenuron-methyl.<br><br>CONCLUSION: We first identified that, in tribenuron-methyl-resistant C.&#x2009;bursa-pastoris, the Pro-197-Ser mutation in the ALS gene, along with GSTF12 and ADP/ATP carrier protein overexpression, jointly mediate its resistance. This enhances our understanding of herbicide-resistance mechanisms and offers a novel perspective for managing tribenuron-methyl-resistant weeds in agricultural practices. &#xa9; 2025 Society of Chemical Industry.}, }
@article {pmid40134643, year = {2025}, author = {Guo, YX and Yan, X and Liu, XC and Liu, YX and Liu, C}, title = {Artificial intelligence-driven strategies for managing renal and urinary complications in inflammatory bowel disease.}, journal = {World journal of nephrology}, volume = {14}, number = {1}, pages = {100825}, pmid = {40134643}, issn = {2220-6124}, abstract = {In this editorial, we discuss the article by Singh et al published in World Journal of Nephrology, stating the need for timely adjustments in inflammatory bowel disease (IBD) patients' long-term management plans. IBD is chronic and lifelong, with recurrence and remission cycles, including ulcerative colitis and Crohn's disease. It's exact etiology is unknown but likely multifactorial. Related to gut flora and immune issues. Besides intestinal symptoms, IBD can also affect various extraintestinal manifestations such as those involving the skin, joints, eyes and urinary system. The anatomical proximity of urinary system waste disposal to that of the alimentary canal makes early detection and the differentiation of such symptoms very difficult. Various studies show that IBD and it's first-line drugs have nephrotoxicity, impacting the patients' life quality. Existing guidelines give very few references for kidney lesion monitoring. Singh et al's plan aims to improve treatment management for IBD patients with glomerular filtration rate decline, specifically those at risk. Most of IBD patients are young and they need lifelong therapy. So early therapy cessation, taking into account drug side effects, can be helpful. Artificial intelligence-driven diagnosis and treatment has a big potential for management improvements in IBD and other chronic diseases.}, }
@article {pmid40133903, year = {2025}, author = {Mitchell, G and Siwela, P and Goldstein, S and Diedericks, AM}, title = {Alcohol industry involvement in the delayed South Africa Draft Liquor Amendment Bill 2016: a case study based on freedom of information requests.}, journal = {Globalization and health}, volume = {21}, number = {1}, pages = {11}, pmid = {40133903}, issn = {1744-8603}, support = {N/A//FORUT/ ; N/A//FORUT/ ; N/A//FORUT/ ; N/A//FORUT/ ; }, mesh = {South Africa ; Humans ; *Alcoholic Beverages/economics/legislation &amp; jurisprudence ; Alcohol Drinking/legislation &amp; jurisprudence ; Industry/legislation &amp; jurisprudence ; Advertising/legislation &amp; jurisprudence ; Food Industry/legislation &amp; jurisprudence ; }, abstract = {BACKGROUND: South Africa is reported to have one of the highest per capita rates of alcohol consumption among drinkers globally, with alcohol harms exacerbating socio-economic inequalities in the country. The Draft Liquor Amendment Bill 2016 proposed new restrictions on alcohol advertising, availability, and liability of retailers and manufacturers for harm related to any contravention of the regulations. To date, the Bill has not progressed through the legislative process. The alcohol industry is known to use a diverse set of strategies to delay evidence-based policies globally.<br><br>METHODS: We aimed to explore Bill-related activity by industry within the National Economic and Development Labour Council, a multi-stakeholder forum that assesses socio-economic policies before they reach parliament. On 06 July 2023 we made a Request for Access to Record, using form two of the Promotion of Access to Information Act (PAIA), no. 2 of 2000 to the National Economic and Development Labour Council for access to minutes of all meetings, reports, and any other publications related to the Bill between January 2016 and December 2022. Informed by Ulucanlar et al's (2023) model and taxonomies of corporate political activity, we extracted data on industry Bill-related activity and thematically analysed key events, presented here as a narrative synthesis.<br><br>RESULTS: We identified activity by 14 alcohol industry organisations related to the Bill between 2016 and 2022. Industry representation on five National Economic and Development Labour Council-related committees identified between 2017 and 2021 facilitated their involvement in Bill-related discussions and supported access to other government departments. Community representation was low in all committees compared to industry, labour, and government. Industry funded two socio-economic assessments of the Bill in 2017 and 2022, despite an independent socio-economic impact assessment having already been completed. The 2017 report delayed progress of the Bill, and the 2022 're-evaluation' was more critical of the proposed measures, with the differing conclusions attributed to different methodologies. During the covid-19 pandemic, industry used a 'carrot and stick' approach of legal threats and donations to attempt to move towards self-regulation via a social compact. The National Economic and Development Labour Council confirmed in 2023 that the social compact was unsuccessful.<br><br>CONCLUSIONS: Early 'regulatory capture' gave the alcohol industry the opportunity to shape assessment of the Bill within the National Economic and Development Labour Council. Our findings are in line with previous studies on corporate influence on policy globally, and support calls for a reassessment of the role and proportion of industry representation within the National Economic and Development Labour Council locally.}, }
@article {pmid40133096, year = {2025}, author = {Shenouda, M and McKeever, PM and Robertson, J}, title = {The long and the short of TDP-43.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2025.03.003}, pmid = {40133096}, issn = {1878-108X}, abstract = {In a recent study, Dykstra and colleagues show that shortened TAR DNA Binding Protein 43 (sTDP-43) isoforms are generated as by-products of TDP-43 autoregulation. sTDP-43 levels are regulated through nonsense-mediated decay and proteasomal and autophagic degradation, and elicit toxicity through dominant negative effects on TDP-43 splicing activity. These results identify mechanisms contributing to sTDP-43 accumulation and toxicity in disease.}, }
@article {pmid40132878, year = {2025}, author = {Klickovic, U and Zampedri, L and Zafeiropoulos, N and Ziff, OJ and Sinclair, CD and Wastling, S and Dudziec, M and Allen, J and Trimmel, K and Howard, RS and Malaspina, A and Sharma, N and Sidle, KC and Shah, S and Nasel, C and Yousry, TA and Greensmith, L and Morrow, JM and Thornton, JS and Fratta, P}, title = {Muscle MRI quantifies disease progression in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335571}, pmid = {40132878}, issn = {1468-330X}, abstract = {BACKGROUND AND OBJECTIVES: Quantitative and operator-independent biomarkers of disease progression are urgently needed in amyotrophic lateral sclerosis (ALS) research. We assess the potential of skeletal muscle MRI as a sensitive and reliable outcome measure for future ALS clinical trials.<br><br>METHODS: In this longitudinal cohort study, muscle MRI of head-neck, upper and lower limb regions, alongside clinical and functional assessments, were acquired at three time points over the individual maximum observation period (iMOP) of 1 year in 20 patients with ALS and 16 healthy controls. Quantitative MRI parameters cross-sectional area (CSA), volume (VOL), fat fraction, functional rest muscle area and water T2 (T2m) were correlated with changes in clinical disease severity (functional rating scales and myometry).<br><br>RESULTS: Among 20 patients with ALS, 17 completed follow-up. Progressive muscle atrophy (CSA, VOL) was observed at hand (rs=0.66), head-neck (partial &#x3b7;&#xb2;=0.47) and lower-limb level (thighs: &#x3b7;&#xb2;=0.56, calves: &#x3b7;&#xb2;=0.54) over iMOP. MRI changes correlated with leg muscle strength (knee extension: r=0.77; plantar flexion: r=0.78), hand grip strength (r=0.71) and functional rating scales (r=0.68).<br><br>INTERPRETATION: Our findings demonstrate the effectiveness of muscle MRI as a sensitive neuroimaging biomarker of disease progression in ALS, highlighting its potential application in clinical trials.}, }
@article {pmid40132681, year = {2025}, author = {Wang, Z and Yang, C and Wang, X and Lyu, W and Liao, H and Liu, X and Liu, H and Zhang, J and Shen, H and Zhang, L and Wang, H}, title = {Decoding stress granules dynamics: Implications for neurodegenerative disease.}, journal = {Progress in neurobiology}, volume = {248}, number = {}, pages = {102758}, doi = {10.1016/j.pneurobio.2025.102758}, pmid = {40132681}, issn = {1873-5118}, abstract = {Stress granules (SGs) are membrane-less cytoplasmic structures formed by cells in response to external stress, primarily composed of mRNA and proteins. The dynamic properties of their assembly, maintenance, and disassembly play crucial roles in cellular homeostasis. Recent studies have increasingly revealed that aberrations in SGs dynamics are closely related to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review summarizes the latest research progress on SGs dynamics in neurodegenerative diseases. It begins with an overview of the basic biological characteristics of SGs and their functions in neurons, followed by an in-depth exploration of the mechanisms and regulatory pathways of SGs dynamics. The review then summarizes potential therapeutic strategies targeting SGs dynamics abnormalities, particularly through small molecule drugs to modulate SGs formation and disassembly, aiming to delay or halt the progression of neurodegenerative diseases. The review also highlights the application prospects of these interventions in treating neurodegenerative diseases. Finally, the review introduces current techniques used to study SGs dynamics, discussing their advantages, limitations, and future development possibilities. This review aims to provide researchers with a comprehensive perspective to advance the understanding and clinical application of SGs dynamics in the field of neurodegenerative diseases.}, }
@article {pmid40132594, year = {2025}, author = {Zelic, M and Blazier, A and Pontarelli, F and LaMorte, M and Huang, J and Tasdemir-Yilmaz, OE and Ren, Y and Ryan, SK and Shapiro, C and Morel, C and Krishnaswami, P and Levit, M and Sood, D and Chen, Y and Gans, J and Tang, X and Hsiao-Nakamoto, J and Huang, F and Zhang, B and Berry, JD and Bangari, DS and Gaglia, G and Ofengeim, D and Hammond, TR}, title = {Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2025.02.024}, pmid = {40132594}, issn = {1097-4180}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation is prominent in ALS, but the cell state dynamics and pathways driving disease remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords and identified altered glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on the inflammation and cell death regulator receptor-interacting protein kinase 1 (RIPK1) and the necroptotic cell death pathway. In superoxide dismutase 1 (SOD1)[G93A] mice, blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses. We used human induced pluripotent stem cell (iPSC)-derived motor neuron, astrocyte, and microglia tri-cultures to identify potential biomarkers that are secreted upon RIPK1 activation in vitro and modulated by RIPK1 inhibition in the cerebrospinal fluid (CSF) of people with ALS. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.}, }
@article {pmid40131525, year = {2025}, author = {Kleinerova, J and Tahedl, M and McKenna, MC and Garcia-Gallardo, A and Hutchinson, S and Hardiman, O and Raoul, C and Ango, F and Schneider, B and Pradat, PF and Tan, EL and Bede, P}, title = {Cerebellar dysfunction in frontotemporal dementia: intra-cerebellar pathology and cerebellar network degeneration.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {289}, pmid = {40131525}, issn = {1432-1459}, support = {JPND-Cofund-2-2019-1/HRBI_/Health Research Board/Ireland ; HRB EIA-2017-019/HRBI_/Health Research Board/Ireland ; ANR France 2022-CEREBRALS//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Frontotemporal Dementia/pathology/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; Aged ; *Cerebellum/pathology/diagnostic imaging/physiopathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/complications/physiopathology ; Magnetic Resonance Imaging ; Diffusion Tensor Imaging ; Neural Pathways/diagnostic imaging/pathology/physiopathology ; Nerve Net/diagnostic imaging/pathology/physiopathology ; Cerebellar Diseases/diagnostic imaging/pathology/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share overlapping clinical, genetic, and neuroimaging features; a spectrum of conditions commonly referred to as the ALS-FTD continuum. The majority of imaging studies focus on supratentorial pathology, and phenotype-defining motor, cognitive, and behavioural profiles are often exclusively attributed to supratentorial degeneration overlooking the contribution of cerebellar pathology.<br><br>METHODS: A multimodal neuroimaging study was conducted to evaluate phenotype-associated cerebello-cerebral connectivity profiles in ALS-FTD, behavioural variant frontotemporal dementia (bvFTD), non-fluent variant (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Structural connectivity, functional connectivity, and volumetric analyses were conducted.<br><br>RESULTS: Radial diffusivity analyses detected impaired bilateral cerebello-frontal, cerebello-parietal, and cerebello-temporal connectivity in all study groups along the ALS-FTD spectrum. Cerebello-occipital disconnection was captured in ALS-FTD and nfvPPA. Spinocerebellar disconnection was detected in C9orf72 negative ALS-FTD and nfvPPA. C9orf72 positive ALS-FTD patients exhibited both anterior and posterior lobe cerebellar volume loss, while bvFTD and nfvPPA patients showed posterior cerebellar atrophy. Flocculonodular degeneration was observed in nfvPPA and cerebellar crura atrophy in bvFTD. Bilateral corticospinal tract and corpus callosum degeneration was detected in ALS-FTD, bvFTD, and nfvPPA. Primary motor cortex volume reductions were captured in both ALS-FTD and nfvPPA.<br><br>CONCLUSIONS: Our analyses capture significant cerebro-cerebellar disconnection in frontotemporal dementia. Corticospinal tract and motor cortex degeneration can be readily&#xa0;detected in non-ALS phenotypes. Intra-cerebellar pathology, coupled with the degeneration of cerebellar projections and the ensuing dysfunction of cerebro-cerebellar networks likely contribute to phenotype-defining clinical profiles in frontotemporal dementia. Infratentorial disease burden and cerebellar network dysfunction should, therefore, be carefully considered in FTD, and phenotype-defining neuropsychological profiles should not be solely attributed to supratentorial degeneration.}, }
@article {pmid40131291, year = {2025}, author = {Penn, J and McAleer, R and Ziegler, C and Cheskes, S and Nolan, B and von Vopelius-Feldt, J}, title = {Effectiveness of Prehospital Critical Care Scene Response for Major Trauma: A Systematic Review.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/10903127.2025.2483978}, pmid = {40131291}, issn = {1545-0066}, abstract = {OBJECTIVES: Major trauma is a leading cause of morbidity and mortality worldwide. It is unclear if the addition of a critical care response unit (CCRU) with capabilities comparable to hospital emergency departments might improve outcomes following major trauma, when added to Basic or Advanced Life Support (BLS/ALS) prehospital care. This systematic review describes the evidence for a CCRU scene response model for major trauma.<br><br>METHODS: We searched Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), CINAHL (EBSCOhost), Science Citation Index Expanded (Web of Science), Conference Proceedings Citation Index - Science (Web of Science), LILACS (Latin American and Caribbean Health Sciences Literature) for relevant publications from 2003 to 2024. We included any study that compared CCRU and BLS/ALS care at the scene of major trauma, reported patient-focused outcomes, and utilized statistical methods to reduce bias and confounding. The risk of bias was assessed by two independent reviewers, using the ROBINS-I tool. Based on our a priori knowledge of the literature, a narrative analysis was chosen. The review was prospectively registered (PROSPERO ID CRD42023490668).<br><br>RESULTS: The search yielded 5243 unique records, of which 26 retrospective cohort studies and one randomized controlled trial met inclusion criteria. Sample sizes ranged from 308 to 153,729 patients. Eighteen of the 27 included studies showed associations between CCRUs and improved survival following trauma, which appear to be more consistently found in more critically injured and adult patients, as well as those suffering traumatic cardiac arrest. The remaining nine studies showed no significant difference in outcomes between CCRU and BLS/ALS care. Most studies demonstrated critical or severe risks of bias.<br><br>CONCLUSIONS: Current evidence examining CCRU scene response for major trauma suggests potential benefits in severely injury patients but is limited by overall low quality. Further high-quality research is required to confirm the benefits from CCRU scene response for major trauma.}, }
@article {pmid40130694, year = {2025}, author = {Burke, KM and Arulanandam, V and Scirocco, E and Royse, T and Hall, S and Weber, H and Arnold, J and Pathak, P and Walsh, C and Paganoni, S}, title = {Assistive Technology in ALS: A Scoping Review of Devices for Limb, Trunk, and Neck Weakness.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1097/PHM.0000000000002742}, pmid = {40130694}, issn = {1537-7385}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons that control voluntary muscles. With no known cure, clinical care is focused on symptom management to maximize function and quality of life. Assistive technology plays a crucial role and enables some restoration of movement and function despite disease progression. This scoping review assesses the effectiveness of assistive technologies tested in people living with ALS, specifically those designed to compensate for upper and lower extremity, trunk, and cervical muscle weakness. A comprehensive search was conducted across PubMed, CINAHL, ERIC, Google Scholar, and through citation chasing. We included 26 articles that tested an assistive device on at least one person living with ALS and evaluated the device's effectiveness in restoring movement or providing stabilization to support functional mobility or activities of daily living. Most studies were pilot feasibility or usability trials, with small numbers of ALS participants. The devices showed various benefits, including improved range of motion, function, and participation in daily activities. This review highlights the potential for assistive devices to enhance function in people living with ALS and underscores the need for comprehensive studies involving larger cohorts of individuals at different stages of ALS.}, }
@article {pmid40129929, year = {2025}, author = {Liang, F and Sun, Y and Yang, J and Shen, Z and Wang, G and Zhu, J and Zhou, C and Xia, Y}, title = {Gut microbiome is associated with radiotherapy response in lung cancer patients with brain metastases.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1562831}, pmid = {40129929}, issn = {2235-2988}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Lung Neoplasms/radiotherapy/pathology/microbiology ; Male ; Female ; Middle Aged ; *Brain Neoplasms/secondary/radiotherapy ; Aged ; *RNA, Ribosomal, 16S/genetics ; *Feces/microbiology ; *Bacteria/classification/isolation &amp; purification/genetics ; Treatment Outcome ; Adult ; }, abstract = {PURPOSE: To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.<br><br>METHODS AND MATERIALS: This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and &#x3b1;-diversity, &#x3b2;-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.<br><br>RESULTS: No significant difference in &#x3b1;-diversity was observed between the groups (P > 0.05), but &#x3b2;-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.<br><br>CONCLUSIONS: The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.}, }
@article {pmid40129635, year = {2025}, author = {Galaz-Araya, C and Zuñiga-Núñez, D and Salas-Sepúlveda, F and Herrera-Morande, A and Aspée, A and Poblete, H and Zamora, RA}, title = {Theoretical evaluation of a bulky ortho-thioalkyl-azobenzene as an alternative to photocontrol structural cytotoxic effects of metal-free and disulfide oxidized hSOD1 in pathogenesis of ALS.}, journal = {RSC advances}, volume = {15}, number = {12}, pages = {9018-9026}, pmid = {40129635}, issn = {2046-2069}, abstract = {This study presents a novel photopharmacological strategy to mitigate the cytotoxic effects of apo-hSOD1[S-S], a misfolded protein implicated in neurodegenerative diseases. Using quantum chemical calculations and molecular dynamics simulations, we demonstrate that ortho-thio-substituted azobenzene photoswitches (ortho-TABPs) can be employed to precisely modulate the dynamics of the crucial electrostatic loop (EL) in apo-hSOD1[S-S]. We establish that larger ortho-S-alkyl substituents on the ortho-TABP enhance its redox stability, favouring the cis conformation through the modulation of the position of the n → π* transition. This stability is crucial for operation within the reducing cellular environment. Furthermore, we demonstrate the successful and consistent photomodulation of EL conformational dynamics in apo-hSOD1[S-S] through covalent tethering of an ortho-TABP. This control is achieved by leveraging the thermodynamically stable trans conformation of the photoswitch, which allosterically influences the EL and consequently, the geometry of the Zn-binding site, a critical determinant of apo-hSOD1[S-S] cytotoxicity. This work paves the way for developing targeted therapies for neurodegenerative diseases by demonstrating the precise and effective photomodulation of apo-hSOD1[S-S] via rationally designed ortho-TABPs.}, }
@article {pmid40128927, year = {2025}, author = {Aikawa, M and Ando, T and Shibayama, H and Kubota, M and Sonoo, M and Fukutake, T}, title = {[A case of amyotrophic lateral sclerosis complicated by syringomyelia associated with Chiari type I malformation].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {}, number = {}, pages = {}, doi = {10.5692/clinicalneurol.cn-002045}, pmid = {40128927}, issn = {1882-0654}, abstract = {The patient was a 78-year-old woman. She underwent foramen magnum decompression for syringomyelia associated with Chiari type I malformation, which had developed with difficulty in raising the left upper limb and muscle weakness in both upper limbs. One year after surgery, weight loss of 20 ‍kg, progressive muscle atrophy and weakness in the extremities, paralytic dysarthria, and fasciculation in the bilateral anterior thighs were observed, and needle electromyography showed acute denervation and chronic denervation in the medial vastus muscle. The rapid postoperative progression of symptoms and lower motor neuron symptoms in the lower extremities could not be explained by syringomyelia associated with Chiari type I malformation and were considered a possible complication of amyotrophic lateral sclerosis (ALS). It is possible that the surgery may have caused ALS progression, and attention to the rate of progression of neurologic symptoms may be important in the diagnosis of ALS complications.}, }
@article {pmid40128823, year = {2025}, author = {Zhang, W and Huang, C and Yao, H and Yang, S and Jiapaer, Z and Song, J and Wang, X}, title = {Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {14}, pmid = {40128823}, issn = {2047-9158}, support = {2023TSYCCX0051//Tianshan Talent Training Program/ ; }, mesh = {Humans ; *Retroelements/genetics ; *Aging/genetics ; *Nervous System Diseases/genetics ; Animals ; }, abstract = {Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.}, }
@article {pmid40128246, year = {2025}, author = {Hu, X and Wei, M and Zhang, H and Yu, M and Wang, M and Zhou, B and Luo, Y and Li, B}, title = {The experience of pain symptoms in patients with amyotrophic lateral sclerosis: a qualitative study.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {10183}, pmid = {40128246}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology ; Middle Aged ; Male ; Female ; *Pain/psychology/etiology ; *Qualitative Research ; Aged ; Adult ; Adaptation, Psychological ; Pain Management/methods ; }, abstract = {ALS is a progressive neurodegenerative disease that has a serious impact on patients and their caregivers. For a long time in the past, ALS was considered a painless disease that was largely ignored by clinicians. Describing the complexity and needs of pain symptoms from the perspective of patients can provide the most intuitive direction for future research. The purpose of our research is to explore the experience of pain symptoms in patients with amyotrophic lateral sclerosis (ALS), provide reference for better understanding of pain symptoms in ALS patients. From April 2023 to May 2023, 27 patients experiencing pain symptoms in Peking University Third Hospital who met the diagnostic criteria of "Chinese Guidelines for the Diagnosis and Treatment of amyotrophic lateral sclerosis" were interviewed by means of objective sampling. The content analysis method was used to describe the pain changes since the disease (amyotrophic lateral sclerosis), the factors that aggravate the pain, the measures to cope with the pain and the needs. The interview results included 3 themes and 11 subthemes. (1) Pain is diverse: the type of pain, the time when pain occurs, the change in pain intensity, and the factors that aggravate pain; (2) Individualized pain coping measures: posture adjustment, medication, physical therapy, warmth, emotional regulation; (3) Patients lack of understanding of pain: insufficient source of knowledge, the single orientation of the solution. The nature, location and aggravating factors of pain in amyotrophic lateral sclerosis patients in China are complicated, which should be paid attention to by clinical staff and scientific researchers. The situation of pain management is not optimistic, and the pain of the vast majority of patients has not been effectively alleviated. It is necessary to realize the importance of self-management and care of others in coping with pain, and conduct further research in the future to find a breakthrough in pain relief, so as to strengthen pain intervention in clinical practice.}, }
@article {pmid40127736, year = {2025}, author = {Maetani, Y and Kurashige, T and Tada, Y and Kume, K and Watanabe, T and Sotomaru, Y and Yamanaka, K and Maruyama, H and Kawakami, H}, title = {Optineurin knock-out forms TDP-43 aggregates to regulate TDP-43 protein levels despite autophagic up-regulation and aberrant TDP-43 expression.}, journal = {Neuroscience research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neures.2025.03.005}, pmid = {40127736}, issn = {1872-8111}, abstract = {Optineurin is a causative gene of amyotrophic lateral sclerosis (ALS) and has many roles in processes such as autophagy and inflammation. However, it is unclear how optineurin causes ALS. Optineurin knock-out (Optn-KO) mice, which have been generated by several researchers, exhibit motor neuron degeneration and TDP-43 aggregates, but no motor deficits. Motor dysfunction in ALS model mice is associated with TDP-43 in the spinal cord. We bred Optn-KO mice with TDP-43 overexpression transgenic mice and evaluated whether increased TDP-43 protein causes motor deficits and whether Optn-KO affects TDP-43 protein level. Optn-KO mice had spinal TDP-43 protein levels and motor function comparable to wild-type mice, and TDP-43-transgenic (TDP-43-tg) mice resulted in motor dysfunction and early death. However, double-mutant TDP-43-tg / Optn-KO mice had lower TDP-43 protein levels than TDP-43-tg mice at 18 months age, and showed inhibition of the TBK1-optinerurin autophagic pathway with aging. Furthermore, Optn-KO caused TDP-43-positive cytoplasmic aggregates. TDP-43 overexpression by itself induced spinal microgliosis, but Optn-KO suppressed that microgliosis. Finally, we showed that Optn-KO mice could not exhibit behavioral dysfunction because TDP-43 protein levels were not elevated despite autophagy inhibition. Thus, downregulation of Optn may suppress TDP-43 toxicity by regulating its abundance through aggregate formation.}, }
@article {pmid40127392, year = {2025}, author = {Vasta, R and De Mattei, F and Tafaro, S and Canosa, A and Manera, U and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and Zocco, G and Pellegrino, G and Minerva, E and Pascariu, D and Iazzolino, B and Callegaro, S and Fuda, G and Salamone, P and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A}, title = {Changes to Average Survival of Patients With Amyotrophic Lateral Sclerosis (1995-2018): Results From the Piemonte and Valle d'Aosta Registry.}, journal = {Neurology}, volume = {104}, number = {8}, pages = {e213467}, doi = {10.1212/WNL.0000000000213467}, pmid = {40127392}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/mortality/therapy/diagnosis ; Humans ; Male ; *Registries ; Female ; Middle Aged ; Aged ; Proportional Hazards Models ; Cohort Studies ; Survival Rate ; Italy/epidemiology ; Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The average survival of patients with amyotrophic lateral sclerosis (ALS) ranges from 2 to 5 years from symptom onset. However, it remains unclear whether this estimate has improved over time. The objective of this study was to analyze the survival trend of a large population-based cohort of patients with ALS over a 24-year period.<br><br>METHODS: Patients from the Piemonte and Valle d'Aosta registry for ALS (PARALS) were categorized into the first (1995-2002), second (2003-2010), or third (2011-2018) epoch based on their diagnosis date. Survival was defined as the time from diagnosis to death, tracheostomy, or censoring date. A Cox proportional hazard model was developed with diagnosis epoch as the primary variable of interest, adjusted for sex, site of onset, age at onset, diagnostic delay, forced vital capacity at diagnosis, &#x394;body mass index from onset to diagnosis, noninvasive mechanical ventilation use, gastrostomy use, and site of follow-up. A subset analysis comparing the 2007-2012 and 2013-2018 cohorts was conducted, incorporating riluzole prescription, genetics, and preslope category as additional covariates.<br><br>RESULTS: A total of 3,134 patients were included, evenly distributed across the 3 epochs (990, 1,023, and 1,121, respectively). The median survival remained stable during the first and second epoch (18.6 months vs 18.3 months) but improved during the third epoch (20.1 months; p = 0.0041), with a hazard ratio (HR) of 0.76 (95% CI 0.67-0.87, p = 0.00003). In the subset analysis, the most recent epoch (2013-2018) showed a continued survival advantage (HR 0.77, 95% CI 0.65-0.90). Of interest, the survival benefit was only evident among intermediate progressors (HR 0.60, 95% CI 0.45-0.80).<br><br>DISCUSSION: In the PARALS, ALS survival increased over time. In a subset analysis, the beneficial effect of the epoch was only evident among intermediate progressors. The improvement in multidisciplinary care provided by tertiary centers may be one possible explanation for this finding, although further dedicated studies are needed to confirm this hypothesis.}, }
@article {pmid40126464, year = {2025}, author = {Shefner, JM and Cudkowicz, ME and Genge, A and Hardiman, O and Al-Chalabi, A and Andrews, JA and Chio, A and Corcia, P and Couratier, P and de Carvalho, M and Heiman-Patterson, T and Henderson, RD and Ingre, C and Johnston, W and Ludolph, A and Maragakis, NJ and Miller, TM and Mora, JS and Petri, S and Simmons, Z and van den Berg, LH and Zinman, L and Kupfer, S and Malik, FI and Meng, L and Simkins, TJ and Wei, J and Wolff, AA and Rudnicki, SA and , }, title = {Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40126464}, issn = {2168-6157}, abstract = {IMPORTANCE: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.<br><br>OBJECTIVE: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.<br><br>A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.<br><br>INTERVENTIONS: Oral reldesemtiv, 300 mg, or placebo twice daily.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 24.<br><br>RESULTS: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n&#x2009;=&#x2009;325) or placebo (n&#x2009;=&#x2009;161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI,&#x2009;-2.17 to -0.08; P&#x2009;=&#x2009;.04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio,&#x2009;0.77-1.10; P&#x2009;=&#x2009;.11).<br><br>CONCLUSIONS AND RELEVANCE: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04944784.}, }
@article {pmid40126385, year = {2025}, author = {Yarlagadda, S and Hazboun, M and Vilke, G and Farah, J and Donofrio-Odmann, JJ}, title = {Epidemiology of Neonate Prehospital Care at the San Diego (US) - Tijuana (Mexico) International Border.}, journal = {Prehospital emergency care}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/10903127.2025.2476196}, pmid = {40126385}, issn = {1545-0066}, abstract = {OBJECTIVES: Neonates, infants 30 days of age or younger are understudied in prehospital emergencies. Our objective was to describe prehospital assessment and care for patients <30 days of age at the San Diego-Tijuana Point of Entry (POE). Additional objectives included describing assessments, care, frequency, and level of care for newborns brought to the border by Mexican ambulances.<br><br>METHODS: This was a retrospective analysis from January 1, 2014, to January 01, 2020, of all 9-1-1 calls involving patients <30&#x2009;days of age at the San Diego POEs. The 9-1-1 responses to newly delivered patients were "newborns". Patients who were not immediately post-delivery were "neonates." Patient demographics, response intervals, clinician interventions, and dispositional data were collected from electronic patient records. Descriptive statistics were applied.<br><br>RESULTS: A total of 57 patients <30&#x2009;days of age were included. With 27 newborn patients, 15 were delivered by emergency medical services (EMS) personnel (27, 55.6%). Initial appearance, pulse, grimace, activity, and respiration (APGAR) scores were 8-10 in 44.4% and 5-7 in 29.6%. Procedures included newborn care (88.9%), advanced life support (ALS) assessment (63.0%), and warming (59.3%). There were five patients that had stimulation, 7 received oxygen, and 3 received Bag-Valve-Mask (BVM) ventilation. No serial heart rates were documented. Regarding 30 neonates, the predominant method of transport to the POE was Mexican ambulance (n 16, 53.3%). Medications administered included oxygen (n 16, 53.3%) and albuterol/ipratropium (n 1, 3.3%). Procedures included ALS assessment (n 19, 63.3%), pulse oximetry (n 22, 73.3%), and 3-lead electrocardiogram (n 8, 26.7%). Three patients (10%) received BVM. Mexican Ambulances brought 16 neonates. A physician or nurse was present in 37.5% of transfers, 50% were incubated, 25% intubated, 37.5% on supplemental oxygen, and 71% had preexisting intravenous access. These were not interfacility transfers but were 9-1-1 activations by U.S. border agents; and 14 neonates did not arrive via Mexican ambulance. Their complaints were respiratory distress (n 7, 50%) and Brief Resolved Unexplained Episode (n 4, 28.6%).<br><br>CONCLUSIONS: We found that 9-1-1 transports at the San Diego-Tijuana POE for patients <30&#x2009;days were few and involved resuscitation, neonates in Mexican ambulances with specialized equipment, physicians, and unfamiliar medications. Neonates arriving via private transport had respiratory distress and BRUE.}, }
@article {pmid40125959, year = {2025}, author = {Gupta, U and Kumar, A and Alam, MI and Balaji, PG and Sharma, A and Yadav, AK}, title = {Synthesis and characterization of protein nanohybrid systems for the brain delivery of Riluzole.}, journal = {Therapeutic delivery}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/20415990.2025.2478805}, pmid = {40125959}, issn = {2041-6008}, abstract = {AIMS: Synthesis and Characterization of Protein NanoHybrid Systems for the Brain Delivery of Riluzole.<br><br>METHODS/MATERIALS: Fullerene is converted into carboxylated fullerene (CF) and then, prepared RZU-loaded BSA nanoparticles conjugated with CF.<br><br>RESULTS: The particle size and zeta potential of RZU-PNH were found to be 210&#x2009;&#xb1;&#x2009;1.15&#x2009;nm and -18.5&#x2009;&#xb1;&#x2009;0.615&#x2009;mV respectively, and entrapment efficiency and loading efficiency of RZU-PNH were found to be 98.8&#x2009;&#xb1;&#x2009;0.53% and 11.6&#x2009;&#xb1;&#x2009;0.43%, respectively. The XRD of the RZU-PNH shows the amorphism behavior and CD revealed that secondary structure of the protein mainly consists of &#x3b1;-helix and&#x3b2;-sheet. The MTT assay showed 88.60% and 90.84% cell viability in both SH-SY5Yand N2a cell lines at a concentration of 20&#x2009;&#x3bc;g/ml and also, no significant nasal ciliotoxicity was observed after incubation with RZU-PNH.<br><br>CONCLUSIONS: Obtained results indicated RZU-PNH formulation to treat amyotrophic lateral sclerosis.}, }
@article {pmid40125702, year = {2025}, author = {Madhavan, S and Deshmukh, S and Cummings, M and Doshi, A and Rezania, K and Freels, S and Sawa, G}, title = {Home-Based Tele-tDCS in Amyotrophic Lateral Sclerosis: Feasibility, Safety, and Preliminary Efficacy.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70038}, pmid = {40125702}, issn = {2328-9503}, support = {R21HD102722//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Transcranial direct current stimulation (tDCS) shows promise as a neuromodulatory intervention in various neurological disorders, but its application in ALS, particularly in a remote, home-based format, remains underexplored. This study investigates the feasibility, safety, and preliminary efficacy of remotely supervised tele-tDCS in ALS patients.<br><br>METHODS: This double-blinded pilot study included 14 spinal-onset ALS participants randomized into two groups: the intervention group received 72 tele-tDCS sessions over 24&#x2009;weeks, and the delayed-start group received 36 sham sessions followed by 36 tele-tDCS sessions. Stimulation was delivered at 2&#x2009;mA for 20&#x2009;min 3 times a week. Primary outcomes included feasibility, safety, and disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Adherence and adverse effects were monitored throughout.<br><br>RESULTS: Ten participants completed the study, with an overall compliance rate of 98.3%. No serious adverse events were reported, and mild side effects, like itching and tingling, were consistent with tDCS literature. The intervention group demonstrated a significantly slower decline in ALSFRS-R scores than the delayed-start group. At 24&#x2009;weeks, the intervention group had a mean ALSFRS-R change of -1.7, compared to -13.6 in the delayed-start group (p&#x2009;=&#x2009;0.0018). Additionally, the change in ALSFRS-R between pre- and mid-intervention significantly differed between groups (p&#x2009;=&#x2009;0.0071).<br><br>INTERPRETATION: Tele-tDCS was feasible, safe, and well-tolerated in individuals with ALS. Preliminary efficacy results suggest that tele-tDCS may slow disease progression, underscoring the potential of tele-tDCS as a promising home-based neuromodulatory intervention in ALS management.<br><br>TRIAL REGISTRATION: Clinical trial registration: NCT04866771.}, }
@article {pmid40125691, year = {2025}, author = {Ono, D and Kawai, H and Kuwahara, H and Yokota, T}, title = {Refining Muscle Morphometry Through Machine Learning and Spatial Analysis.}, journal = {Neuropathology and applied neurobiology}, volume = {51}, number = {2}, pages = {e70012}, doi = {10.1111/nan.70012}, pmid = {40125691}, issn = {1365-2990}, mesh = {Humans ; *Machine Learning ; Retrospective Studies ; Spatial Analysis ; Neuromuscular Diseases/pathology/diagnosis ; Muscle, Skeletal/pathology ; Male ; Female ; Middle Aged ; Muscular Diseases/pathology/diagnosis ; Adult ; Aged ; }, abstract = {AIMS: Muscle morphology provides important information in differentiating disease aetiology, but its measurement remains challenging because of the lack of an efficient and objective method. This study aimed to quantitatively refine the morphological features of muscle fibres in neuromuscular diseases using machine learning.<br><br>METHODS: In this retrospective study, we analysed muscle biopsy specimens on haematoxylin and eosin-staining. Machine learning-based software was developed to segment muscle fibre contours and perform automated muscle morphometry and subsequent graph theory-based spatial analysis of atrophied fibre grouping. A decision tree-based framework, LightGBM, was trained to predict underlying aetiologies based on morphometric and spatial variables.<br><br>RESULTS: The study included 100 muscle samples, including 20 normal muscles, 49 myopathies and 19 neuropathies. The fine-tuned segmentation model, YOLOv8, achieved a mask average precision of 0.819. The muscle morphometry revealed the significance of fibre circularity. The mean circularity was higher in the myopathy group, and the SD of circularity was elevated in the neuropathy group. Although most cases were consistent with textbook findings, atypical presentations, such as dermatomyositis with angular atrophy and amyotrophic lateral sclerosis with round atrophy, were objectively documented. Spatial analysis quantified grouped atrophy, showing the potential to feature specific atrophy patterns. The LightGBM model successfully predicted the final clinical diagnosis of the myopathies and neuropathies with an accuracy of 0.852, which exceeded that of 0.808 by human annotation.<br><br>CONCLUSION: Automated muscle morphometry and spatial analysis provide quantification of muscle morphology and patterns of atrophy, which will facilitate objective and efficient investigation of neuromuscular diseases.}, }
@article {pmid40124885, year = {2025}, author = {Dethier, C and Azirar, S and Verluyten, L and Boonen, H and Grosber, M and Gutermuth, J}, title = {Response to Fässler et al's "Successful treatment of refractory folliculitis decalvans with apremilast".}, journal = {JAAD case reports}, volume = {57}, number = {}, pages = {122-123}, pmid = {40124885}, issn = {2352-5126}, }
@article {pmid40124731, year = {2025}, author = {Liu, QZ and Sun, NZ}, title = {Investigation on the quality of life after anterior minimally invasive total hip arthroplasty: Commentary on recent findings.}, journal = {World journal of orthopedics}, volume = {16}, number = {3}, pages = {105318}, pmid = {40124731}, issn = {2218-5836}, abstract = {This editorial critically evaluated the recent study by Ishikura et al, which examined the impact of anterior minimally invasive total hip arthroplasty (MIS-THA) on postoperative quality of life, with a specific focus on the timeline and influencing factors for return to work and resumption of driving. Ishikura et al's research demonstrated that anterior MIS-THA could shorten recovery time, reduce postoperative pain, and significantly enhance patients' quality of life and productivity. Their findings identified occupational type and work intensity as key determinants of postoperative recovery. By synthesizing evidence from multiple studies, this analysis systematically evaluated the clinical advantages of anterior MIS-THA-including reduced soft tissue trauma and accelerated functional recovery-while acknowledging its limitations, such as a steep surgical learning curve and early postoperative complication risks. The discussion emphasized the necessity of designing personalized rehabilitation protocols that accounted for patients' occupational demands. Notably, while current findings primarily derived from retrospective analyses, the article highlighted the need for prospective cohort studies to validate these observations. The commentary also addressed ongoing debates in the field, particularly the elevated complication rates associated with the direct anterior approach compared to posterior techniques, thereby underscoring the critical role of surgeon expertise in optimizing procedural safety. Collectively, this evaluation advanced our understanding of postoperative recovery dynamics in anterior MIS-THA and provides evidence-based insights to refine clinical rehabilitation frameworks.}, }
@article {pmid40122623, year = {2025}, author = {Ghanizada, H and Nedergaard, M}, title = {The glymphatic system.}, journal = {Handbook of clinical neurology}, volume = {209}, number = {}, pages = {161-170}, doi = {10.1016/B978-0-443-19104-6.00006-1}, pmid = {40122623}, issn = {0072-9752}, mesh = {Humans ; *Glymphatic System ; Neurodegenerative Diseases/therapy ; Animals ; Brain ; }, abstract = {The glymphatic system, a brain-wide network-supporting cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, is essential for removing metabolic waste from the brain. This system's proper functioning is crucial for maintaining neural health and preventing the accumulation of harmful substances that can lead to neurodegenerative diseases. This chapter explores the glymphatic system's mechanisms, its dysfunction in various neurologic disorders, and potential therapeutic strategies. Recent discoveries reveal the glymphatic system's involvement in aging, sleep, cerebral edema, and conditions, such as Alzheimer, Parkinson, Huntington diseases, amyotrophic lateral sclerosis, small vessel disease, hydrocephalus, migraine, stroke, traumatic brain injury, and psychiatric disorders, where impaired waste clearance contributes to disease pathogenesis. Moreover, therapeutic interventions targeting glymphatic dysfunction present promising avenues for mitigating the effects of neurodegenerative diseases. The chapter underscores the potential of integrating glymphatic research into broader clinical practices, offering new strategies for disease management and prevention.}, }
@article {pmid40122396, year = {2025}, author = {Cao, Y and Xu, Y and Cao, M and Chen, N and Zeng, Q and Lai, MKP and Fan, D and Sethi, G and Cao, Y}, title = {Fluid-based biomarkers for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {108}, number = {}, pages = {102739}, doi = {10.1016/j.arr.2025.102739}, pmid = {40122396}, issn = {1872-9649}, abstract = {Neurodegenerative diseases, such as Alzheimer's Disease (AD), Multiple Sclerosis (MS), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are increasingly prevalent as global populations age. Fluid biomarkers, derived from cerebrospinal fluid (CSF), blood, saliva, urine, and exosomes, offer a promising solution for early diagnosis, prognosis, and disease monitoring. These biomarkers can reflect critical pathological processes like amyloid-beta (Aβ) deposition, tau protein hyperphosphorylation, α-syn misfolding, TDP-43 mislocalization and aggregation, and neuronal damage, enabling detection long before clinical symptoms emerge. Recent advances in blood-based biomarkers, particularly plasma Aβ, phosphorylated tau, and TDP-43, have shown diagnostic accuracy equivalent to CSF biomarkers, offering more accessible testing options. This review discusses the current challenges in fluid biomarker research, including variability, standardization, and sensitivity issues, and explores how combining multiple biomarkers with clinical symptoms improves diagnostic reliability. Ethical considerations, future directions involving extracellular vehicles (EVs), and the integration of artificial intelligence (AI) are also highlighted. Continued research efforts will be key to overcoming these obstacles, enabling fluid biomarkers to become crucial tools in personalized medicine for neurodegenerative diseases.}, }
@article {pmid40120962, year = {2025}, author = {Zhang, X and Wang, J and Zhang, J and Jiang, C and Liu, X and Wang, S and Zhang, Z and Rastegar-Kashkooli, Y and Dialameh, F and Peng, Q and Tao, J and Ding, R and Wang, J and Cheng, N and Wang, M and Wang, F and Li, N and Xing, N and Chen, X and Fan, X and Wang, J and Wang, J}, title = {Humanized rodent models of neurodegenerative diseases and other brain disorders.}, journal = {Neuroscience and biobehavioral reviews}, volume = {172}, number = {}, pages = {106112}, doi = {10.1016/j.neubiorev.2025.106112}, pmid = {40120962}, issn = {1873-7528}, abstract = {Central Nervous System (CNS) diseases significantly affect human health. However, replicating the onset, progression, and pathology of these diseases in rodents is challenging. To address this issue, researchers have developed humanized animal models. These models introduce human genes or cells into rodents. As a result, rodents become more suitable for studying human CNS diseases and their therapies in vivo. This review explores the preparation protocols, pathological and behavioral characteristics, benefits, significance, and limitations of humanized rodent models in researching various CNS diseases, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, glial cells-related CNS diseases, N-methyl-D-aspartic acid receptor encephalitis, and others. Humanized rodent models have expanded the opportunities for in vivo exploration of human neurodegenerative diseases, other brain disorders, and their treatments. We can enhance translational research on CNS disorders by developing, investigating, and utilizing these models.}, }
@article {pmid40119776, year = {2025}, author = {Pesti, B and Langa, X and Kumpesa, N and Valdeolivas, A and Sultan, M and Rottenberg, S and Hahn, K}, title = {Mini Review: Spatial Transcriptomics to Decode the Central Nervous System.}, journal = {Toxicologic pathology}, volume = {}, number = {}, pages = {1926233251325204}, doi = {10.1177/01926233251325204}, pmid = {40119776}, issn = {1533-1601}, abstract = {Spatial transcriptomics (ST) is revolutionizing our understanding of the central nervous system (CNS) by providing spatially resolved gene expression data. This mini review explores the impact of ST on CNS research, particularly in neurodegenerative diseases like Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. We describe two foundational ST methods: sequencing-based and imaging-based. Key studies are reviewed highlighting the power of ST data sets to map transcriptomes to disease-specific histomorphology, elucidate molecular mechanisms of regional and cellular vulnerability, integrate single-cell data with tissue mapping, and reveal receptor-ligand interactions. Despite current challenges like data interpretation and resolution limits, ST holds promise for identifying novel drug targets, evaluating their therapeutic potential, and bridging gaps between animal models and human studies to advance development of CNS-targeting compounds.}, }
@article {pmid40119207, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Author Correction: Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {913}, doi = {10.1038/s41593-025-01941-2}, pmid = {40119207}, issn = {1546-1726}, }
@article {pmid40118328, year = {2025}, author = {Mansour, HM and El-Khatib, AS}, title = {Oligonucleotide-based therapeutics for neurodegenerative disorders: Focus on antisense oligonucleotides.}, journal = {European journal of pharmacology}, volume = {998}, number = {}, pages = {177529}, doi = {10.1016/j.ejphar.2025.177529}, pmid = {40118328}, issn = {1879-0712}, abstract = {Antisense oligonucleotides (ASOs) specifically bind to target RNA sequences and regulate protein expression through various mechanisms. ASOs are a promising therapeutic approach for treating neurodegenerative diseases. The ASO field is a growing area of drug development that focuses on targeting the root cause of diseases at the RNA level, providing a promising alternative to therapies that target downstream processes. Addressing challenges related to off-target effects and inadequate biological activity is essential to successfully develop ASO-based therapies. Researchers have investigated various chemical modifications and delivery strategies to overcome these challenges. This review discusses oligonucleotide-based therapies, particularly ASOs. We discuss the chemical modifications and mechanisms of action of ASOs. Additionally, we recap the results of preclinical and clinical studies testing different ASOs in various neurodegenerative disorders, including spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In conclusion, ASO drugs show promise as a therapeutic option for treating neurodegenerative diseases.}, }
@article {pmid40117902, year = {2025}, author = {Wi, JH and Lee, H and Park, JM and Heo, Y and Jo, S and Lee, J and Kim, Y and Jung, C and Kim, NJ and Song, GY and Kim, P and Kim, H and Lee, S}, title = {Development of a TBK1 and ALK dual inhibitor for alleviating depressive behavior via anti-inflammatory effects.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {186}, number = {}, pages = {117991}, doi = {10.1016/j.biopha.2025.117991}, pmid = {40117902}, issn = {1950-6007}, abstract = {Polypharmacology offers innovative strategies for treating immune and inflammatory dysregulation in complex diseases. Here, we identified ALS-04, a dual inhibitor of TANK-binding kinase 1 (TBK1) and anaplastic lymphoma kinase (ALK), which are closely linked to stimulator of interferon genes (STING)-mediated immune responses. ALS-04 effectively suppressed 2'3'-cyclic GMP-AMP (cGAMP)- and lipopolysaccharide (LPS)-induced type I interferon and pro-inflammatory responses by targeting the STING-TBK1 and STING-ALK pathways. Furthermore, ALS-04 significantly alleviated depressive symptoms, including anhedonia and behavioral despair, in an LPS-induced mouse model of depression. These findings highlight the therapeutic potential of dual TBK1 and ALK inhibition in depression by modulating immune and inflammatory pathways.}, }
@article {pmid40117341, year = {2025}, author = {Koehn, LM and Steele, JR and Schittenhelm, RB and Nicolazzo, JA}, title = {Sex-Specific Markers of Neuroinflammation and Neurodegeneration in the Spinal Cord Proteome of the SOD1[G93A] Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Journal of proteome research}, volume = {24}, number = {4}, pages = {1956-1970}, doi = {10.1021/acs.jproteome.4c00990}, pmid = {40117341}, issn = {1535-3907}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Female ; *Spinal Cord/metabolism/pathology ; Mice ; Male ; Disease Models, Animal ; *Proteome/genetics/metabolism ; *Superoxide Dismutase-1/genetics ; Proteomics/methods ; Biomarkers/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/pathology/genetics ; Sex Factors ; Sex Characteristics ; Superoxide Dismutase/genetics ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has no cure. The underlying mechanistic details of sex differences in the ALS spinal cord, the site of disease onset, are not understood to an extent that could guide novel drug development. To address this, the spinal cords of 120-day-old wild-type (WT) and SOD1[G93A] (familial mouse model of ALS with mutant superoxide dismutase 1) mice were subjected to untargeted, quantitative proteomics using tandem mass tag acquisition on high-resolution mass spectrometric instrumentation. Compared to WT, both male and female SOD1[G93A] spinal cords exhibited an upregulation of neuroinflammatory cascades of both peripheral and central origins, as well as a downregulation of proteins reflective of death and dysfunction of cells within the spinal cord. However, female and male SOD1[G93A] mouse spinal cords exhibited sex-specific differences in proteins compared to respective WT that related to immune response, as well as cellular structure, function, and homeostasis. The proteomic datasets presented provide entire cohort and sex-specific spinal cord drug targets and disease biomarkers in the SOD1[G93A] mouse model of ALS that may guide future drug development and sex selection in preclinical study designs utilizing the SOD1[G93A] model.}, }
@article {pmid40116411, year = {2025}, author = {Albrethsen, J and Drici, L and Slot Vilmann, LM and Holmboe, SA and Thomsen, CE and Rogaczewska Groendahl, VL and Ottenheijm, ME and Nielsen, AB and Christoffersen, C and Aksglaede, L and Hagen, CP and Wewer Albrechtsen, NJ and Juul, A}, title = {Targeted proteomics of serum IGF-I, -II, IGFBP-2, -3, -4, -5, -6 and ALS.}, journal = {Clinical chemistry and laboratory medicine}, volume = {}, number = {}, pages = {}, pmid = {40116411}, issn = {1437-4331}, abstract = {OBJECTIVES: The insulin-like growth factors (IGFs) regulate growth in humans. IGF-I and IGF binding protein (IGFBP)-3 are biomarkers in children with growth disorders. We investigate a targeted proteomics method for absolute quantitation of eight IGF protein family members in human serum, including the peptide hormones IGF-I and -II, and the six binding proteins IGFBP-2, -3, -4, -5, -6 and acid labile subunit (ALS).<br><br>METHODS: Serum preparation was optimized for targeted proteomics of IGF related proteins on a clinical LC-MS/MS platform (UHPLC coupled with Triple-Q MS). We created quality controls, standards and internal standards and 289 serum samples from healthy children and adolescents were measured in ten batches over two months. The method was compared to WHO reference standards, clinical and research immunoassays, and relative proteomics profiling.<br><br>RESULTS: The sensitivity and reproducibility were sufficient for most but not all IGF protein family members. Targeted proteomics correlated well with clinical immunoassays for&#xa0;IGF-I (R[2]=0.88) and for IGFBP-3 (R[2]=0.46), (p<0.001). The correlation between targeted proteomics and non-clinical immunoassays for IGF-II, IGFBP-2, -4, -5, -6 and ALS varied between proteins.<br><br>CONCLUSIONS: We present a method for parallel quantification of IGF-I, IGFBP-3, 5 and ALS for clinical verification studies, whereas targeted proteomics of the five remaining IGF related proteins (IGF-II, IGFBP-2, -4, and -6) require further examination. The sensitivity of our new IGF-I method suggests a possible diagnostic role for targeted proteomics of IGF-I in the management of children with extremely low levels of circulating IGF-I.}, }
@article {pmid40116377, year = {2025}, author = {Zhu, Y and Li, M and Zhou, M and Hong, D}, title = {Letter on Wine Glass Sign in Bulbar-Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27239}, pmid = {40116377}, issn = {1531-8249}, }
@article {pmid40116361, year = {2025}, author = {Li, C and Noonan, AM and Hays, J and Roychowdhury, S and Malalur, P and Elkhatib, R and Manne, A and Mittra, A and Rahman, S and Yan, L and Hill, K and Abbott, N and Phelps, M and Na, JY and Liang, B and Storts, H and Khan, M and Zhang, EH and Miles, W and Yildiz, V and Wei, L and Wang, JJ and Jin, N}, title = {Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase 1 Clinical Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-3964}, pmid = {40116361}, issn = {1557-3265}, abstract = {BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU)-based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. New treatment strategies are needed for metastatic CRC patients with microsatellite stable disease. Preclinical studies showed that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-FU to reduce cell viability in CRC cell lines.<br><br>METHODS: In this single-arm, phase 1 trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapy.<br><br>RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients previously received FOLFOX, and 5 patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, 9 had stable disease, and 1 had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% CI 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively.<br><br>CONCLUSION: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX.}, }
@article {pmid40116017, year = {2025}, author = {Addy, G and Scirocco, E and Gelevski, D and Rohrer, M and Roderick, A and McCormack, M and Weiss Sadan, A and Scalia, J and Parikh, N and Giacomelli, E and Locatelli, M and Neel, DV and D'Agostino, D and Leite, A and Yu, H and Sherman, AV and Mock, J and Kalmes, A and Luppino, S and Babu, S and Berry, J and Cudkowicz, M and Paganoni, S}, title = {An Expanded Access Protocol of RNS60 in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28398}, pmid = {40116017}, issn = {1097-4598}, support = {//The study drug was provided at no cost by Revalesio, and program costs were covered by philanthropic donations to the Sean M. Healey &amp; AMG Center for ALS/ ; }, abstract = {AIMS: RNS60 is an investigational product in clinical development for amyotrophic lateral sclerosis (ALS). RNS60 slowed disease progression in the ALS SOD1[G93A] mouse model and was safe and well tolerated both in an open-label pilot study and a randomized, placebo-controlled, multicenter phase 2 trial in people living with ALS. The objective of this ongoing expanded access protocol (EAP) was to provide RNS60 to people living with ALS who are ineligible for controlled clinical trials and to collect data on the safety and tolerability of dosing RNS60 via twice-daily nebulization rather than the previously studied daily nebulization with weekly intravenous administration.<br><br>METHODS: Eligible participants (&#x2265;&#x2009;18&#x2009;years old, diagnosed with ALS per investigator assessment, and ineligible for an ALS clinical trial testing RNS60) were treated with twice-daily nebulization of RNS60 at home. Safety was evaluated by the assessment of adverse events and routine safety labs.<br><br>RESULTS: A total of 84 participants have been treated with RNS60 via nebulization twice daily for up to 48&#x2009;months so far. The most common treatment-related adverse event was increased secretions [N&#x2009;=&#x2009;27 (32%)]. Serious adverse events (SAEs) [69 occurrences; N&#x2009;=&#x2009;38 (45%) with at least one SAE] and deaths [N&#x2009;=&#x2009;24 (28%)] were deemed not related to RNS60.<br><br>DISCUSSION: This EAP supports the benign side effect profile of RNS60 when administered via twice-daily nebulization and demonstrates the feasibility of long-term EAPs as a complementary approach to controlled trials in people with advanced ALS.}, }
@article {pmid40113485, year = {2025}, author = {Anzilotti, S and Franco, C and Valsecchi, V and Cuomo, O and Lombardi, G and Di Muraglia, N and De Iesu, N and Laudati, G and Annunziato, L and Canzoniero, LMT and Giuseppe, P}, title = {Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00571}, doi = {10.1016/j.neurot.2025.e00571}, pmid = {40113485}, issn = {1878-7479}, abstract = {The imbalance in cellular ionic homeostasis represents a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Zinc Transporter 1 (ZnT1), the first described member of the ZnT family, stands out as the sole member of the SLC30 family responsible for exporting cytosolic zinc to the extracellular space. While ZnT1 is expressed across all tissues and cell types studied, it exhibits the highest prominence within the central nervous system. In ALS SOD1[G93A] mice, a reduction in ZnT1 expression consistent with disease progression has been observed, prompting our investigation into its role in ALS pathophysiology. Remarkably, through the use of a sequence complementary to the microRNA let-7a (anti-Let-7a) able to modulate ZnT1 expression, we demonstrated in ALS mice its capability to: (1) prevent the reduction in ZnT1 levels in the spinal cord; (2) preserve motor neuron survival in the ventral spinal horn; (3) decrease astroglial and microglial activation while sparing resident microglial cells in the spinal cord; and (4) improve the lifespan and alleviate motor symptoms.}, }
@article {pmid40109661, year = {2025}, author = {Hong, Y and Shi, JQ and Feng, S and Huang, SQ and Yuan, ZH and Liu, S and Zhang, XH and Zhou, JS and Jiang, T and Zhao, HD and Zhang, YD}, title = {The systemic inflammation markers as potential predictors of disease progression and survival time in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1552949}, pmid = {40109661}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal and untreatable neurodegenerative disease with only 3-5 years' survival time after diagnosis. Inflammation has been proven to play important roles in ALS progression. However, the relationship between systemic inflammation markers and ALS has not been well established, especially in Chinese ALS patients. The present study aimed to assess the predictive value of systemic inflammation markers including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic immune-inflammation index (SII) for Chinese amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Seventy-two Chinese ALS patients and 73 controls were included in this study. The rate of disease progression was calculated as the change of Revised ALS Functional Rating Scale (ALSFRS-R) score per month. Patients were classified into fast progressors if the progression rate > 1.0 point/month and slow progressors if progression rate &#x2264; 1.0 point/month. The value of NLR, PLR, LMR, and SII were measured based on blood cell counts. The association between systemic inflammation markers and disease progression rate was confirmed by logistic regression analysis. Kaplan-Meier curve and Cox regression models were used to evaluate factors affecting the survival outcome of ALS patients.<br><br>RESULTS: For Chinese ALS patients, NLR, PLR and SII were higher, LMR was lower when compared with controls. All these four markers were proved to be independent correlated with fast progression of ALS. Both Kaplan-Meier curve and Cox regression analysis indicated that higher NLR and lower LMR were associated with shorter survival time in the ALS patients.<br><br>DISCUSSION: In conclusion, the systemic inflammation markers, especially NLR and LMR might be independent markers for rapid progression and shorter survival time in Chinese ALS patients.}, }
@article {pmid40109277, year = {2025}, author = {Ding, XY and Habimana, JD and Li, ZY}, title = {The role of DPP6 dysregulation in neuropathology: from synaptic regulation to disease mechanisms.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1547495}, pmid = {40109277}, issn = {1662-5102}, abstract = {As a transmembrane protein, DPP6 modulates the function and properties of ion channels, playing a crucial role in various tissues, particularly in the brain. DPP6 interacts with potassium channel Kv4.2 (KCND2), enhancing its membrane expression and channel kinetics. Potassium ion channels are critical in progressing action potential formation and synaptic plasticity. Therefore, dysfunction of DPP6 can lead to significant health consequences. Abnormal DPP6 expression has been identified in several diseases, such as amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), spinal bulbar muscular atrophy (SBMA), and idiopathic ventricular fibrillation. Recent research has indicated a connection between DPP6 and Alzheimer's disease as well. The most common symptoms resulting from DPP6 dysregulation are mental deficiency and muscle wastage. Notably, these symptoms do not always occur at the same time. Besides genetic factors, environmental factors also undoubtedly play a role in diseases related to DPP6 dysregulation. However, it remains unclear how the expression of DPP6 gets regulated. This review aims to summarize the associations between DPP6 and neurological diseases, offering insights as well as proposing hypotheses to elucidate the underlying mechanisms of DPP6 dysregulation.}, }
@article {pmid40108302, year = {2025}, author = {Ma, W and Polgár, E and Dickie, AC and Hajer, MA and Quillet, R and Gutierrez-Mecinas, M and Yadav, M and Hachisuka, J and Todd, AJ and Bell, AM}, title = {Anatomical characterisation of somatostatin-expressing neurons belonging to the anterolateral system.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {9549}, pmid = {40108302}, issn = {2045-2322}, support = {MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; 219433/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; 304005/Z/23/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; *Somatostatin/metabolism/genetics ; Mice ; *Neurons/metabolism ; *Spinal Cord/metabolism/cytology ; Axons/metabolism ; Male ; Pain/metabolism/genetics ; }, abstract = {Anterolateral system (ALS) spinal projection neurons are essential for pain perception. However, these cells are heterogeneous, and there has been extensive debate about the roles of ALS populations in the different pain dimensions. We recently performed single-nucleus RNA sequencing on a developmentally-defined subset of ALS neurons, and identified 5 transcriptomic populations. One of these, ALS4, consists of cells that express Sst, the gene coding for somatostatin, and we reported that these were located in the lateral part of lamina V. Here we use a Sst[Cre] mouse line to characterise these cells and define their axonal projections. We find that their axons ascend mainly on the ipsilateral side, giving off collaterals throughout their course in the spinal cord. They target various brainstem nuclei, including the parabrachial internal lateral nucleus, and the posterior triangular and medial dorsal thalamic nuclei. We also show that in the L4 segment Sst is expressed by ~ 75% of ALS neurons in lateral lamina V and that there are around 120 Sst-positive lateral lamina V cells on each side. Our findings indicate that this is a relatively large population, and based on projection targets we conclude that they are likely to contribute to the affective-motivational dimension of pain.}, }
@article {pmid40106466, year = {2025}, author = {Lemmers, SAM and Le Luyer, M and Stoll, SJ and Hoffnagle, AG and Ferrell, RJ and Gamble, JA and Guatelli-Steinberg, D and Gurian, KN and McGrath, K and O'Hara, MC and Smith, ADAC and Dunn, EC}, title = {Inter-rater reliability of stress signatures in exfoliated primary dentition - Improving scientific rigor and reproducibility in histological data collection.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0318700}, pmid = {40106466}, issn = {1932-6203}, mesh = {Humans ; *Dental Enamel ; Reproducibility of Results ; *Tooth, Deciduous ; Stress, Physiological ; Observer Variation ; Female ; Child ; Male ; Stress, Psychological ; Data Collection/methods ; }, abstract = {Accentuated Lines (ALs) in tooth enamel can reflect metabolic disruptions from physiological or psychological stresses during development. They can therefore serve as a retrospective biomarker of generalized stress exposure in archaeological and clinical research. However, little consensus exists on when ALs are identified and inter-rater reliability is poorly quantified across studies. Here, we sought to address this gap by examining the reliability of accentuated (AL) markings across raters, in terms of both the presence versus absence of ALs and their intensity (HAL= Highly Accentuated, MAL= Mildly Accentuated, RL= Retzius Line). Ratings were made and compared across observers (with different levels of experience) and pairs of raters (who agreed on AL coding through consensus meetings) (N = 15 teeth, eight observers). Results indicated that more experience in AL assessment does not necessarily produce higher reliability between raters. Most disagreements in intensity ratings occurred in categories other than HAL. Furthermore, when AL assessment was performed by pairs of raters, reliability was significantly higher than individual assessments (Gwet's AC1 = 0.28 to 0.56 for line presence assessment; Gwet's AC1 = 0.48 to 0.64 for line intensity assessment). Based on these results, we recommend a workflow called IRRISS (Improving Reliability and Reporting In Scoring of Stress-markers) to increase rigor and reproducibility in histological analysis of dental collections. The introduction of IRRISS is well-timed, given the surge in studies of teeth occurring across anthropological, epidemiological, medical, forensic, and climate research fields.}, }
@article {pmid40105438, year = {2025}, author = {Ueha, R and Dealino, MA and Koyama, M and Yamakawa, K and Matsumoto, N and Sato, T and Goto, T and Mizukami, A and Kondo, K}, title = {Improved Pharyngeal Contraction and Oral Intake Status After Modified Central-Part Laryngectomy for Late-Stage ALS.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {}, number = {}, pages = {}, doi = {10.1002/ohn.1229}, pmid = {40105438}, issn = {1097-6817}, abstract = {OBJECTIVE: To investigate the effects of modified central-part laryngectomy with pharyngeal space reduction (CPL-PR) on patients with weak deglutitive pharyngeal contraction, as seen in late-stage amyotrophic lateral sclerosis (ALS).<br><br>STUDY DESIGN: Retrospective case series.<br><br>SETTING: Single-institution academic center.<br><br>METHODS: Patients with late-stage ALS confined at The University of Tokyo Hospital between 2019 and March 2024 in whom CPL-PR had been performed were identified. Patients who had undergone simultaneous pharyngeal flap surgery or had no preoperative high-resolution manofluorography done were excluded. Preoperatively, penetration-aspiration scale (PAS) scores were determined via videofluoroscopic swallowing study. Functional oral intake scale (FOIS) scores and high-resolution manometric parameters were measured and compared preoperatively and postoperatively.<br><br>RESULTS: Eighteen patients were identified with a median age of 66.5 (interquartile range [IQR]: 58.0-74.8). The median preoperative PAS score was 7.5 (IQR: 5.5-8.0), indicating severe dysphagia. There was significant improvement in oral intake status with FOIS scores increasing from 1 (IQR: 1-1) to 3 (IQR: 2-3) at 3 months postoperatively (P&#x2009;=&#x2009;.0002). Significant increases in velopharyngeal closure integral (P&#x2009;=&#x2009;.024) and mesohypopharyngeal contractile integral (P&#x2009;=&#x2009;.0001) were observed. Upper esophageal sphincter (UES) resting pressure was reduced (P&#x2009;=&#x2009;.0002), and UES relaxation time was prolonged during swallowing (P&#x2009;<&#x2009;.0001).<br><br>CONCLUSION: There were tangible improvements in pharyngeal contraction, UES bolus passage, and oral intake status following CPL-PR, which contribute to regaining oral intake in late-stage ALS. CPL-PR is an option for patients requiring tracheostomy who wish to prevent aspiration and regain their ability to take food orally.}, }
@article {pmid40105291, year = {2025}, author = {Ozeki-Hayashi, R and Wilkinson, DJC}, title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.}, journal = {AJOB empirical bioethics}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/23294515.2025.2474928}, pmid = {40105291}, issn = {2329-4523}, abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.<br><br>METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n&#x2009;=&#x2009;7), the UK (n&#x2009;=&#x2009;5), and the US (n&#x2009;=&#x2009;4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.<br><br>RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.<br><br>CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.}, }
@article {pmid40105198, year = {2025}, author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , }, title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28393}, pmid = {40105198}, issn = {1097-4598}, support = {//Immunity Pharma/ ; }, abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.<br><br>METHODS: Nine participants with ALS and a progression rate >&#x2009;0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36&#x2009;months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.<br><br>RESULTS: The mean&#x2009;&#xb1;&#x2009;SD duration of IPL344 follow-up was 14.0&#x2009;&#xb1;&#x2009;12.5&#x2009;months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean&#x2009;&#xb1;&#x2009;SE slope of decline in ALSFRS-R was -0.53&#x2009;&#xb1;&#x2009;0.15 (48% slower progression vs. historical controls, p&#x2009;=&#x2009;0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p&#x2009;=&#x2009;0.034), with increased rather than reduced body weight (p&#x2009;=&#x2009;0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p&#x2009;=&#x2009;0.04). Plasma NfL concentrations were lowered by 27% (n&#x2009;=&#x2009;6). Unadjusted median survival for participants in the IPL344 group was 43.4&#x2009;months [95% CI: 20.5, NA] compared with 19.1&#x2009;months [17.4, 23.0] in the historical control group.<br><br>DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.}, }
@article {pmid40103545, year = {2025}, author = {Sonaglioni, A and Torretta, P and Nicolosi, GL and Lombardo, M}, title = {Left ventricular mechanics assessment in amyloidosis patients: a systematic review and meta-analysis.}, journal = {Minerva cardiology and angiology}, volume = {}, number = {}, pages = {}, doi = {10.23736/S2724-5683.24.06683-3}, pmid = {40103545}, issn = {2724-5772}, abstract = {BACKGROUND: Over the last decade, a small number of studies have used speckle tracking echocardiography (STE) or cardiac magnetic resonance (CMR) for measuring left ventricular (LV) mechanics in patients with amyloidosis. This systematic review and meta-analysis aimed at assessing the overall influence of amyloidosis on LV global longitudinal strain (GLS) and regional longitudinal strain at basal (BLS), mid (MLS) and apical (ALS) level, respectively.<br><br>METHODS: All imaging studies assessing LV-GLS, LV-BLS, LV-MLS and LV-ALS in amyloidosis patients versus healthy controls, selected from PubMed and EMBASE databases, were included. The risk of bias was assessed by using the National Institutes of Health (NIH) Quality Assessment of Case-Control Studies. Continuous data (LV-GLS, LV-BLS, LV-MLS and LV-ALS) were pooled as a standardized mean differences (SMDs) comparing amyloidosis group with healthy controls. The overall SMDs of LV-GLS, LV-BLS, LV-MLS and LV-ALS were calculated using the random-effect model.<br><br>RESULTS: The full-texts of 13 studies with 553 amyloidosis patients and 575 healthy controls were analyzed. STE (53.8%) and CMR (46.2%) studies were separately analyzed. Average LV-GLS magnitude was significantly impaired in amyloidosis patients vs. controls in both STE (13.8&#xb1;3.9 vs. 19.8&#xb1;2.7%) and CMR (12.3&#xb1;4 vs. 17.9&#xb1;3.5%) studies. The impairment of segmental strain detected in amyloidosis patients was prevalent at basal and mid level, with relative "apical sparing." SMDs obtained for LV-GLS (SMD -1.80, 95% CI: -2.35, -1.24, P <0.001), LV-BLS (-1.98; 95% CI: -2.51, -1.45, P <0.001) and LV-MLS (-1.84; 95% CI: -2.46, -1.23, P <0.001) assessment were significantly larger than that obtained for LV-ALS (-0.72; 95% CI: -1.31, -0.13, P=0.02) measurement. Substantial heterogeneity was found among the studies assessing LV-GLS (I[2]=92.5%), LV-BLS (I[2]=91.4%), LV-MLS (I[2]=94.3%) and LV-ALS (I[2]=94.6%). Egger's test yielded a P value of 0.10, 0.20, 0.09 and 0.55 for LV-GLS, LV-BLS, LV-MLS and LV-ALS assessment respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for LV-GLS, LV-BLS, LV-MLS and LV-ALS (all P<0.05).<br><br>CONCLUSIONS: Amyloidosis has a large negative effect on LV-GLS, primarily related to the deterioration of segmental longitudinal strain at the basal and mid level, with relative apical sparing.}, }
@article {pmid40102416, year = {2025}, author = {Rivas-Fernández, JP and Vuillemin, M and Pilgaard, B and Klau, LJ and Fredslund, F and Lund-Hanssen, C and Welner, DH and Meyer, AS and Morth, JP and Meilleur, F and Aachmann, FL and Rovira, C and Wilkens, C}, title = {Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2670}, pmid = {40102416}, issn = {2041-1723}, support = {315385//Norges Forskningsr&#xe5;d (Research Council of Norway)/ ; 226244//Norges Forskningsr&#xe5;d (Research Council of Norway)/ ; 294946//Norges Forskningsr&#xe5;d (Research Council of Norway)/ ; DFF170746//Det Frie Forskningsr&#xe5;d (Danish Council for Independent Research)/ ; 2021-SGR-00680//Government of Catalonia | Ag&#xe8;ncia de Gesti&#xf3; d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants)/ ; NNF10CC1016517//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; }, mesh = {*Polysaccharide-Lyases/metabolism/chemistry ; *Alginates/chemistry/metabolism ; *Catalytic Domain ; Crystallography, X-Ray ; Kinetics ; Magnetic Resonance Spectroscopy ; Models, Molecular ; }, abstract = {Alginate lyases (ALs) catalyze the depolymerization of brown macroalgae alginates, widely used naturally occurring polysaccharides. Their molecular reaction mechanism remains elusive due to the lack of catalytically competent Michaelis-Menten-like complex structures. Here, we provide structural snapshots and dissect the mechanism of mannuronan-specific ALs from family 7 polysaccharide lyases (PL7), employing time-resolved NMR, X-ray, neutron crystallography, and QM/MM simulations. We reveal the protonation state of critical active site residues, enabling atomic-level analysis of the reaction coordinate. Our approach reveals an endolytic and asynchronous syn β-elimination reaction, with Tyr serving as both Brønsted base and acid, involving a carbanion-type transition state. This study not only reconciles previous structural and kinetic discrepancies, but also establishes a comprehensive PL reaction mechanism which is most likely applicable across all enzymes of the PL7 family as well as other PL families.}, }
@article {pmid40102061, year = {2025}, author = {Tran, K and Hayes, HA and Bromberg, M}, title = {A prospective observational study of decision-making by patients with amyotrophic lateral sclerosis upon recommendation for PEG enteral feeding tubes.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1002/ncp.11290}, pmid = {40102061}, issn = {1941-2452}, abstract = {OBJECTIVE: To understand challenges surrounding acceptance of a percutaneous endoscopic gastroscopic enteral feeding tube by patients with amyotrophic lateral sclerosis: a prospective observational study.<br><br>METHODS: This was a prospective observational study of 41 patients and care partners attending a multidisciplinary Motor Neuron Disease clinic. Surveys were administered pregastrostomy tube placement (N&#x2009;=&#x2009;23) and postplacement (N&#x2009;=&#x2009;41). Some were not available both pre- and postplacement). For preplacement, we queried barriers affecting their decision for receiving a gastrostomy tube at the time of recommendation. For postplacement, we queried factors that influenced their decision as well as perceived benefit and satisfaction with use.<br><br>RESULTS: Patient concerns about receiving a gastrostomy tube centered on the procedure, possible pain/infection (48%), limitations on activities (44%), impact on body image, and possible extension of life. For patients who received a gastrostomy tube, satisfaction was very high (93%), and there was reduced patient (59%) and care partners (54%) stress. The average BMI was 28.6&#x2009;kg/m[2] at diagnosis, and there was no net gain in weight. The average time until placement of a gastrostomy tube following recommendation was 145 days (range 13-824 days).<br><br>CONCLUSIONS: Despite counseling at multiple time points, the decision to obtain a feeding tube is often challenging for patients and care partners. Gastrostomy tube placement was perceived as a substantial benefit. Addressing these barriers may reduce concerns and promote earlier decision-making to maximize the benefits of placing a gastrostomy tube sooner.}, }
@article {pmid40101794, year = {2025}, author = {Krüger, DR and Jeschke, E and Gehrke, T and Günster, C and Halder, AM and Leicht, H and Malzahn, J and Schräder, P and Wirtz, DC and Zacher, J and Heller, KD}, title = {Impact of Hospital Case Volume on the Complication Rate in Hip Arthroplasty: An Analysis of Nationwide AOK Data.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2538-6446}, pmid = {40101794}, issn = {1864-6743}, abstract = {Aufgrund des demografischen Wandels und damit verbundener erwarteter Steigerungen der Fallzahlen von primärer Hüftendoprothetik und Revisionseingriffen ist es wichtig, Faktoren zu identifizieren, die Komplikationen und Revisionen reduzieren können. Ein solcher Faktor ist die Fallzahl eines Krankenhauses. Studien haben gezeigt, dass Krankenhäuser mit höheren Fallzahlen niedrigere Morbiditäts- und Komplikationsraten aufweisen. Die meisten Studien basieren dabei auf Registerdaten, die oft unvollständig sind und keine patientenspezifischen Faktoren beinhalten.In dieser Studie wurden bundesweite pseudonymisierte stationäre Abrechnungsdaten und Versichertenstammdaten der Allgemeinen Ortskrankenkassen (AOK) im Zeitraum von 2017 bis 2019 bei Patienten mit primärer Hüftendoprothese analysiert. Zur Analyse des Einflusses der Fallzahl auf das Outcome wurden 5 Fallzahlkategorien gebildet (I: 1-49, II: 50-99, III: 100-199, IV: 200-399, V: ≥ 400 Operationen pro Jahr). Als Endpunkte wurden 90-Tage-Sterblichkeit, 1-Jahres-Revisionsoperationen, chirurgische Komplikationen (90 Tage bzw. 365 Tage), periprothetische Femurfrakturen (90 Tage) und schwere Allgemeinkomplikationen im Krankenhausaufenthalt betrachtet. Der Einfluss der Fallzahl auf das Outcome wurde mittels multipler logistischer Regression unter Berücksichtigung patientenspezifischer Faktoren bestimmt.Die Analyse von 137494 Fällen aus 993 Kliniken zeigt einen statistisch signifikanten Zusammenhang zwischen der Fallzahlgruppe und der Häufigkeit von Revisionsoperationen, chirurgischen Komplikationen, periprothetischen Femurfrakturen und allgemeinen Komplikationen. Bei Kliniken mit einer Fallzahl von weniger als 50 pro Jahr zeigte sich eine Risikoerhöhung um 65%-88% für diese Endpunkte gegenüber der fallzahlstärksten Gruppe. Für den Endpunkt Sterblichkeit ergibt eine dichotome Betrachtung der Fallkategorien ebenfalls einen signifikanten Einfluss der Fallzahlen.Die Studie zeigt, dass, auch unter Berücksichtigung patientenspezifischer Faktoren, höhere Fallzahlen bei primärer Hüftendoprothetik in Krankenhäusern mit niedrigeren Komplikationsraten verbunden sind. Diese Erkenntnisse unterstreichen die Bedeutung der Fallzahl als Faktor zur Verbesserung der Versorgungsqualität in der Hüftendoprothetik.}, }
@article {pmid40100917, year = {2025}, author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S}, title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.}, journal = {PloS one}, volume = {20}, number = {3}, pages = {e0319866}, pmid = {40100917}, issn = {1932-6203}, mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; }, abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.}, }
@article {pmid40100796, year = {2025}, author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J}, title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {6}, pages = {6558-6575}, doi = {10.1021/acs.jmedchem.4c03127}, pmid = {40100796}, issn = {1520-4804}, mesh = {Animals ; *Armadillo Domain Proteins/antagonists &amp; inhibitors/metabolism ; Mice ; *Cytoskeletal Proteins/antagonists &amp; inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Drug Discovery ; Male ; }, abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.}, }
@article {pmid40100285, year = {2025}, author = {De Bertier, S and Lautrette, G and Amador, MD and Miki, T and Boillée, S and Lobsiger, CS and Bohl, D and Darios, F and Machat, S and Duchesne, M and Vourc'h, P and Fauret-Amsellem, AL and Corcia, P and Guy, N and Couratier, P and Seilhean, D and Millecamps, S}, title = {MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {272}, pmid = {40100285}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *tau Proteins/genetics ; Male ; Female ; Middle Aged ; Mutation ; Pedigree ; Adult ; Aged ; Brain/pathology ; Animals ; Mutation, Missense ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.<br><br>METHODS: We analyzed a whole-exome sequencing database comprising 470 ALS patients and explored the pathogenicity of the identified variants through familial, clinical, neuropathological, and cellular studies.<br><br>RESULTS: We identified two missense variants in the Tau repeat domains: the novel p.I308T variant, in a patient with early-onset ALS, and the p.P364S mutation in three families with spinal- or respiratory-onset ALS. Segregation of this mutation with disease could be confirmed in two affected cousins. The observation of p.P364S patient's tissue showed accumulations of hyperphosphorylated Tau in various brain regions, prominent in the motor cortex with Lewy body-like inclusions, along with a C-terminal cleaved form of Tau in muscle. In NSC-34 motor neuron cells expressing p.I308T or p.P364S mutants, Tau was discontinuous along the neurites, with clusters of mitochondria resulting from impaired mitochondrial motility.<br><br>CONCLUSION: These findings expand the molecular understanding of ALS to include MAPT mutations. MAPT analysis should be incorporated into ALS genetic screening, particularly in patients with a familial history of the disease. Recognizing the full spectrum of MAPT-linked neurodegenerative diseases is of considerable interest, given the ongoing efforts to develop MAPT-targeted therapies.}, }
@article {pmid40099869, year = {2025}, author = {Kim, SB and Lee, JS and Lan, X and Huang, W and Taylor, DJ and Kwon, YT and Zhang, Y and Ji, CH}, title = {The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/15548627.2025.2473393}, pmid = {40099869}, issn = {1554-8635}, abstract = {ATE1 (arginyltransferase 1; EC 2.3.2) transfers the amino acid arginine (Arg) from Arg-tRNA[Arg] to the N-terminal (Nt) residues of proteins, such as aspartate (Asp), glutamate (Glu), and oxidized cysteine (Cys). The resulting Nt-Arg acts as an N-degron that regulates the degradation of various biomaterials via the ubiquitin/Ub-proteasome system (UPS) or the autophagy-lysosome system (ALS). In the UPS, Arg/N-degrons are recognized by cognate N-recognins, leading to substrate ubiquitination and proteasomal degradation. In the ALS, the same degrons bind the macroautophagy/autophagy receptor SQSTM1/p62 (sequestosome 1) to facilitate self-polymerization of SQSTM1 associated with cargoes and SQSTM1 interaction with LC3-II on phagophores. A key unresolved question is why only a small subset of proteins acquires Arg/N-degrons, given the rather weak binding affinity of ATE1 for Nt-substrates. In this study, we determined the cryo-EM structures of human ATE1 in complex with Arg-tRNA[Arg] and an Nt-Asp peptide. ATE1 harbors two adjacent pockets that each bind an Nt-substrate or Arg-tRNA[Arg], the latter being wrapped by a long, unstructured loop. In the apo state, two ATE1 monomers form a homodimer. ATE1 achieves the selectivity for its peptidyl-ligands through these multivalent interactions, with Kd values in the micro-molar range. These results reveal the structural principle of Nt-arginylation at the crossroads of the UPS and ALS.Abbreviations: ALS: autophagy-lysosome system; Arg: arginine; Asp: aspartate; ATE1: arginyltransferase 1; Cys: cysteine; CysO2(H): Cys sulfinic acid; Glu: glutamate; Nt: N-terminal; UBR: ubiquitin protein ligase E3 component n-recognin; UPS: ubiquitin-proteasome system; ZZ: ZZ-type zinc finger.}, }
@article {pmid40099804, year = {2025}, author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z}, title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {31}, number = {3}, pages = {e70316}, pmid = {40099804}, issn = {1755-5949}, support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Prefrontal Cortex ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.<br><br>METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10&#x2009;Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6&#x2009;months post-treatment, and 12&#x2009;months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.<br><br>RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74&#x2009;&#xb1;&#x2009;6.39 to 81.98&#x2009;&#xb1;&#x2009;6.51 and 79.22&#x2009;&#xb1;&#x2009;6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p&#x2009;=&#x2009;0.031, p&#x2009;=&#x2009;0.042). The Zarit score also significantly decreased from 57.65&#x2009;&#xb1;&#x2009;3.42 to 52.24&#x2009;&#xb1;&#x2009;3.34 and 56.42&#x2009;&#xb1;&#x2009;3.41 at the 3-month and 6-month post-treatment time points, respectively (p&#x2009;=&#x2009;0.003, p&#x2009;=&#x2009;0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6&#x2009;months' follow-up.<br><br>CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.}, }
@article {pmid40099353, year = {2025}, author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV}, title = {Cutting-edge insights: LC-OCT and 5% cyclosporine for early lichen sclerosus treatment.}, journal = {Dermatology reports}, volume = {}, number = {}, pages = {}, doi = {10.4081/dr.2025.10279}, pmid = {40099353}, issn = {2036-7392}, abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting genital areas. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. Cyclosporine, a calcineurin inhibitor, has shown efficacy in managing immune-mediated skin diseases and is delivered effectively through the Pentravan® vehicle. [...].}, }
@article {pmid40099231, year = {2025}, author = {Hwang, DW and Ser, J and Ziabrev, K and Park, GK and Jo, MJ and Yokomizo, S and Bao, K and Yamashita, A and Cho, H and Henary, M and Kashiwagi, S and Choi, HS}, title = {Image-Guided Monitoring of Mitochondria and Blood-Brain Barrier Dysfunction in Amyotrophic Lateral Sclerosis Mice.}, journal = {Biomaterials research}, volume = {29}, number = {}, pages = {0162}, pmid = {40099231}, issn = {1226-4601}, abstract = {Early detection of amyotrophic lateral sclerosis (ALS) progression is critical for improving disease management and therapeutic outcomes. However, the clinical heterogeneity and variability in ALS symptoms often lead to delayed diagnosis and suboptimal therapeutic interventions. Since mitochondrial dysfunction is a hallmark of ALS, we hypothesized that monitoring mitochondrial function could serve as a reliable strategy for early diagnosis and therapeutic monitoring of ALS. To address this, we synthesized and characterized 2 novel near-infrared fluorophores, ALS04 and ALS05, designed to target mitochondria and lysosomes. Their physicochemical properties, serum protein binding, fluorescence characteristics, photostability, and pharmacokinetics were systematically evaluated. We found that benzothiazole-based fluorophores exhibit excellent mitochondrial targeting, optimal optical properties, biocompatibility, and favorable biodistribution in vivo. Interestingly, ALS04 showed superior mitochondrial accumulation compared to ALS05, despite their similar physicochemical properties. This enhanced accumulation can be attributed to the lower molecular weight and higher lipophilicity of ALS04. Real-time fluorescence imaging revealed a substantial reduction in ALS04 signals in mitochondrial-rich tissues such as brown fat, highlighting its potential for monitoring mitochondrial dysfunction in early-stage ALS. Furthermore, the detection of ALS04 in the mouse brain suggests its ability to monitor blood-brain barrier hyperpermeability, another key feature of ALS pathology. These findings establish ALS04 as a promising noninvasive imaging tool for monitoring biomarkers associated with ALS progression. Its ability to detect early-stage pathophysiological changes in an ALS mouse model highlights its potential for advancing our understanding of ALS mechanisms and facilitating the identification of novel therapeutic targets.}, }
@article {pmid40097890, year = {2025}, author = {Dezfouli, MA and Shalilahmadi, D and Shamsaei, G and Esmaeili, A and Majdinasab, N and Rashidi, SK}, title = {Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {40097890}, issn = {2240-2993}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1β levels were evaluated as plasma biomarkers in the incidence and progression of ALS.<br><br>METHODS: 32 ALS patients and 32 healthy subjects were assessed. In all patients, the functional disability was determined by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the respiratory dysfunction was assessed by the percent predicted forced vital capacity (ppFVC) index in spirometry examination. Plasma levels of miR-223, NLRP3 and IL-1&#x3b2; were assessed in ALS and control groups.<br><br>RESULTS: Compared to the healthy controls, ALS patients showed decreased miR-223 expression (P&#x2009;<&#x2009;0.0001), increased NLRP3 expression (P&#x2009;=&#x2009;0.0002) and increased IL-1&#x3b2; level (P&#x2009;=&#x2009;0.0003). The areas under the ROC curves for miR-223, NLRP3 and IL-1&#x3b2; were 0.82, 0.76 and 0.75 respectively. The ALSFRS-R and ppFVC values were positively correlated with miR-223 and negatively correlated with NLRP3 and IL-1&#x3b2; levels.<br><br>CONCLUSION: Our results indicated that changes in miR-223, NLRP3 and IL-1&#x3b2; levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.}, }
@article {pmid40097762, year = {2025}, author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH}, title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40097762}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.}, }
@article {pmid40097438, year = {2025}, author = {Ayyadurai, VAS and Deonikar, P and Kamm, RD}, title = {A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.}, journal = {NPJ systems biology and applications}, volume = {11}, number = {1}, pages = {27}, pmid = {40097438}, issn = {2056-7189}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuromuscular Junction/metabolism/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; Animals ; Systems Biology/methods ; }, abstract = {A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.}, }
@article {pmid40097075, year = {2025}, author = {Cuevas, EP and Madruga, E and Valenzuela-Martínez, I and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A}, title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.}, journal = {Neurobiology of disease}, volume = {208}, number = {}, pages = {106871}, doi = {10.1016/j.nbd.2025.106871}, pmid = {40097075}, issn = {1095-953X}, abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.}, }
@article {pmid40095345, year = {2025}, author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A}, title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40095345}, issn = {1559-1182}, abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.}, }
@article {pmid40094392, year = {2025}, author = {Resch, M and Frickel, JS and Dischinger, K and Wen, RCS and Hell, K and Harner, ME}, title = {The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.}, journal = {Journal of cell science}, volume = {}, number = {}, pages = {}, doi = {10.1242/jcs.263661}, pmid = {40094392}, issn = {1477-9137}, support = {413985647//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.}, }
@article {pmid40093130, year = {2025}, author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Bae, M and Shao, DD and Sahile, B and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA}, title = {Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40093130}, issn = {2692-8205}, support = {R01 HG012573/HG/NHGRI NIH HHS/United States ; R56 AG079857/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; R01 AG082346/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 NS032457/NS/NINDS NIH HHS/United States ; DP2 AG086138/AG/NIA NIH HHS/United States ; R01 AG070921/AG/NIA NIH HHS/United States ; R01 AG088082/AG/NIA NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10[-10]). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.}, }
@article {pmid40092960, year = {2025}, author = {Liu, Y and Li, XF}, title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {3}, pages = {100463}, pmid = {40092960}, issn = {1948-5204}, abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.}, }
@article {pmid40092497, year = {2025}, author = {Fujii, Y and Kanbayashi, T and Takahashi, K and Hamada, Y and Kobayashi, S and Sonoo, M}, title = {Correlation between decremental responses in repetitive nerve stimulation and disease progression rate in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {40-46}, pmid = {40092497}, issn = {2467-981X}, abstract = {OBJECTIVE: Decrement responses in repetitive nerve stimulation (RNS) are theoretically expected to correlate with the disease progression speed in amyotrophic lateral sclerosis (ALS). However, actual results have been controversial. We investigated this issue using ΔFS calculated from the ALS functional rating scale revised version (ALSFRS-R) and the duration of illness.<br><br>METHODS: RNS results of the abductor pollicis brevis, trapezius, and deltoid muscles in our previous study were reviewed. We investigated correlations and multiple regressions regarding decremental percentage (Decr%), the amplitude of the initial compound muscle action potential (Amp), and progression speed parameters, i.e. &#x394;FS or &#x394;UL-FS, the latter being the &#x394;FS for the upper-limb questions in ALSFRS-R.<br><br>RESULTS: Included subjects were 124 patients with ALS, 47 of whom were upper-limb onset. Multiple regression analyses revealed that Decr% is largely determined by Amp and that &#x394; FS or &#x394;UL-FS showed no or little contributions to Decr%.<br><br>CONCLUSIONS: Decremental responses in RNS does not predict the speed of progression of the functional impairment in patients with ALS.<br><br>SIGNIFICANCE: This study suggests that the decremental responses in RNS in ALS are contributed by the impaired neuromuscular transmission in chronic sprouts following extensive reinnervation, as well as by the immature sprouts.}, }
@article {pmid40092496, year = {2025}, author = {Theuriet, J and Bohic, A and Bonjour, M and Bernard, E and Cluse, F and Svahn, J and Jomir, L and Vallet, AE and Demia, M and Roux, L and Bârsan, IC and Alves, L and Dion, M and Meens, L and Moussy, M and Bouhour, F and Péréon, Y and Pegat, A}, title = {Contralateral R1 response in blink reflex in patients with amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {10}, number = {}, pages = {47-51}, pmid = {40092496}, issn = {2467-981X}, abstract = {OBJECTIVE: This study aimed to compare the frequency of blink reflex's contralateral R1 responses (R1') between patients with amyotrophic lateral sclerosis (ALS), non-ALS motor deficit patients, and healthy volunteers.<br><br>METHODS: A total of 120 participants were prospectively recruited: 40 with ALS, 40 with a non-ALS motor deficit, and 40 healthy volunteers. Blink reflexes were recorded from orbicularis oculi muscles following supraorbital nerve stimulation.<br><br>RESULTS: R1' was more frequent in the ALS group (42.5&#xa0;%) compared to healthy volunteers (12.5&#xa0;%, p&#xa0;=&#xa0;0.00588), and compared to non-ALS patients (7.5&#xa0;%, p&#xa0;=&#xa0;0.000789). Bilateral R1' was observed only in ALS patients (22.5&#xa0;%). No clinically significant difference was found in the latencies or amplitudes of the R1, R2, or R1' responses among groups. R1' was more frequent in ALS patients with pseudobulbar affect (71.4&#xa0;%) compared to those without (36.4&#xa0;%).<br><br>CONCLUSIONS: The higher frequency of R1' in ALS highlights its potential role in distinguishing ALS from other motor disorders. Its sensitivity was low, but bilateral R1' was specific to ALS. The higher frequency of R1' among ALS patients with pseudobulbar affect potentially reflects corticobulbar neuron degeneration.<br><br>SIGNIFICANCE: The R1', especially when bilateral, could serve as an additional diagnostic biomarker for ALS, although its clinical relevance should be considered within the broader diagnostic context.}, }
@article {pmid40091916, year = {2025}, author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F}, title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.}, journal = {Cureus}, volume = {17}, number = {2}, pages = {e78903}, pmid = {40091916}, issn = {2168-8184}, abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.}, }
@article {pmid40091372, year = {2025}, author = {Jaspers Focks, RJ and Helleman, J and van den Berg, LH and Visser-Meily, JM and Gaytant, MA and Wijkstra, PJ and Beelen, A}, title = {Initiating non-invasive ventilation in patients with Amyotrophic Lateral Sclerosis in The Netherlands: A centralised approach to respiratory care.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251319167}, doi = {10.1177/22143602251319167}, pmid = {40091372}, issn = {2214-3602}, abstract = {BACKGROUND: In the Netherlands a centralised approach to respiratory care for patients with Amyotrophic Lateral Sclerosis is used based on national guidelines. Patients with Amyotrophic Lateral Sclerosis are referred to one of 4 centres for Home Mechanical Ventilation.<br><br>OBJECTIVE: Our aim was to evaluate the respiratory care according to the Dutch guideline by evaluation of reasons for starting non-invasive ventilation, timing of initiating and survival in patients with Amyotrophic Lateral Sclerosis using non-invasive ventilation.<br><br>METHOD: A retrospective chart-review was performed of 323 patients, who had been referred to centres for Home Mechanical Ventilation in 2016-2018. Data collected included symptoms of hypoventilation, forced vital capacity, blood gasses, criteria for (not) initiating non-invasive ventilation, and survival. Kaplan-Meyer curves and Multivariate Cox proportional hazard regression were used in the analysis.<br><br>RESULTS: The main criteria used for initiating non-invasive ventilation were hypercapnia (77%) and the presence of orthopnea and/or dyspnoea (25%). Median survival after starting non-invasive ventilation was 11 months, and was shorter for patients with bulbar disease onset and older age. The proportion of the total disease duration that was spent on non-invasive ventilation was not significantly affected by age, sex or site of disease. Seventy nine percent of the patients who didn't start non-invasive ventilation had reached a joint decision with their caregivers and/or physicians.<br><br>CONCLUSION: Key outcomes of the Dutch centralised respiratory care approach have shown that most patients were initiated on non-invasive ventilation due to presence of hypercapnia and/or dyspnoea/orthopnea, which is according to the Dutch guidelines. Half of patients spent at least 33% of their disease duration on non-invasive ventilation. To help find the optimal criteria and timing for non-invasive ventilation it would be useful for other countries to share their key outcomes as well.}, }
@article {pmid40090808, year = {2025}, author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP}, title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.}, journal = {Trends in endocrinology and metabolism: TEM}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tem.2025.02.004}, pmid = {40090808}, issn = {1879-3061}, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.}, }
@article {pmid40089090, year = {2025}, author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X}, title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.}, journal = {Cellular signalling}, volume = {131}, number = {}, pages = {111715}, doi = {10.1016/j.cellsig.2025.111715}, pmid = {40089090}, issn = {1873-3913}, abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.}, }
@article {pmid40087396, year = {2025}, author = {Omar, OMF and Kimble, AL and Cheemala, A and Tyburski, JD and Pandey, S and Wu, Q and Reese, B and Jellison, ER and Hao, B and Li, Y and Yan, R and Murphy, PA}, title = {Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.}, journal = {Nature neuroscience}, volume = {}, number = {}, pages = {}, pmid = {40087396}, issn = {1546-1726}, support = {19IPLOI34770151//American Heart Association (American Heart Association, Inc.)/ ; 23PRE1027078//American Heart Association (American Heart Association, Inc.)/ ; R00-HL125727//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; RF1-NS117449//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS074256//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; GM135592//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; AG046929//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, abstract = {Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.}, }
@article {pmid40086112, year = {2025}, author = {Liampas, I and Veltsista, D and Germeni, A and Batzikosta, P and Michou, E and Kefalopoulou, Z and Chroni, E}, title = {F waves in amyotrophic lateral sclerosis: A systematic review and meta-analysis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {55}, number = {4}, pages = {103061}, doi = {10.1016/j.neucli.2025.103061}, pmid = {40086112}, issn = {1769-7131}, abstract = {OBJECTIVE: This systematic review and meta-analysis aimed to determine the pattern of F-wave abnormalities and their potential utility in the early diagnosis of amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Medline and Embase were thoroughly searched. We primarily emphasized F-wave recordings from the abductor digiti minimi, following stimulation of the ulnar nerve at the wrist. Data from case-control studies involving individuals with ALS versus healthy controls (HC) or other well-defined patient groups were reviewed and -if appropriate- quantitatively synthesized.<br><br>RESULTS: Twenty-nine studies were included in this systematic review and 17 of them in the analytic part. The pattern of F-abnormalities in ALS compared to HC was as follows: decreased persistence (MD=20.25 %,15.67-24.84 %), mildly prolonged minimum latency (MD=1.59msec,1.11-2.06msec), increased maximum amplitude (MD=196&#x3bc;V,106-287&#x3bc;V) and elevated Index total Freps (MD=33.9 %,26.0-41.8 %). Affected limbs (with substantial weakness in clinical examination and/or muscle wasting and/or abnormal nerve conduction studies) exhibited more marked abnormalities in persistence, minimum latency, and Index total Freps, whereas abnormalities in these parameters were very mild in clinically unaffected limbs. More prominent increases in maximum amplitude accompanied pyramidal dysfunction. Of note, isolated upper motor neuron (UMN) disorders exhibited a comparable increase in Index total Freps without a decrease in persistence.<br><br>CONCLUSIONS: The pattern of F wave abnormalities may raise suspicion of involvement of the under-study lower motor neuron (LMN) pool in ALS. These findings may identify LMN dysfunction even at a preclinical stage and prompt extensive electromyographic investigations. UMN involvement may to some extent differentiate the profile of F wave abnormalities in ALS.}, }
@article {pmid40085521, year = {2025}, author = {Mercan, M and Seyhan, S and Yayla, V}, title = {The phenotyping dilemma in VRK1-related motor neuron disease: a Turkish family with young-onset amyotrophic lateral sclerosis caused by a novel mutation.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/21678421.2025.2477732}, pmid = {40085521}, issn = {2167-9223}, abstract = {Objective: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. Methods: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. Results: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (p = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). Conclusion: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.}, }
@article {pmid40084393, year = {2025}, author = {Helmold, B and Nathaniel, G and Barkhaus, P and Bertorini, T and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Denson, K and Glass, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Maragakis, N and Cadavid, JM and Mcdermott, C and Pattee, G and Pierce, K and Wang, O and Wicks, P and Bedlack, R}, title = {ALSUntangled #78: Zinc.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/21678421.2025.2476688}, pmid = {40084393}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we assess the utilization of dietary zinc supplements for modulating ALS pathology and progression. Studies in mouse models of ALS have demonstrated that high-dose zinc supplementation may be harmful, but moderate doses could potentially be beneficial. Clinical data is limited, and only one trial has explored zinc supplementation within PALS. This study reported potential benefits in slowing ALS progression but lacked statistical analyses and failed to report quantitative evidence. Numerous case reports from individual patients at varying doses have demonstrated no benefit. Zinc supplements at moderate doses are generally low cost and not associated with severe complications, but further research is required to determine the safety and efficacy of zinc supplementation within PALS. Therefore, we cannot at this time, endorse zinc supplementation to slow ALS progression.}, }
@article {pmid40080233, year = {2025}, author = {Aydın, &#x15e; and Özdemir, S and Adıgüzel, A}, title = {The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {34}, pmid = {40080233}, issn = {1559-1166}, mesh = {Humans ; *Biomarkers/blood ; *Cell-Free Nucleic Acids/blood ; *Neurodegenerative Diseases/blood/diagnosis/genetics ; Animals ; }, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders.}, }
@article {pmid40077653, year = {2025}, author = {de Carvalho Vilar, MD and Coutinho, KMD and de Lima Vale, SH and Dourado Junior, MET and de Medeiros, GCBS and Piuvezam, G and Brandao-Neto, J and Leite-Lais, L}, title = {Evidence-Based Nutritional Recommendations for Maintaining or Restoring Nutritional Status in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {5}, pages = {}, pmid = {40077653}, issn = {2072-6643}, support = {grant number 302298/2017-7 (Jose Brandao-Neto)//National Council for Scientific and Technological Development/ ; TED 132/2018//Ministry of Health (Brazil) - Laboratory of Technological Innovation in Health from the Federal University of Rio Grande do Norte - LAIS/UFRN/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diet therapy/therapy/complications ; Humans ; *Nutritional Status ; *Nutrition Assessment ; Evidence-Based Medicine ; Quality of Life ; Nutritional Support/methods ; Dietary Supplements ; Deglutition Disorders/diet therapy/therapy ; Gastrostomy ; Nutrition Therapy/methods ; }, abstract = {Background/Objectives: This study is a systematic review of guidelines that aims to synthesize evidence-based recommendations to support appropriate nutritional management for patients with amyotrophic lateral sclerosis (ALS). Methods: PubMed/MEDLINE, Embase, Scopus, SciELO, Web of Science, LILACS, ScienceDirect, and Google Scholar were searched for records published up to July 2024. Clinical practice guidelines addressing any aspect of nutritional intervention in ALS were included. No language or country of publication restrictions were applied. Data extraction was performed by two independent reviewers. The methodological quality of the reports was assessed using the AGREE II instrument. Discrepancies were resolved by consensus. Results: The findings and main recommendations were summarized narratively. A total of 837 records were identified, and 11 were included in this review. The overall AGREE II scores for the included studies ranged from 3 to 7. The summary of nutritional recommendations was organized into topics: (1) dysphagia, (2) nutritional assessment, (3) energy, (4) protein, (5) supplementation, and (6) percutaneous endoscopic gastrostomy (PEG). This review summarizes relevant and updated nutritional recommendations to maintain or restore the nutritional status of patients with ALS, contributing to their quality of life and survival time. Conclusions: These nutritional recommendations will help health professionals and caregivers to implement and standardize nutritional care according to evidence-based practice in ALS. PROSPERO registration number CRD42021233088.}, }
@article {pmid40076771, year = {2025}, author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C}, title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.}, journal = {International journal of molecular sciences}, volume = {26}, number = {5}, pages = {}, pmid = {40076771}, issn = {1422-0067}, support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; }, mesh = {*Edaravone/pharmacology/chemistry/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; Drug Delivery Systems/methods ; Free Radical Scavengers/chemistry/pharmacology ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System/chemistry ; Polyethylene Glycols/chemistry ; }, abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.}, }
@article {pmid40075757, year = {2025}, author = {Rizzo, GEM and Coluccio, C and Forti, E and Fugazza, A and Binda, C and Vanella, G and Di Matteo, FM and Crinò, SF and Lisotti, A and Maida, MF and Aragona, G and Mauro, A and Repici, A and Anderloni, A and Fabbri, C and Tarantino, I and On Behalf Of The I-Eus Group, }, title = {Endoscopic Ultrasound-Guided Anastomoses of the Gastrointestinal Tract: A Multicentric Experience.}, journal = {Cancers}, volume = {17}, number = {5}, pages = {}, pmid = {40075757}, issn = {2072-6694}, support = {N/A//I-EUS working group/ ; }, abstract = {This multicenter retrospective study included patients undergoing EUS-guided GI anastomoses from 2016 to 2023. Indications for EUS-guided anastomosis were GOO, ALS or patients with altered anatomy needing endoscopic interventions. The primary outcome was technical success, while secondary outcomes included clinical success, safety, lumen-apposing metal stent (LAMS) patency, and the need for reinterventions. A total of 216 patients (mean age 64.5 [±13.94] years; 49.1% males) were included. In total, 149 cases (69%) were GOO, 44 (20.4%) cases were bilioenteric anastomotic strictures or lithiasis in altered anatomy, 14 cases (6.5%) were ALS, and 9 patients (4.2%) were for ERCP in altered anatomy after EUS-GG. Overall, EUS-GE was performed in 181 patients (83.8%), EUS-JJ in 44 cases (20.4%), and EUS-GG in 10 (4.6%). Technical success was 94.91%, and clinical success was 93.66%. The adverse event (AE) rate was 11.1%. The reintervention rate was 7.69%. The median follow-up was 85 days. In conclusions, EUS-guided GI anastomoses are technically feasible and safe in both malignant and benign diseases.}, }
@article {pmid40075315, year = {2025}, author = {Soliman, R and Fahmy, N and Swelam, MS}, title = {Headache types and characteristics in patients with Amyotrophic Lateral Sclerosis.}, journal = {The journal of headache and pain}, volume = {26}, number = {1}, pages = {53}, pmid = {40075315}, issn = {1129-2377}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Female ; Male ; Middle Aged ; Cross-Sectional Studies ; Adult ; Headache/etiology/epidemiology/diagnosis ; Aged ; Tension-Type Headache/diagnosis ; Severity of Illness Index ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons, this result in muscle denervation, atrophy and consequently death takes place due to respiratory failure within 3-5 years of onset of symptoms.<br><br>OUR AIM: Was to investigate types and frequency of headache in ALS patients.<br><br>METHODS: This is cross sectional hospital based study. Clinically definite 100 ALS Patients (diagnosed according to El Escorial revised criteria) were recruited out of 137 ALS patients presented to the Neuromuscular Clinic in Ain Shams university Hospital from February 2022 to June 2024. Patients were screened for headache types and symptoms diagnosed according to International Headache Society criteria (IHS). Headache severity and impact were assessed using Arabic versions of Headache Impact Test (HIT) and Migraine Disability Assessment (MIDAS). Depression was also assessed via Arabic version of Beck's Depression Inventory (BDI). ALS symptoms severity was assessed via Arabic version of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Cognitive functions were assessed via the Egyptian version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS&#x2011;EG). Demographic data and ALS related parameters were collected.<br><br>RESULTS: Among 100 patients with clinically definite ALS, 79 patients reported headaches, 62 of them had primary headaches; with tension-type headache being the most commonly reported in 46 patients, Migraine in 16 patients. Fifteen ALS patients had secondary headaches; among them 12 had headache secondary to respiratory insufficiency and 3 patients developed headache after the initiation of Riluzole therapy. Two patients had non specific headache. Mean age for the patients at ALS presentation was 43.9&#x2009;&#xb1;&#x2009;13.8, Mean ALSFRS-R score 33.3&#x2009;&#xb1;&#x2009;9.04. The relationships between headache and clinical features of ALS were also investigated.<br><br>IN CONCLUSION: ALS patients should be evaluated for Headache; Not only headache secondary to respiratory compromise and hypercapnea, but also primary headaches which can be overlooked in patients with ALS.}, }
@article {pmid40075110, year = {2025}, author = {Raas, Q and Haouy, G and de Calbiac, H and Pasho, E and Marian, A and Guerrera, IC and Rosello, M and Oeckl, P and Del Bene, F and Catanese, A and Ciura, S and Kabashi, E}, title = {TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {98}, pmid = {40075110}, issn = {2058-7716}, support = {682622//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, abstract = {Pathogenic mutations within the TBK1 gene leading to haploinsufficiency are causative of amyotrophic lateral sclerosis (ALS). This gene is linked to autophagy and inflammation, two cellular mechanisms reported to be dysregulated in ALS patients, although its functional role in the pathogenesis could involve other players. We targeted the TBK1 ortholog in zebrafish, an optimal vertebrate model for investigating genetic defects in neurological disorders. We generated zebrafish models with invalidating tbk1 mutations using CRISPR-Cas9 or tbk1 knockdown models using antisense morpholino oligonucleotide (AMO). The early motor phenotype of zebrafish injected with tbk1 AMO beginning at 2 days post fertilization (dpf) is associated with the degeneration of motor neurons. In parallel, CRISPR-induced tbk1 mutants exhibit impaired motor function beginning at 5 dpf and increased lethality beginning at 9 dpf. A metabolomic analysis showed an association between tbk1 loss and severe dysregulation of nicotinamide metabolism, and incubation with nicotinamide riboside rescued the motor behavior of tbk1 mutant zebrafish. Furthermore, a proteomic analysis revealed increased levels of inflammatory markers and dysregulation of programmed cell death pathways. Necroptosis appeared to be strongly activated in TBK1 fish, and larvae treated with the necroptosis inhibitor necrosulfonamide exhibited improved survival. Finally, a combined analysis of mutant zebrafish and TBK1-mutant human motor neurons revealed dysregulation of the KEGG pathway "ALS", with disrupted nuclear-cytoplasmic transport and increased expression of STAT1. These findings point toward a major role for necroptosis in the degenerative features and premature lethality observed in tbk1 mutant zebrafish. Overall, the novel tbk1-deficient zebrafish models offer a great opportunity to better understand the cascade of events leading from the loss of tbk1 expression to the onset of motor deficits, with involvement of a metabolic defect and increased cell death, and for the development of novel therapeutic avenues for ALS and related neuromuscular diseases.}, }
@article {pmid40074931, year = {2025}, author = {Michielsen, A and van Veenhuijzen, K and Hiemstra, F and Jansen, IM and Kalkhoven, B and Veldink, JH and Kruitwagen, ET and van Es, M and van Zandvoort, MJE and van den Berg, LH and Westeneng, HJ}, title = {Cognitive impairment within and beyond the FTD spectrum in ALS: development of a complementary cognitive screen.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {268}, pmid = {40074931}, issn = {1432-1459}, support = {grant agreement no 772376- EScORIAL//H2020 European Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Male ; Female ; *Frontotemporal Dementia/complications/diagnosis/physiopathology ; *Cognitive Dysfunction/etiology/diagnosis/physiopathology ; Middle Aged ; Aged ; *Neuropsychological Tests ; }, abstract = {OBJECTIVE: To investigate cognitive impairments in amyotrophic lateral sclerosis (ALS), extending both within and beyond the established frontotemporal dementia (FTD) spectrum, using the Complementary Cognitive ALS Screen (C-CAS).<br><br>METHODS: The C-CAS, designed to complement the Edinburgh cognitive and behavioural ALS screen (ECAS), explores cognitive (sub)domains not investigated by the ECAS. Normative data were collected, and models adjusted for age, sex, and education level were developed. Item scores below the 5th percentile in controls were considered abnormal. A sum score was constructed, and C-CAS impairments were compared between ALS patients and controls, and to ECAS impairments.<br><br>RESULTS: Data from 314 controls and 184 ALS patients were analyzed. The C-CAS is feasible, well-tolerated, and takes 15-20&#xa0;min to complete. ALS patients performed worse across all 12 items. Within the FTD spectrum, impairments in social cognition, inhibition, and cognitive flexibility were identified in up to 16%, 14%, and 12% of ALS patients, respectively, with minimal overlap with ECAS impairments. Beyond the FTD spectrum, impairments were found in visuoconstruction, incidental non-verbal memory and body orientation (13% each), with minimal overlap with ECAS memory or visuospatial impairments. Overall, 24% of the ALS patients obtained an abnormal C-CAS sum score. Compared to the ECAS, the C-CAS detected additional impairments in 15% of ALS patients. Item-specific and sum score results based on normative data can be accessed at (https://apps4mnd.com/ccas/).<br><br>INTERPRETATION: We identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.}, }
@article {pmid40074537, year = {2025}, author = {Mkhize, L and Marimani, M and Duze, ST}, title = {Characterization of Vibrio cholerae from the Jukskei River in Johannesburg, South Africa.}, journal = {Letters in applied microbiology}, volume = {78}, number = {3}, pages = {}, doi = {10.1093/lambio/ovaf036}, pmid = {40074537}, issn = {1472-765X}, support = {138279//National Research Foundation/ ; RKSST23//Carnegie DTA/ ; }, mesh = {South Africa ; *Vibrio cholerae/genetics/isolation &amp; purification/classification ; *Rivers/microbiology ; *Cholera/microbiology/epidemiology ; Humans ; Cholera Toxin/genetics ; Genome, Bacterial ; Virulence Factors/genetics ; Bacterial Proteins/genetics ; }, abstract = {The current study aimed to isolate and characterize Vibrio cholerae isolated from the Jukskei River, one of the largest Rivers in Johannesburg, South Africa. Water samples collected from the Jukskei River were subjected to culture-based methods for the detection and isolation of V. cholerae. Twenty-four V. cholerae were isolated, confirmed using real-time PCR, and sequenced using the MInION portable nanopore-sequencing device. Reference-based genome assemblies were constructed from the raw reads using the EPI2ME software followed by bioinformatics analysis using the Centre for Genomic Epidemiology website. All the V. cholerae isolates isolated from the Jukskei River were classified as non-O1/non-O139 and none of the isolates harbored the cholera toxin gene, ctxA. All 24 V. cholerae isolates belonged to sequence type 741, virulent genes including toxR, vspD, als, hlyA, makA, and rtxA as well as the Vibrio pathogenicity island 2 were detected amongst the isolates. Antimicrobial resistance genes (parC, varG, and gyrA) were detected in 83% of isolates. Although V. cholerae non-O1/non-O139 are not associated with epidemic cholera they can still cause mild to life-threatening illnesses. Therefore, increased surveillance should be considered to better understand the public health risks to the local community.}, }
@article {pmid40074390, year = {2025}, author = {Cappa, SF}, title = {Hemispheric asymmetry in neurodegenerative diseases.}, journal = {Handbook of clinical neurology}, volume = {208}, number = {}, pages = {101-112}, doi = {10.1016/B978-0-443-15646-5.00009-9}, pmid = {40074390}, issn = {0072-9752}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; *Functional Laterality/physiology ; Brain/pathology/physiopathology ; }, abstract = {Hemispheric asymmetry in pathologic involvement is frequently observed in neurodegenerative disorders (NDD) and is responsible for differences in cognitive and motor clinical manifestations in individual patients. While asymmetry is modest in typical Alzheimer disease (AD), atypical AD presentations with prominent language impairment [logopenic/phonologic variant of primary progressive aphasia (L/Phv-PPA)] are associated with prevalent involvement of the language-dominant hemisphere. Similarly, in the frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, the semantic (Sv) and nonfluent/agrammatic (Nf/Av) variants of PPA are due to asymmetric pathology involving the language-dominant hemisphere. A reversed (typically right-sided) pattern of asymmetry is often found in conditions associated with prominent disorders of behavior and social cognition (i.e., behavioral variant of frontotemporal degeneration-Bv FTD). Asymmetry is generally modest and less consistent in NDD with prevalent motor manifestations, such as Parkinson disease (PD). Overall, the pattern of hemispheric involvement reflects the network-specific selectivity of NDD and is compatible with the spreading of pathology along connection pathways.}, }
@article {pmid40073860, year = {2025}, author = {Zhang, Z and Fu, X and Wright, N and Wang, W and Ye, Y and Asbury, J and Li, Y and Zhu, C and Wu, R and Wang, S and Sun, S}, title = {PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2025.02.005}, pmid = {40073860}, issn = {1097-4199}, support = {RF1 NS113820/NS/NINDS NIH HHS/United States ; }, abstract = {The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.}, }
@article {pmid40073394, year = {2025}, author = {Janes, WE and Marchal, N and Song, X and Popescu, M and Mosa, ASM and Earwood, JH and Jones, V and Skubic, M}, title = {Integrating Ambient In-Home Sensor Data and Electronic Health Record Data for the Prediction of Outcomes in Amyotrophic Lateral Sclerosis: Protocol for an Exploratory Feasibility Study.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e60437}, pmid = {40073394}, issn = {1929-0748}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnosis ; *Electronic Health Records ; *Feasibility Studies ; Machine Learning ; Male ; Female ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to rapid physiological and functional decline before causing untimely death. Current best-practice approaches to interdisciplinary care are unable to provide adequate monitoring of patients' health. Passive in-home sensor systems enable 24×7 health monitoring. Combining sensor data with outcomes extracted from the electronic health record (EHR) through a supervised machine learning algorithm may enable health care providers to predict and ultimately slow decline among people living with ALS.<br><br>OBJECTIVE: This study aims to describe a federated approach to assimilating sensor and EHR data in a machine learning algorithm to predict decline among people living with ALS.<br><br>METHODS: Sensor systems have been continuously deployed in the homes of 4 participants for up to 330 days. Sensors include bed, gait, and motion sensors. Sensor data are subjected to a multidimensional streaming clustering algorithm to detect changes in health status. Specific health outcomes are identified in the EHR and extracted via the REDCap (Research Electronic Data Capture; Vanderbilt University) Fast Healthcare Interoperability Resource directly into a secure database.<br><br>RESULTS: As of this writing (fall 2024), machine learning algorithms are currently in development to predict those health outcomes from sensor-detected changes in health status. This methodology paper presents preliminary results from one participant as a proof of concept. The participant experienced several notable changes in activity, fluctuations in heart rate and respiration rate, and reductions in gait speed. Data collection will continue through 2025 with a growing sample.<br><br>CONCLUSIONS: The system described in this paper enables tracking the health status of people living with ALS at unprecedented levels of granularity. Combined with tightly integrated EHR data, we anticipate building predictive models that can identify opportunities for health care services before adverse events occur. We anticipate that this system will improve and extend the lives of people living with ALS.<br><br>DERR1-10.2196/60437.}, }
@article {pmid40072375, year = {2025}, author = {Gong, Z and Ba, L and Li, Z and Hou, H and Zhang, M}, title = {CD16[-]CD56[bright] NK Cells: A Protective NK Cell Subset for Progression and Prognosis in Amyotrophic Lateral Sclerosis.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1597}, pmid = {40072375}, issn = {2152-5250}, abstract = {Amyotrophic lateral sclerosis (ALS) is a non-neuron-autonomous disease where peripheral immune dysregulation significantly impacts disease progression. However, the immunopathological mechanisms of natural killer (NK) cells in ALS remain largely unexplored. This study enrolled 241 ALS patients and 102 healthy controls (HC), analyzing lymphocyte subsets, including T cells, B cells, and NK cells. A sub-cohort of 81 ALS patients was followed up for one year at three-month intervals. Linear mixed and Cox proportional hazards models were used to evaluate the association between lymphocyte subsets and ALS progression and prognosis. Our results revealed significant reductions in total T cells, helper T cells (Th), and NK cells in ALS patients compared to HC (P &amp;;lt 0.05). Slow-progressing ALS patients exhibited higher counts of total T cells, Th, CD16-CD56[bright] NK cells, and CD16[+]CD56[bright] NK cells, while showing lower counts of CD16[+]CD56[dim] NK cells compared to fast-progressing ALS patients (P &amp;;lt 0.05). ALS patients with lower CD16[-]CD56[bright] NK cell counts experienced a faster decline in motor function than those with higher counts (P &amp;;lt 0.05). Elevated CD16[-]CD56[bright] NK cell counts were associated with improved ALS prognosis (HR, 0.73; 95% CI: 0.60-0.90; P &amp;;lt 0.05). This study suggests that CD16[-]CD56[bright] NK cells play a protective role in ALS progression and prognosis, offering a potential therapeutic target for ALS.}, }
@article {pmid40072076, year = {2025}, author = {Calvo, B and Schembri-Wismayer, P and Durán-Alonso, MB}, title = {Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.}, journal = {Cells}, volume = {14}, number = {5}, pages = {}, pmid = {40072076}, issn = {2073-4409}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Aging/pathology ; Animals ; Stem Cells/metabolism ; Neurogenesis ; }, abstract = {Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.}, }
@article {pmid40070688, year = {2025}, author = {Hosseini Faradonbeh, SM and Seyedalipour, B and Keivan Behjou, N and Rezaei, K and Baziyar, P and Hosseinkhani, S}, title = {Structural insights into SOD1: from in silico and molecular dynamics to experimental analyses of ALS-associated E49K and R115G mutants.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1532375}, pmid = {40070688}, issn = {2296-889X}, abstract = {Protein stability is a crucial characteristic that influences both protein activity and structure and plays a significant role in several diseases. Cu/Zn superoxide dismutase 1 (SOD1) mutations serve as a model for elucidating the destabilizing effects on protein folding and misfolding linked to the lethal neurological disease, amyotrophic lateral sclerosis (ALS). In the present study, we have examined the structure and dynamics of the SOD1 protein upon two ALS-associated point mutations at the surface (namely, E49K and R115G), which are located in metal-binding loop IV and Greek key loop VI, respectively. Our analysis was performed through multiple algorithms on the structural characterization of the hSOD1 protein using computational predictions, molecular dynamics (MD) simulations, and experimental studies to understand the effects of amino acid substitutions. Predictive results of computational analysis predicted the deleterious and destabilizing effect of mutants on hSOD1 function and stability. MD outcomes also indicate that the mutations result in structural destabilization by affecting the increased content of β-sheet structures and loss of hydrogen bonds. Moreover, comparative intrinsic and extrinsic fluorescence results of WT-hSOD1 and mutants indicated structural alterations and increased hydrophobic surface pockets, respectively. As well, the existence of β-sheet-dominated structures was observed under amyloidogenic conditions using FTIR spectroscopy. Overall, our findings suggest that mutations in the metal-binding loop IV and Greek key loop VI lead to significant structural and conformational changes that could affect the structure and stability of the hSOD1 molecule, resulting in the formation of toxic intermediate species that cause ALS.}, }
@article {pmid40069959, year = {2025}, author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C}, title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2475893}, pmid = {40069959}, issn = {2167-9223}, abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.}, }
@article {pmid40069809, year = {2025}, author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H}, title = {Nursing contribution to end-of-life care decision-making in patients with neurological diseases on an acute hospital ward: documentation of signs and symptoms.}, journal = {BMC nursing}, volume = {24}, number = {1}, pages = {271}, pmid = {40069809}, issn = {1472-6955}, support = {71545//Icelandic Nurses Association/ ; }, abstract = {BACKGROUND: Recognizing impending death in patients with neurological diseases presents challenges for nurses and other healthcare professionals. This study aimed to identify nursing contribution to end-of-life (EOL) care decision-making for patients with neurological diseases in an acute hospital ward and to compare signs and symptoms among subgroups of patients.<br><br>METHODS: In this retrospective study, we analyzed data from 209 patient health records using the Neurological End-Of-Life Care Assessment Tool to evaluate the care in the last 3 to 7 days of life. Key aspects included the need for EOL care, EOL care decision-making, signs and symptoms of imminent death, and communication with relatives. The patient records pertain to patients who died in an acute neurological ward between January 2011 and August 2020; 123 with ischemic stroke, 48 with hemorrhagic stroke, 27 with amyotrophic lateral sclerosis [ALS], and 11 with Parkinson's disease or extrapyramidal and movement disorders [PDoed]. Both descriptive and inferential statistical analyses were performed to analyze the data.<br><br>RESULTS: Nurses identified the need for EOL care in 36% of cases and contributed to EOL decision-making as information brokers (15%), advocates (6%), and supporters (6%). They identified disease progression in 44% of the cases. The mean number of signs and symptoms in both the acute and progressive disease groups was 6.5 and ranged from 1 to 14. Patients with stroke without a documented EOL decision had more severe symptoms, including respiratory congestion (68%) and dyspnea (37%), than those with EOL decision. A higher frequency of no food intake was documented in patients with stroke receiving EOL care (p&#x2009;=&#x2009;0.007) compared to those without. Among patients with ALS or PDoed, those with EOL decision showed a trend toward a higher frequency of unconsciousness or limited consciousness than those without EOL decision (p&#x2009;=&#x2009;0.067). For all groups of patients, conversations with relatives occurred in 85% instances and family meetings in 93%.<br><br>CONCLUSIONS: Nurses made substantial contributions to EOL care decision-making for patients with neurological diseases. To improve early identification of imminent death in patients with neurological diseases in acute hospital wards, healthcare professionals must investigate barriers contributing to delayed recognition.<br><br>CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid40069360, year = {2025}, author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X}, title = {Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {748-756}, pmid = {40069360}, issn = {1546-1726}, support = {2019YFA0508701//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; 2022YFA1303300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; Rats ; Motor Neurons/metabolism/pathology ; *Electron Transport Complex IV/genetics ; *Mitochondria/metabolism/genetics ; Humans ; Disease Models, Animal ; Mutation/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS.}, }
@article {pmid40067829, year = {2025}, author = {O'Neill, K and Shaw, R and Bolger, I and ,  and Tam, OH and Phatnani, H and Gale Hammell, M}, title = {ALS molecular subtypes are a combination of cellular and pathological features learned by deep multiomics classifiers.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115402}, doi = {10.1016/j.celrep.2025.115402}, pmid = {40067829}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/classification ; Humans ; Neuroglia/pathology/metabolism ; Transcriptome/genetics ; Spinal Cord/pathology/metabolism ; Neurons/metabolism/pathology ; Deep Learning ; Microglia/pathology/metabolism ; Male ; DNA-Binding Proteins/metabolism/genetics ; Oxidative Stress ; Female ; Multiomics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes. Applying DANCer to an expanded cohort from the NYGC ALS Consortium highlights two subtypes that strongly correlate with disease duration: ALS-TE in cortex and ALS-Glia in spinal cord. Finally, single-nucleus transcriptomes demonstrate that ALS subtypes are recapitulated in neurons and glia, with both ALS-wide and subtype-specific alterations in all cell types. In summary, ALS molecular subtypes represent a combination of cellular and pathological features that correlate with clinical features of ALS.}, }
@article {pmid40067821, year = {2025}, author = {,  and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , }, title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1138-1149}, pmid = {40067821}, issn = {1538-3598}, abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.<br><br>OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.<br><br>CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n&#x2009;=&#x2009;120) or regimen-specific placebo (n&#x2009;=&#x2009;41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.<br><br>INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n&#x2009;=&#x2009;61), CNM-Au8 30 mg daily (n&#x2009;=&#x2009;59), or matching placebo (n&#x2009;=&#x2009;41) for 24 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.<br><br>RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n&#x2009;=&#x2009;120) vs placebo (n&#x2009;=&#x2009;163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).<br><br>CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.}, }
@article {pmid40067755, year = {2025}, author = {,  and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , }, title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.}, journal = {JAMA}, volume = {333}, number = {13}, pages = {1128-1137}, pmid = {40067755}, issn = {1538-3598}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.<br><br>OBJECTIVE: To determine the effects of pridopidine, a &#x3c3;1-receptor agonist, in ALS.<br><br>Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.<br><br>INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n&#x2009;=&#x2009;121) or matching oral placebo (n&#x2009;=&#x2009;42) for a planned duration of 24 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.<br><br>RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n&#x2009;=&#x2009;121; placebo, n&#x2009;=&#x2009;163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).<br><br>CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.}, }
@article {pmid40067754, year = {2025}, author = {,  and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S and , }, title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {40067754}, issn = {2168-6157}, abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.<br><br>OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.<br><br>Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.<br><br>INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.<br><br>MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.<br><br>RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability&#x2009;=&#x2009;0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.<br><br>CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.<br><br>TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.}, }
@article {pmid40066150, year = {2025}, author = {Stains, EL and Kennalley, AL and Tian, M and Boehnke, KF and Kraus, CK and Piper, BJ}, title = {Medical Cannabis in the United States: Comparing 2017 and 2024 State Qualifying Conditions to the 2017 National Academies of Sciences Report.}, journal = {Mayo Clinic proceedings. Innovations, quality &amp; outcomes}, volume = {9}, number = {2}, pages = {100590}, pmid = {40066150}, issn = {2542-4548}, abstract = {OBJECTIVE: To compare the 2017 National Academies of Sciences, Engineering, and Medicine cannabis report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 and 2024 and to determine the evidence level of the QCs approved in each state.<br><br>PATIENTS AND METHODS: The 2017 National Academies of Sciences (NAS) report assessed therapeutic evidence for over 20 medical conditions treated with MC. We identified the QCs of 38 states (including Washington DC) where MC was legal in 2024 and compared them to the QCs listed by these states in 2017. The QCs were then categorized on the basis of NAS-established levels of evidence: limited, moderate, or substantial/conclusive evidence of effectiveness, limited evidence of ineffectiveness, or no/insufficient evidence to support or refute effectiveness. This study was completed from January 31, 2023 to June 20,&#xa0;2024.<br><br>RESULTS: Most states listed at least one QC with substantial evidence-80.0% in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial/conclusive evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (long-term pain) was categorized by the NAS as having substantial evidence for effectiveness. However, 7 were rated as either ineffective (eg, glaucoma) or insufficient evidence.<br><br>CONCLUSION: Most QCs lack evidence for use on the basis of the 2017 NAS report. Many states recommend QCs with little evidence (amyotrophic lateral sclerosis) or even those for which MC is ineffective (depression). These findings highlight a disparity between state-level MC recommendations and the evidence to support them.}, }
@article {pmid40065593, year = {2025}, author = {Chen, S and Carter, D and Prier, J and Bingham, J and Patel, S and Kotay, M and Brockenbrough, PB and Gwathmey, K}, title = {Racial Disparities in ALS Progression: Time to Clinical Events Observed in a Single Center.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28390}, pmid = {40065593}, issn = {1097-4598}, abstract = {INTRODUCTION/AIMS: Studies examining racial differences in ALS have previously focused on diagnostic delay and disease severity. Time to critical clinical events has rarely been investigated, despite its importance in revealing differences in ALS patients' disease courses. This study explores racial disparities in time to specific clinical events in Black and non-Hispanic White ALS patients at a single center.<br><br>METHODS: We performed a retrospective analysis of 33 Black and 170 non-Hispanic White ALS patients examined at Virginia Commonwealth University between 2017 and 2023. Diagnosis dates, referral dates for wheelchair, noninvasive ventilation (NIV), augmentative and alternative communication (AAC) and hospice, along with demographic and clinical factors, were collected. We analyzed the racial difference for events occurring before or on the day of diagnosis using logistic regression models, and for events occurring after diagnosis using Cox proportional hazard models, adjusting for relevant demographic and clinical factors.<br><br>RESULTS: Black patients had significantly higher odds of acquiring a wheelchair (odds ratio&#x2009;=&#x2009;4.06, p&#x2009;=&#x2009;0.015) and NIV before diagnosis (odds ratio&#x2009;=&#x2009;2.93, p&#x2009;=&#x2009;0.017). Following diagnosis, Black patients had 1.72 times the hazards for wheelchair referral (p&#x2009;=&#x2009;0.051), 2.17 times the hazard for NIV referral (p&#x2009;<&#x2009;0.001), 1.84 times the hazard for AAC referral (p&#x2009;=&#x2009;0.034), and 1.59 times the hazard for hospice referral (p&#x2009;=&#x2009;0.24).<br><br>DISCUSSION: Our single-center findings demonstrate a large racial difference in time to clinical events for Black versus White ALS patients referred for NIV, AAC, hospice, and wheelchair, suggesting more advanced disease at the time of presentation or more rapid progression.}, }
@article {pmid40065553, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Walsh, T and McDermott, CJ and ,  and , }, title = {Further development of a patient-reported outcome measure to assess the impact of oral secretion problems in people living with MND.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2469721}, pmid = {40065553}, issn = {2167-9223}, abstract = {Objective: Oral secretion problems are common yet poorly managed in people living with MND (plwMND). A validated patient-reported outcome for measuring saliva symptoms in this patient group would facilitate better monitoring of individuals. This study aimed to assess the validity, reliability and sensitivity to change of a revised version of the clinical saliva score for MND (CSS-MNDr). Methods: Data were collected as part of a longitudinal, observational saliva management study. The CSS-MNDr, ALS Functional Rating Scale, a Global Rating of Change questionnaire and saliva-specific modified Likert scale were completed at each study visit, each of which probed the severity of saliva symptoms. Construct validity, test-retest reliability and sensitivity of the CSS-MNDr were assessed and the minimal important difference of the instrument was estimated. Results: The CSS-MNDr showed excellent test-retest reliability (intraclass correlation coefficient >0.9). Construct validity showed the CSS-MNDr performed as expected, with bulbar-onset participants scoring significantly higher than those who reported limb-onset across all visits (group mean scores). Strong correlation of total scores with the ALSFRS-R saliva question was demonstrated (-0.8), with the thick subscore correlating less well (-0.5). A minimal important difference in the range of -2.5 to -3.6 over 3 months was estimated for worsening symptoms. Conclusions: The CSS-MNDr has been validated as a reliable patient reported outcome for measuring saliva problems in plwMND. With separate scores for thick and thin secretion problems, the CSS-MNDr is the most comprehensive tool for assessing salivary problems in plwMND reported to date.}, }
@article {pmid40065552, year = {2025}, author = {Shibata, N and Kataoka, I and Okamura, Y and Murakami, K and Kato, Y and Yamamoto, T and Masui, K}, title = {Implications for soluble iron accumulation, oxidative stress, and glial glutamate release in motor neuron death associated with sporadic amyotrophic lateral sclerosis.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/neup.13033}, pmid = {40065552}, issn = {1440-1789}, abstract = {Oxidative stress in sporadic amyotrophic lateral sclerosis (ALS) has been evidenced by accumulation of oxidatively modified products of nucleic acids, lipids, sugars, and proteins in the motor neuron system of brains and spinal cords obtained at autopsy from the patients. We recently demonstrated soluble iron accumulation in activated microglia of sporadic ALS spinal cords. This finding could indicate that iron-mediated Fenton reaction is most likely to be responsible for oxidative stress associated with this disease. The excitatory amino acid neurotoxicity hypothesis for sporadic ALS has been proposed based on increased glutamate and aspartate concentrations in cerebrospinal fluid from the patients. Initially, the increase in extracellular excitatory amino acid levels was considered to reflect excessive release from the axon terminal of upper motor neurons. However, it is a question of whether the damaged upper motor neurons continue releasing glutamate even in advanced stage of this disease. To address this issue, we hypothesized that glial cells might be a glutamate release source. Our immunohistochemical analysis on autopsied human spinal cords revealed that ferritin, hepcidin, ferroportin, aconitase 1, tumor necrosis factor-α (TNF-α), TNF-α-converting enzyme (TACE), and glutaminase-C (GAC) were expressed mainly in microglia and that cystine/glutamate antiporter (xCT) was expressed mainly in astrocytes. We next performed cell culture experiments. Cultured microglia treated with soluble iron over-released glutamate and TNF-α via aconitase 1 and TACE, respectively. Cultured microglia treated with TNF-α over-released glutamate via GAC. Cultured microglia treated with hepcidin, of which expression is known to be upregulated by TNF-α, showed downregulated expression of ferroportin. Cultured astrocytes treated with hydrogen peroxide over-released glutamate via xCT. These observations provide in vivo and in vitro evidence that microglia and astrocytes are glutamate suppliers in response to soluble iron overload and oxidative stress, respectively, in sporadic ALS.}, }
@article {pmid40064496, year = {2025}, author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ}, title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.}, journal = {eNeuro}, volume = {12}, number = {3}, pages = {}, pmid = {40064496}, issn = {2373-2822}, abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.}, }
@article {pmid40064491, year = {2025}, author = {Izumi, Y and Nakayama, Y}, title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {3}, pages = {259-263}, doi = {10.11477/mf.188160960770030259}, pmid = {40064491}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Communication ; Patient Care Team ; }, abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.}, }
@article {pmid40063887, year = {2025}, author = {Hayden, CD and Murphy, BP and Gilsenan, D and Nasseroleslami, B and Hardiman, O and Murray, D}, title = {Clinical validation of a novel hand dexterity measurement device.}, journal = {PLOS digital health}, volume = {4}, number = {3}, pages = {e0000744}, pmid = {40063887}, issn = {2767-3170}, abstract = {The lack of sensitive objective outcome measures for hand dexterity is a barrier for clinical assessment of neurological conditions and has negatively affected clinical trials. Here, we clinically validate a new method for measuring hand dexterity, a novel hand worn sensor that digitises the Finger Tapping Test. The device was assessed in a cohort of 180 healthy controls and 51 people with Amyotrophic Lateral Sclerosis (ALS) and compared against rating scales and traditional measures (Nine Hole Peg test and grip dynamometry). 14 features were extracted from the device and using a logistic regression algorithm, a 0-100 dexterity performance score was generated for each participant, which accounted for age/sex differences. The device returned objective ratings of a participant's hand dexterity (dominant, non-dominant and overall score). The average overall dexterity performance score in all healthy participants was 88 ± 17 (mean ± standard deviation). The overall dexterity score was statistically significantly worse in participants with ALS (age/sex matched healthy subset: 80 ± 20, ALS: 45 ± 32, p-value < 0.0001). The device also had a higher completion rate, (94% dominant hand) compared to the traditional measures (82% dominant hand). This test and scoring system have been validated and the regression model was developed using a framework that is potentially applicable to any relevant condition. This device could act as an objective outcome measure in clinical trials and may be useful in improving patient care.}, }
@article {pmid40063831, year = {2025}, author = {Kubinski, S and Claus, L and Schüning, T and Zeug, A and Kalmbach, N and Staege, S and Gschwendtberger, T and Petri, S and Wegner, F and Claus, P and Hensel, N}, title = {Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddaf020}, pmid = {40063831}, issn = {1460-2083}, support = {ZE994//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.}, }
@article {pmid40061974, year = {2025}, author = {Zhang, ZN and Hao, L and Han, S and Li, SS and Lin, SX and Miao, YD}, title = {Harnessing the prognostic power of preoperative systemic immune-inflammation index/albumin ratio in hepatocellular carcinoma resection.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {102261}, pmid = {40061974}, issn = {1948-9366}, abstract = {The recent study by Chen et al, published in the World Journal of Gastroenterology, introduces a groundbreaking assessment tool-the preoperative systemic immune-inflammation index/albumin (SII/ALB) ratio-for patients with hepatocellular carcinoma (HCC) undergoing curative resection. This study not only establishes the independent prognostic significance of the SII/ALB ratio but also incorporates it into a predictive nomogram, enhancing its utility for clinical decision-making. The SII/ALB ratio, by integrating inflammatory and nutritional biomarkers, offers a novel lens through which the prognosis of HCC patients can be viewed, suggesting a more tailored approach to patient management. The development of the nomogram, validated for its accuracy in predicting patient outcomes, marks a pivotal advance, potentially guiding surgical decisions and postoperative care. However, the study's focus on a single-center cohort prompts the need for validation in a broader, more diverse patient population to ensure its applicability across various clinical settings. Moreover, longitudinal studies could elucidate the dynamic changes in SII/ALB post-surgery, offering insights into its potential as a continuous monitor for recurrence and long-term survival. This abstract aim to underscore the critical findings of Chen et al's study while calling for further research to explore the full potential of the SII/ALB ratio in the global management of hepatocellular carcinoma.}, }
@article {pmid40061972, year = {2025}, author = {Yi, XM and Cai, HQ and Jiao, Y}, title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {100257}, pmid = {40061972}, issn = {1948-9366}, abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.}, }
@article {pmid40061966, year = {2025}, author = {Wang, H and Jiao, Y and Ma, Q and Liu, YH}, title = {Overview of endoscopic biliary stenting in malignant obstructive jaundice.}, journal = {World journal of gastrointestinal surgery}, volume = {17}, number = {2}, pages = {103378}, pmid = {40061966}, issn = {1948-9366}, abstract = {This article discusses Wang et al's essay. Endoscopic biliary stenting, a less invasive alternative to surgery, is effective for malignant obstructive jaundice. This article summarizes the pathophysiology of biliary obstruction, the technical aspects of stenting, and the clinical outcomes. By comparison of endoscopic stenting with percutaneous biliary drainage, improvements and complications are focused on. Additionally, patient selection for stenting and future advancements in stent technology are important. Overall, endoscopic biliary stenting is a valuable palliative option for patients with malignant jaundice, especially those ineligibles for surgery.}, }
@article {pmid40060668, year = {2025}, author = {Axakova, A and Ding, M and Cote, AG and Subramaniam, R and Senguttuvan, V and Zhang, H and Weile, J and Douville, SV and Gebbia, M and Al-Chalabi, A and Wahl, A and Reuter, J and Hurt, J and Mitchell, A and Fradette, S and Andersen, PM and van Loggerenberg, W and Roth, FP}, title = {Landscapes of missense variant impact for human superoxide dismutase 1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060668}, issn = {2692-8205}, support = {RM1 HG010461/HG/NHGRI NIH HHS/United States ; UM1 HG011989/HG/NHGRI NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1. Diagnosis based on SOD1 sequencing can not only be definitive but also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging, given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over two thousand SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting 'missense variant effect maps' not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUS, offering the potential to identify additional patients who would benefit from therapy approved for SOD1-ALS.}, }
@article {pmid40060539, year = {2025}, author = {Petrescu, J and Roque, CG and Jackson, CA and Daly, A and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and McDade, K and Gregory, JM and Smith, C and Phatnani, H}, title = {Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.02.26.640433}, pmid = {40060539}, issn = {2692-8205}, abstract = {Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response. We also find that executive and language cognitive impairments differ from ALS without cognitive impairment, and from each other, in the extent and pattern of neuronal dysregulation and neuron-glial interactions across different brain regions. These findings reveal a relationship between cognitive phenotype and prefrontal cortex dysfunction in ALS.}, }
@article {pmid40060442, year = {2025}, author = {Deng, X and Bradshaw, G and Kalocsay, M and Mitchison, T}, title = {Tubulin Regulates the Stability and Localization of STMN2 by Binding Preferentially to Its Soluble Form.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40060442}, issn = {2692-8205}, support = {R35 GM131753/GM/NIGMS NIH HHS/United States ; }, abstract = {Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons is not known. STMN2 is known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons and showed that degradation occurs mainly by the ubiquitin-proteasome system. The membrane targeting N-terminal domain of STMN2 promoted fast turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted stabilization. Proximity labeling and imaging showed that STMN2 localizes to trans-Golgi network membranes and that tubulin binding reduces this localization. Pull-down assays showed that tubulin prefers to bind to soluble over membrane-bound STMN2. Our data suggest that STMN2 interconverts between a soluble form that is rapidly degraded unless bound to tubulin and a membrane-bound form that does not bind tubulin. We propose that STMN2 is sequestered and stabilized by tubulin binding, while its neuroprotective function depends on an unknown molecular activity of its membrane-bound form.}, }
@article {pmid40060160, year = {2025}, author = {Mangalindan, KE and Wyatt, TR and Brown, KR and Shapiro, M and Maggio, LA}, title = {Investigating the Road to Equity: A Scoping Review of Solutions to Mitigate Implicit Bias in Assessment within Medical Education.}, journal = {Perspectives on medical education}, volume = {14}, number = {1}, pages = {92-106}, pmid = {40060160}, issn = {2212-277X}, mesh = {Humans ; *Education, Medical/methods ; Bias ; Educational Measurement/methods ; }, abstract = {INTRODUCTION: In medical education, assessments have high-stakes implications. Yet, assessments are rife with unconscious bias, which contributes to inequitable social structures. Implicit bias in assessment must be addressed because medical educators use assessments to guide learning and promote development of physicians' careers. In this scoping review, the authors map the literature on implicit bias in assessment, as it applies to: 1) the types of implicit bias addressed, 2) the targets and types of interventions studied or proposed, and 3) how publications describe intervention efficacy.<br><br>METHODS: The authors conducted a scoping review of the literature on interventions to mitigate implicit bias that was published between January 2010 and August 2023. Author pairs independently screened articles for inclusion and extracted data. Discrepancies were resolved with discussion and consensus. Qualitative and quantitative analysis was informed by Anderson et al's three assessment orientations: fairness, assessment for inclusion (AfI), and justice.<br><br>RESULTS: 7,831 articles were identified; 54 articles were included. The majority (n = 37; 69%) of articles focus on implicit bias toward those underrepresented in medicine. Interventions to mitigate implicit bias were targeted toward admissions and applications, faculty training, recruitment, summative assessments, and evaluation templates. Interventions had fairness (n = 43; 96%) and AfI (n = 22; 49%) orientations; no articles used a justice-orientation. For the sub-set of research studies (n = 40), almost all (n = 34; 85%) examined a single program/institution.<br><br>DISCUSSION: This scoping review showed that more work is necessary to address different types of implicit biases, move scholarship beyond single-institution studies, refine existing interventions, and evaluate how efficacy is defined.}, }
@article {pmid40059194, year = {2025}, author = {Shang, Q and Zhou, J and Ye, J and Chen, M}, title = {Adverse events reporting of edaravone: a real-world analysis from FAERS database.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {8148}, pmid = {40059194}, issn = {2045-2322}, mesh = {*Edaravone/adverse effects/therapeutic use ; Humans ; *Adverse Drug Reaction Reporting Systems ; *Databases, Factual ; United States ; United States Food and Drug Administration ; Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Drug-Related Side Effects and Adverse Reactions ; Female ; Male ; }, abstract = {For individuals with amyotrophic lateral sclerosis (ALS), intravenous edaravone is approved as a disease-modifying medication; yet, there have been many reports of adverse events (AEs). We examined the AEs associated with edaravone in this study using actual data from the FDA's (Food and Drug Administration) adverse event reporting system (FAERS). By extracting large-scale data from the FAERS database, this study used the signals of edaravone-associated AEs were quantified using the multiitem gamma Poisson shrinker (MGPS) method based on disproportionality, the Bayesian confidence propagation neural network (BCPNN), the reporting odds ratio (ROR), and the proportional reporting ratio (PRR). In the FAERS database, this study extracted data between April 2017 and March 2024, and edaravone was identified as the "primary suspect (PS)" in 2,986 AE reports. AEs associated with edaravone specifically targeted 27 system organ types (SOCs). Unexpectedly serious AEs that weren't mentioned in the drug insert, include abnormal hepatic function, catheter site thrombosis, pain, cerebral hemorrhage, infection, cerebral infarction, poor venous access, disseminated intravascular coagulation, vein collapse and cerebral venous sinus thrombosis. Our research found possible signals of new AEs that may offer substantial backing for clinical surveillance and edaravone risk assessment, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instruction.}, }
@article {pmid40030015, year = {2025}, author = {Johnson, EA and Nowar, R and Viola, KL and Huang, W and Zhou, S and Bicca, MA and Zhu, W and Kranz, DL and Klein, WL and Silverman, RB}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {10}, pages = {e2402117122}, pmid = {40030015}, issn = {1091-6490}, support = {R01 AG061708/AG/NIA NIH HHS/United States ; R56 AG050492/AG/NIA NIH HHS/United States ; AG061708//HHS | National Institutes of Health (NIH)/ ; AG050492//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Amyloid beta-Peptides/metabolism ; Animals ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; Neurons/metabolism/drug effects ; Mice ; Hippocampus/metabolism/pathology ; Alzheimer Disease/metabolism/drug therapy/pathology ; Lysosomes/metabolism ; Protein Aggregation, Pathological/metabolism/drug therapy ; Autophagy/drug effects ; }, abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, }
@article {pmid40057796, year = {2025}, author = {Mitra, J and Kodavati, M and Dharmalingam, P and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML}, title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {54}, pmid = {40057796}, issn = {2051-5960}, support = {R03AG064266/AG/NIA NIH HHS/United States ; R03AG064266/AG/NIA NIH HHS/United States ; RF1NS112719/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Disease Models, Animal ; *DNA Repair ; *Gene Knock-In Techniques ; *Cellular Senescence/physiology ; Motor Neurons/metabolism/pathology ; Mice, Transgenic ; Inflammation/metabolism/pathology/genetics ; DNA Ligase ATP/metabolism/genetics ; }, abstract = {TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.}, }
@article {pmid40057753, year = {2025}, author = {Sharbafshaaer, M and Siciliano, M and Passaniti, C and Sant'Elia, V and Silvestro, M and Russo, A and Esposito, S and Tedeschi, G and Trojano, L and Trojsi, F}, title = {Screening of visuospatial abilities in amyotrophic lateral sclerosis (ALS): a pilot study using the battery for visuospatial abilities (BVA).}, journal = {Orphanet journal of rare diseases}, volume = {20}, number = {1}, pages = {110}, pmid = {40057753}, issn = {1750-1172}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Neuropsychological Tests ; Visual Perception/physiology ; }, abstract = {BACKGROUND: Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC).<br><br>METHODS: Twenty-three patients with early ALS and 23 age- and education-matched HC underwent the Battery for Visuospatial Abilities (BVA), including 4 visuo-perceptual and 4 visuo-representational subtests.<br><br>RESULTS: When compared to HC, ALS scored worse in 2 visuo-perceptual subtests (i.e., Line Length Judgment and Line Orientation Judgment) and 1 visuo-representational tasks (i.e., Hidden Figure Identification, HFI) (p&#x2009;<&#x2009;0.01). No correlations arose between ALS clinical features and BVA performance. More than 80% of the ALS cohort obtained abnormal scores in the HFI subtest.<br><br>CONCLUSIONS: Our findings revealed that patients with ALS scored worse (compared to HC) on selective tests tapping "perceptual" and "representational" visuospatial abilities, since the early stages of disease. In clinical practice, our findings highlight the need for multi-domain neuropsychological assessment, for monitoring disease courses and properly organizing care management of patients with ALS.}, }
@article {pmid40057669, year = {2025}, author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX}, title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.}, journal = {Therapeutic innovation &amp; regulatory science}, volume = {}, number = {}, pages = {}, pmid = {40057669}, issn = {2168-4804}, abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).<br><br>METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).<br><br>CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.}, }
@article {pmid40056685, year = {2025}, author = {Jakhar, M and Barone, V}, title = {Single atom catalysts adsorbed on reduced monolayers for enhanced kinetics in Al-S batteries.}, journal = {Journal of colloid and interface science}, volume = {689}, number = {}, pages = {137226}, doi = {10.1016/j.jcis.2025.03.015}, pmid = {40056685}, issn = {1095-7103}, abstract = {Rechargeable aluminum-sulfur (Al-S) batteries have attracted significant attention as potential next-generation energy storage devices due to their safety, the natural abundance of the elemental components, and high theoretical energy density. However, their utilization is hindered by sluggish reaction kinetics and poor reversibility. Introducing single-atom catalysts (SACs) can promote redox processes at the cathode and help in mitigating the shuttle effect of Al polysulfides (Al2Sx). While the electrochemical, thermodynamic, and thermal stabilities of SACs (Co, Fe, Ir, Ni, Pt, and Rh) have been explored in previous studies, this work focuses on their potential role in enhancing reaction kinetics in Al-S batteries. Our calculations indicate that SACs-based substrates exhibit more robust binding energies for capturing Al2Sx than the bare surfaces. Additionally, SACs lower the free energies associated with the rate-determining step during discharging and exhibit lower decomposition barriers during charging. Moreover, the interaction of soluble Al2Sx with the electrolyte reveals that SAC supported polysulfides are less likely to dissolve in the electrolyte than their pristine counterparts. The analysis of the underlying mechanisms of the interaction of molecules and the Co@ substrate reveals the ability of this substrate to accommodate large volume changes and support a sulfur loading up to 53.37 wt% during the charging and discharging cycles, without causing fractures. The mechanism driving this enhanced performance is extensively investigated through charge transfer, bond strength, and d-band center analyses. Our findings present an effective strategy for designing SACs substrates to improve the electrochemical performance of Al-S cathodes.}, }
@article {pmid40056552, year = {2025}, author = {Newell, ME and Babbrah, A and Aravindan, A and Kulkarni, S and Ellershaw, A and Dupati, A and Rathnam, R and Shaffer, G and Estrada, L and Curtis, C and Leneaux, J and Driver, EM and Halden, RU}, title = {Wastewater-borne markers of neurodegenerative disease: β-methylamino-L-alanine and aminomethylphosphonic acid.}, journal = {The Science of the total environment}, volume = {970}, number = {}, pages = {179032}, doi = {10.1016/j.scitotenv.2025.179032}, pmid = {40056552}, issn = {1879-1026}, mesh = {*Wastewater/chemistry ; *Amino Acids, Diamino/analysis ; *Biomarkers/analysis ; *Water Pollutants, Chemical/analysis ; *Neurodegenerative Diseases/epidemiology ; Cyanobacteria Toxins ; Glycine/analogs &amp; derivatives/analysis ; Organophosphonates/analysis ; Tandem Mass Spectrometry ; Humans ; Environmental Monitoring ; Chromatography, Liquid ; Glyphosate ; }, abstract = {Exposure to toxic organic chemicals such as β-methylamino-L-alanine (BMAA) and glyphosate has been associated with neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). We explored the utility of BMAA and glyphosate's metabolite aminomethylphosphonic acid (AMPA) for serving as potential markers of NDDs by comparing levels of wastewater-borne BMAA and AMPA with regional U.S. rates of NDD prevalence. Newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were applied to U.S. wastewater samples (n = 87) and resultant concentrations of putative biomarkers were statistically compared to NDD prevalence rates in conjunction with environmental data on algal blooms and agricultural glyphosate use. Locations of algal blooms were found to be significantly associated (p = 0.01) with ALS prevalence rates per 100,000 people. BMAA levels in wastewater were highly correlated (p < 0.0001) with ALS prevalence rates by region. BMAA in wastewater typically peaked in summer months. We conclude that NDD biomarker detection in wastewater holds potential value, with BMAA outperforming AMPA. Furthermore, prevalence data for NDDs may have to be reported to the Centers for Disease Control and Prevention at a higher geospatial resolution to further enhance the value for the present type of analysis. Further method development is needed for AMPA to be quantified using LC-MS/MS. Future method developments focusing on metabolites (e.g., AMPA) may enable epidemiologists to determine human exposure levels rather than the mere occurrence of toxic organic chemicals in the environment.}, }
@article {pmid40056503, year = {2025}, author = {Zhan, A and Zhong, K and Zhang, K}, title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151582}, doi = {10.1016/j.bbrc.2025.151582}, pmid = {40056503}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Proteostasis ; Animals ; Mitochondria/metabolism ; Protein Aggregates ; Homeostasis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.}, }
@article {pmid40056413, year = {2025}, author = {Kahn, OI and Dominguez, SL and Glock, C and Hayne, M and Vito, S and Sengupta Ghosh, A and Adrian, M and Burgess, BL and Meilandt, WJ and Friedman, BA and Hoogenraad, CC}, title = {Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.}, journal = {Cell reports}, volume = {44}, number = {3}, pages = {115382}, doi = {10.1016/j.celrep.2025.115382}, pmid = {40056413}, issn = {2211-1247}, mesh = {Animals ; *Neurofilament Proteins/metabolism ; *Neurons/metabolism/pathology ; Mice ; *Myeloid Cells/metabolism ; *Mice, Knockout ; Microglia/metabolism/pathology ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Neuroinflammatory Diseases/metabolism/pathology ; Mice, Inbred C57BL ; Humans ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Macrophages/metabolism ; Calpain/metabolism ; }, abstract = {Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.}, }
@article {pmid40056296, year = {2025}, author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Liu, M and Zhang, M}, title = {Association between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis.}, journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society}, volume = {}, number = {}, pages = {}, pmid = {40056296}, issn = {1619-1560}, support = {82271478//the National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; }, abstract = {PURPOSE: The aim of this study was to investigate the relationship between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: The heart activity of 65 patients with ALS (28 with normal cognition [ALS-CN]; 37 with impaired cognition [ALS-CI]) and 38 healthy controls (HCs) was measured by 24-h Holter monitoring. Heart rate (HR) measures and heart rate variability (HRV) parameters were compared between the three study groups and, additionally, correlated with five Edinburgh Cognitive and Behavioral ALS Screen (ECAS) domains in the ALS subgroups. Age, gender, and educational level were adjusted. Factors associated with cognitive status were assessed using logistic regression. Survival predictors in patients with ALS were analyzed using the Kaplan-Meier estimator and Cox regression.<br><br>RESULTS: Compared to the HCs, patients with ALS-CI exhibited lower RRI (R-R-interval; P&#x2009;=&#x2009;0.017), SDNN (standard deviation of all normal RR intervals; P&#x2009;=&#x2009;0.013), SDNN Index (P&#x2009;=&#x2009;0.044), and VLF power (very low-frequency power; P&#x2009;=&#x2009;0.012). Total power was reduced in the ALS-CI group compared to the HCs (P&#x2009;=&#x2009;0.036) and ALS-CN group (P&#x2009;=&#x2009;0.048). In patients with ALS-CN, language negatively correlated with mean HR (P&#x2009;=&#x2009;0.001) and positively with the RRI (P&#x2009;=&#x2009;0.003), SDNN (P&#x2009;=&#x2009;0.001), SDANN (standard deviation of the average NN intervals; P&#x2009;=&#x2009;0.005), total power (P&#x2009;=&#x2009;0.006), VLF power (P&#x2009;=&#x2009;0.011), and low-frequency power (P&#x2009;=&#x2009;0.026). Visuospatial function correlated positively with the SDNN Index (P&#x2009;=&#x2009;0.041). In patients with ALS-CI, executive function (P&#x2009;=&#x2009;0.015) and ECAS total score (P&#x2009;=&#x2009;0.009) negatively correlated with the RMSSD (square root of mean sum-of-squares of differences between adjacent NN intervals), while visuospatial function correlated positively with normalized LF value (LFnu; P&#x2009;=&#x2009;0.049). No associations were observed between the other cognitive domains and any of the 14 HRV/HR measures in patients with either ALS-CI or ALS-CN. SDNN&#x2009;&#x2264;&#x2009;100&#xa0;ms was linked to cognitive impairment (P&#x2009;=&#x2009;0.039) and also showed a borderline association (P&#x2009;=&#x2009;0.066) with poorer survival, while cognitive impairment (P&#x2009;=&#x2009;0.010) was significantly linked to worse outcomes.<br><br>CONCLUSIONS: Patients with ALS with cognitive impairment demonstrated reduced cardiac autonomic modulations and altered cognitive autonomic associations. Cognitive impairment was linked to reduced survival, with baseline SDNN&#x2009;&#x2264;&#x2009;100&#xa0;ms identified as a potential marker.}, }
@article {pmid40056187, year = {2025}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, &#xd6; and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Correction: Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {272}, number = {4}, pages = {259}, doi = {10.1007/s00415-025-12952-1}, pmid = {40056187}, issn = {1432-1459}, }
@article {pmid40055545, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Author Correction: Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {913}, doi = {10.1038/s41593-025-01926-1}, pmid = {40055545}, issn = {1546-1726}, }
@article {pmid40054065, year = {2025}, author = {Tserennadmid, B and Nam, MK and Park, JH and Rhim, H and Kang, S}, title = {HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).}, journal = {Biochemical and biophysical research communications}, volume = {756}, number = {}, pages = {151533}, doi = {10.1016/j.bbrc.2025.151533}, pmid = {40054065}, issn = {1090-2104}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; Humans ; *Protein Aggregates ; *Proteolysis ; *Mutation ; Fluorescence Resonance Energy Transfer ; Heat-Shock Proteins/metabolism/genetics/chemistry ; Protein Folding ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) protein aggregates in motor neurons, leading to progressive motor dysfunction and ultimately death. While the molecular chaperone heat shock protein 104 (Hsp104) has been shown to reduce protein misfolding by disaggregating protein aggregates, fully degrading these disaggregated proteins remains a significant challenge. In this study, we have investigated the effects of Hsp104 and its hyperactive variant, HAP, in combination with caseinolytic protease P (CIpP), on the disaggregation and degradation of SOD1 aggregates. Using laser confocal microscopy, fluorescence loss in photobleaching (FLIP), and biomolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assays, we demonstrate that Hsp104 effectively disaggregates SOD1 aggregates across 14 different G93 mutants, classified based on the properties of substituted amino acids, thus restoring protein mobility. Notably, the HAP/CIpP system not only disaggregates ALS-associated SOD1[G93A] aggregates but also promotes their proteolytic degradation, as evidenced by a significant reduction in high-order oligomers observed through BiFC and FRET assays. This dual mechanism of action presents. the HAP/CIpP system holds significant therapeutic potential for ALS and other neurodegenerative diseases characterized by protein aggregates, as it enables both effective disaggregation and degradation of toxic protein aggregates, thereby maintaining protein homeostasis.}, }
@article {pmid40053600, year = {2025}, author = {Nie, Y and Szebényi, K and Wenger, LMD and Lakatos, A and Chinnery, PF}, title = {Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.}, journal = {Science advances}, volume = {11}, number = {10}, pages = {eadr0690}, pmid = {40053600}, issn = {2375-2548}, mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA, Mitochondrial/genetics ; *Organoids/metabolism/pathology ; *Mutation ; *Brain/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Astrocytes/metabolism/pathology ; Mitochondria/genetics/metabolism ; DNA Repeat Expansion/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.}, }
@article {pmid40053462, year = {2025}, author = {Fazzini, L and Martis, A and Pateri, MI and Maccabeo, A and Borghero, G and Puligheddu, M and Montisci, R and Marchetti, MF}, title = {Long-term outcomes and worse clinical course in Takotsubo syndrome patients with amyotrophic lateral sclerosis.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {26}, number = {4}, pages = {184-190}, doi = {10.2459/JCM.0000000000001711}, pmid = {40053462}, issn = {1558-2035}, mesh = {Humans ; *Takotsubo Cardiomyopathy/mortality/epidemiology/complications/physiopathology/diagnosis/therapy ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/complications/epidemiology/therapy/physiopathology ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; Time Factors ; Prevalence ; Aged, 80 and over ; Hospital Mortality ; Risk Factors ; Prognosis ; Cause of Death ; Risk Assessment ; Respiration, Artificial/statistics &amp; numerical data ; Shock, Cardiogenic/mortality/epidemiology/etiology/therapy/diagnosis ; }, abstract = {AIMS: Takotsubo syndrome (TTS) is usually triggered by either physical/psychological stressors or comorbidities, neurological among others. The prevalence of amyotrophic lateral sclerosis (ALS) among TTS and whether it has a worse clinical course is not known. We aim to describe ALS prevalence and its impact on clinical presentation, clinical course, and long-term mortality.<br><br>METHODS: We retrospectively screened the overall TTS population admitted and followed up at our institution between 2007 and 2020. Clinical, electrocardiographic, and echocardiographic data were collected. Kaplan-Meier method was applied for time-to-event analysis to assess the outcome of interest of all-cause death.<br><br>RESULTS: Eighty-five patients with TTS were included in our study. Overall, the mean age was 70&#x200a;&#xb1;&#x200a;12&#x200a;years, 86% were females. Six patients (7% prevalence) were affected by ALS. At admission, patients with ALS were more likely to present left ventricular systolic dysfunction (P&#x200a;=&#x200a;0.007). The clinical course of ALS patients was more likely complicated by cardiogenic shock (P&#x200a;=&#x200a;0.003) which required catecholamines infusion (P&#x200a;=&#x200a;0.001) and mechanical ventilation (P&#x200a;=&#x200a;0.009). Despite similar in-hospital mortality rates, ALS patients exhibited significantly elevated all-cause mortality during a median 6-year follow-up (hazard ratio, 19.189, 95% confidence interval 5.639-65.296, log-rank test P&#x200a;<&#x200a;0.001) with significantly shorter hospitalization to death time (P&#x200a;=&#x200a;0.039).<br><br>CONCLUSIONS: Our findings highlight a notable prevalence of ALS among TTS patients, with worse clinical presentation and in-hospital course in ALS-affected individuals. While in-hospital mortality rates were comparable, highlighting the reversible nature of TTS in both groups, long-term follow-up revealed significantly heightened all-cause mortality in ALS patients, emphasizing the impact of ALS on patient prognosis.}, }
@article {pmid40051750, year = {2025}, author = {Dib, A and Salem, J and Fares, M}, title = {Recurrent Spontaneous Pneumothorax in the Setting of Amyotrophic Lateral Sclerosis.}, journal = {European journal of case reports in internal medicine}, volume = {12}, number = {3}, pages = {005151}, pmid = {40051750}, issn = {2284-2594}, abstract = {UNLABELLED: Spontaneous pneumothorax (SP) occurrence in amyotrophic lateral sclerosis (ALS) patients is relatively rare and may thus be under-recognised. This latter is a progressive neurodegenerative disorder, leading to muscle weakness and such respiratory complications. This article reports a case manifesting such a rare association.<br><br>LEARNING POINTS: The presence of spontaneous pneumothorax in amyotrophic lateral sclerosis patients can exacerbate respiratory insufficiency, leading to acute respiratory failure.Given the under-recognition of this latter complication, clinicians should maintain a high index of suspicion, especially in patients with amyotrophic lateral sclerosis presenting with sudden onset of dyspnoea or chest pain.Early detection and appropriate management are crucial to prevent further respiratory compromise.}, }
@article {pmid40051509, year = {2025}, author = {Syed, SA and Singh, J and Elkholy, H and Rojnić Palavra, I and Tomicevic, M and Eric, AP and Pinto da Costa, M and Guloksuz, S and Radhakrishnan, R}, title = {International perspectives on physician knowledge, attitudes, and practices related to medical cannabis.}, journal = {Frontiers in public health}, volume = {13}, number = {}, pages = {1463871}, pmid = {40051509}, issn = {2296-2565}, support = {UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Medical Marijuana/therapeutic use ; Female ; Cross-Sectional Studies ; Male ; Adult ; *Health Knowledge, Attitudes, Practice ; *Physicians/psychology/statistics &amp; numerical data ; Surveys and Questionnaires ; *Attitude of Health Personnel ; Middle Aged ; Internationality ; Practice Patterns, Physicians'/statistics &amp; numerical data ; }, abstract = {BACKGROUND: The trends of recreational use of cannabis and the use of cannabis for medical indications (i.e., "medical cannabis") have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making, and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there is growing evidence of negative health outcomes related to the use of cannabis. In this rapidly shifting landscape, the role of physician attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis.<br><br>METHODS: We conducted a cross-sectional survey of physicians from 17 countries between 2016 and 2018. The survey consisted of questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify the predictors of physician willingness to recommend medical cannabis.<br><br>RESULTS: A total of 323 physicians responded to the survey, among which 53% were women. The mean age was 35.4&#x202f;&#xb1;&#x202f;9.5&#x202f;years, with 10.04&#x202f;&#xb1;&#x202f;8.6&#x202f;years of clinical experience. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis and 33% noted inadequate knowledge regarding medical cannabis). The majority of respondents (84%) recognized the risk of psychosis with cannabis use, while only 23% correctly identified the risk of addiction with daily cannabis use. Overall, willingness to recommend medical cannabis was the highest for chemotherapy-induced nausea (67%), refractory chronic neuropathic pain (52%), and spasticity in amyotrophic lateral sclerosis (ALS; 51%).<br><br>CONCLUSION: This international study examining physician knowledge, attitudes, and practices related to medical cannabis revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is a wide variability in willingness to recommend medical cannabis, which is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.}, }
@article {pmid40050936, year = {2025}, author = {Jeejan, J and Rao, L and Sadasivan, S and Lopes, R and Dsouza, N}, title = {Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis.}, journal = {Genomics &amp; informatics}, volume = {23}, number = {1}, pages = {7}, pmid = {40050936}, issn = {1598-866X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease prevalent in American and European populations, with its onset and progression significantly influenced by mutations in the superoxide dismutase 1 (SOD1) protein. While previous studies have highlighted the effects of mutations in the metal-binding region and catalytic region and dimerisation of SOD1, the impact of mutations involving the Cysteine residue at the N-terminal end remains unexplored. This study investigates the effects of Cysteine-to-Trp, Phe, Ser, and Gly mutations at the 6th position of SOD1's N-terminal end on its structural dynamics and functional impairment. Our computational analysis using PolyPhen-2, PROVEAN, Meta-SNP, and PhD-SNP predicted mutations to be deleterious, with their negative impacts likely contributing to disease development. Furthermore, stability studies and bonding pattern changes due to the mutations, analysed by mCSM, SDM, DUET, Dynamut2, and PremPS revealed changes in free energy and disruption in intramolecular interactions. The molecular dynamics studies revealed distinct changes in stability patterns among the mutations, particularly in Cys6Trp and Cys6Phe. All the mutations primarily altered the catalytic region of the protein; additionally, Cys6Phe and Cys6Gly caused disruption in the metal-binding region. The impact of mutations on the dimerisation of SOD1, analysed using MM/PBSA showed destabilisation due to Cys6Phe mutation. These findings provide molecular insights into the clinical symptoms observed in patients, highlighting the critical impact of the Cys6Phe mutation on the metal-binding and catalytic loops of SOD1 along with destabilisation of dimer formation. Overall, our analysis offers valuable insights into the molecular mechanisms driving structural changes in SOD1 due to mutations, contributing to a deeper understanding of their role in ALS pathogenicity.}, }
@article {pmid40050651, year = {2025}, author = {Gregorio-Sanz, M&#xc1; and Marzo-Campos, JC and Segura-Heras, JV}, title = {Effects of nursing music intervention on cardiovascular patients transferred in advanced life support ambulances.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7919}, pmid = {40050651}, issn = {2045-2322}, support = {PROMETEO/2021/063//Generalitat Valenciana/ ; }, mesh = {Humans ; Male ; Female ; Aged ; *Ambulances ; *Music Therapy/methods ; *Cardiovascular Diseases/therapy/prevention &amp; control ; Middle Aged ; Case-Control Studies ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Blood Pressure ; }, abstract = {Patients with acute cardiovascular disease require out-of-hospital care during the most critical and vulnerable periods of their illness. This study aims to evaluate the influence of musical intervention in patients with acute cardiovascular disease during transfer in Advanced Life Support (ALS) ambulances using an analytical randomized controlled case-control experimental study conducted according to CONSORT guidelines. Forty-one subjects took part in the study. The patients required the administration of nitrates/antiarrhythmics (n = 11, 26.8%), (n = 5, 12.2%) antiemetics, and (n = 7, 17.1%) opioids. Statistically significant differences were found for blood pressure and the variable cardiovascular drugs between groups. The use of music therapy to complement other health measures in ALS ambulances lowers blood pressure values and reduces the need to administrate cardiovascular drugs, thus avoiding their possible side effects. It is easy to implement, has a low cost and should be monitored and controlled as a specific nursing intervention, included in the care of patients transferred by ambulances on a routine basis.}, }
@article {pmid40050016, year = {2025}, author = {Martin, J and Johnson, R and Yemane, L and Unaka, N and Ebo, C and Hippolyte, J and Jones, M and Quinn, M and Barber, A and Floyd, B and Blankenburg, R and Hilgenberg, SL}, title = {Multi-institutional exploration of pediatric residents' perspectives on anti-racism curricula: a qualitative study.}, journal = {Medical education online}, volume = {30}, number = {1}, pages = {2474134}, pmid = {40050016}, issn = {1087-2981}, mesh = {Humans ; *Internship and Residency ; *Curriculum ; *Qualitative Research ; *Focus Groups ; *Pediatrics/education ; *Racism/psychology ; United States ; Male ; Female ; Attitude of Health Personnel ; Antiracism ; }, abstract = {BACKGROUND: Anti-racism curricula are increasingly being recognized as an integral component of medical education. To our knowledge, there has not yet been a publication exploring resident perspectives from multiple institutions and explicitly representing both underrepresented in medicine (UIM) and non-UIM perspectives.<br><br>OBJECTIVE: To explore and compare UIM and non-UIM pediatric residents' perspectives on the content and qualities of meaningful anti-racism curricula.<br><br>METHODS: We performed an IRB-approved multi-institutional, qualitative study that incorporated Sotto-Santiago et al's conceptual framework for anti-racism education. Between February and May 2021, we conducted focus groups of UIM and non-UIM pediatric residents at three large residency programs in the United States. We developed focus group guides using literature review, expert consensus, feedback from study team racial equity experts, and piloting. Focus groups were conducted virtually, audio-recorded, and transcribed verbatim. We employed thematic analysis to code transcripts, create categories, and develop themes until we reached thematic sufficiency. We completed member checking to ensure trustworthiness of themes.<br><br>RESULTS: Forty residents participated (19 UIM and 21 non-UIM) in a total of six focus groups. We identified 7 themes, summarized as: 1) racism in medicine is pervasive, therefore (2) anti-racism education is critical to the development of competent physicians, and 3) education should extend to all healthcare providers. 4) Residents desired education focused on action-oriented strategies to advance anti-racism, 5) taught by those with both learned and lived experiences with racism, 6) in a psychologically safe space for UIM residents, and 7) with adequate time and financial resources for successful implementation and engagement.<br><br>CONCLUSION: Our multi-institutional study affirms the need for pediatric resident anti-racism education, promotes co-creation as a method to affect culture change, and provides practical strategies for curricular design and implementation.}, }
@article {pmid40050010, year = {2025}, author = {Sun, J and De Vocht, J and Stam, D and Lien, CH and Huang, YA and Lamaire, N and Laroy, M and Vansteelandt, K and D'Hondt, A and Van Den Bossche, MJA and Vandenberghe, R and Peeters, RR and Sunaert, S and van Damme, P and Vandenbulcke, M and Van den Stock, J}, title = {Neural correlates of memory deficits in premanifest C9orf72-repeat expansions.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335169}, pmid = {40050010}, issn = {1468-330X}, abstract = {BACKGROUND: The premanifest stage in carriers of hexanucleotide repeat expansions in the C9orf72 gene (C9RE) is associated with memory impairment. The present study examines whether the impairment is general across domains or disproportionately affects specific stimulus categories such as socioemotional events, and its underlying functional neuroanatomy.<br><br>METHODS: This task-based fMRI-study included 21 premanifest C9RE (preC9RE) carriers and 24 controls. Participants encoded stimuli of (emotional and neutral) faces and houses, followed by a recognition task. Using univariate and multivoxel pattern analyses at whole-brain level and region-of-interest level, we investigated the neural change during encoding and retrieval processes, as well as the neural pattern similarity between encoding and retrieval.<br><br>RESULTS: Compared with controls, the preC9RE group demonstrated poorer performance in memorising faces (U=104, p=0.002), while their ability to memorise houses remained intact. The preC9RE group exhibited distinct neural patterns in the anterior insula during face encoding compared with the controls (accuracy>0.765, p<0.05). During face retrieval, the preC9RE group showed an increased neural response to encoded faces versus new faces in the right anterior insula (U=394, p=0.015). Individuals with preC9RE exhibited reduced encoding-retrieval neural similarity in the salience network specifically related to face stimuli (U=120, p=0.023).<br><br>CONCLUSIONS: The findings reveal functional changes in the salience network related to impaired social memory at the premanifest stage of C9RE. The findings further underscore the high potential of multidimensional neural response patterns as a sensitive biomarker for neurodegenerative functional changes, and the salience network as biomarker for C9RE disease staging.}, }
@article {pmid40049531, year = {2025}, author = {Zhang, N and Dong, X}, title = {Causal relationship between gut microbiota, lipids, and neuropsychiatric disorders: A Mendelian randomization mediation study.}, journal = {Journal of affective disorders}, volume = {379}, number = {}, pages = {19-35}, doi = {10.1016/j.jad.2025.02.091}, pmid = {40049531}, issn = {1573-2517}, abstract = {BACKGROUND: Numerous studies have shown an interconnection between the gut microbiota and the brain via the "gut-brain" axis. However, the causal relationships between gut microbiota, lipids, and neuropsychiatric disorders remain unclear. This study aimed to analyze potential associations among gut microbiota, lipids, and neuropsychiatric disorders-including AD, PD, ALS, MS, SCZ, MDD, and BD-using summary data from large-scale GWAS.<br><br>METHODS: Bidirectional Mendelian randomization (MR) with inverse variance weighting (IVW) was the primary method. Supplementary analyses included sensitivity analyses, Steiger tests, and Bayesian weighted MR (BWMR). Mediation analyses used two-step MR (TSMR) and multivariable MR (MVMR).<br><br>RESULTS: The analyses revealed 51 positive correlations (risk factors) (&#x3b2;&#xa0;>&#xa0;0, P&#xa0;<&#xa0;0.05) and 47 negative correlations (protective factors) (&#x3b2;&#xa0;<&#xa0;0, P&#xa0;<&#xa0;0.05) between gut microbiota and neuropsychiatric disorders. In addition, 35 positive correlations (&#x3b2;&#xa0;>&#xa0;0, P&#xa0;<&#xa0;0.05) and 22 negative correlations (&#x3b2;&#xa0;<&#xa0;0, P&#xa0;<&#xa0;0.05) between lipids and neuropsychiatric disorders were observed. Assessment of reverse causality with the seven neuropsychiatric disorders as exposures and the identified gut microbiota and lipids as outcomes revealed no evidence of reverse causality (P&#xa0;>&#xa0;0.05). Mediation analysis indicated that the effect of the species Bacteroides plebeius on MDD is partially mediated through the regulation of phosphatidylcholine (16:0_20:4) levels (mediation proportion&#xa0;=&#xa0;10.9&#xa0;% [95&#xa0;% CI&#xa0;=&#xa0;0.0110-0.2073]).<br><br>CONCLUSION: This study provides evidence of a causal relationship between gut microbiota and neuropsychiatric disorders, suggesting lipids as mediators. These findings offer new insights into the mechanisms by which gut microbiota may influence neuropsychiatric disorders.}, }
@article {pmid40049292, year = {2025}, author = {Faure-de Baets, J and Besnard, J and Banville, F and Cassereau, J and Allain, P}, title = {Effects of virtual reality mindfulness on cognition and well-being in ALS: A randomized trial protocol.}, journal = {Contemporary clinical trials}, volume = {152}, number = {}, pages = {107876}, doi = {10.1016/j.cct.2025.107876}, pmid = {40049292}, issn = {1559-2030}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons but also leading to significant non-motor symptoms, including cognitive impairments, anxiety, depression, and behavioral changes, which severely impact quality of life. While mindfulness-based interventions (MBIs) have shown promise in alleviating psychological distress, their accessibility is often limited due to patients' physical impairments. Virtual reality (VR) could enhance engagement and immersion, offering a novel, more inclusive therapeutic approach. This randomized controlled trial (RCT) aims to evaluate the efficacy of a VR-based MBI compared to traditional mindfulness for ALS patients. Forty-six participants will be randomly assigned to an eight-week mindfulness program delivered either via VR or in a conventional format. The primary outcome is quality of life, assessed using the ALS-Specific Quality of Life Scale (ALSSQOL-R). Secondary outcomes include cognitive function, anxiety, depression, behavioral changes, and mindfulness propensity, evaluated at baseline, post-intervention, and three-month follow-up. The study will also examine VR usability and potential accessibility challenges for ALS patients. By addressing a critical gap in non-pharmacological psychological care, this study will provide key insights into the feasibility and benefits of VR-based MBIs. If effective, VR mindfulness could offer an innovative, scalable solution to improve emotional well-being and quality of life in ALS, making psychological support more accessible for patients with severe physical limitations.}, }
@article {pmid40049153, year = {2025}, author = {Cho, HW and Jung, S and Park, KH and Choi, JW and Heo, JS and Kim, J and Yun, H and Yu, D and Son, J and Choi, BM}, title = {Deep Learning-based Multi-class Classification for Neonatal Respiratory Diseases on Chest Radiographs in Neonatal Intensive Care Units.}, journal = {Neonatology}, volume = {}, number = {}, pages = {1-19}, doi = {10.1159/000545107}, pmid = {40049153}, issn = {1661-7819}, abstract = {Objective Accurate and timely interpretation of chest radiographs is essential for assessing respiratory distress and guiding clinical management to improve outcomes of critically ill newborns. This study aimed to introduce a deep learning-based automated algorithm designed to classify various neonatal respiratory diseases and healthy lungs using a large dataset of high-quality, multi-class labeled chest X-ray images from neonatal intensive care units (NICUs). Methods Portable supine chest X-ray images for six common conditions (healthy lung, respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), air leak syndrome (ALS), atelectasis, and bronchopulmonary dysplasia (BPD)) and demographic variables (gestational age and birth weight) were retrospectively collected from 10 university hospitals in Korea. Ground truth for manual classification of these conditions was generated by 20 neonatologists and validated by others from different hospitals. The dataset, consisting 34,598 for training, 4,370 for validation, and 4,370 for testing, was used to train a modified ResNet50-based deep-learning model for automatic classification. Results The automatic classification algorithm showed high concordance with human-annotated classifications, achieving an overall testing accuracy of 83.96% and an F1-score of 83.68%. The F1-score for each condition was 87.38% for "healthy lung", and 92.19% for "BPD", 90.65% for "ALS", 90.30% for "RDS", 86.56% for "atelectasis", and 70.84% for "TTN". Conclusion We introduced a deep learning-based automated algorithm to classify neonatal respiratory diseases using a large dataset of high-quality, multi-class labeled chest X-ray images, incorporating non-imaging data, which could support neonatologists in making timely and accurate decisions for critically ill newborns.}, }
@article {pmid40048825, year = {2025}, author = {Kacker, K and Chetty, N and Feldman, AK and Bennett, J and Yoo, PE and Fry, A and Lacomis, D and Harel, NY and Nogueira, RG and Majidi, S and Opie, NL and Collinger, JL and Oxley, TJ and Putrino, DF and Weber, DJ}, title = {Motor activity in gamma and high gamma bands recorded with a Stentrode from the human motor cortex in two people with ALS.}, journal = {Journal of neural engineering}, volume = {22}, number = {2}, pages = {}, pmid = {40048825}, issn = {1741-2552}, support = {UH3 NS120191/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Motor Cortex/physiopathology/physiology ; Male ; *Brain-Computer Interfaces ; *Gamma Rhythm/physiology ; *Electrocorticography/methods/instrumentation ; Middle Aged ; Female ; Stents ; Electrodes, Implanted ; Motor Activity/physiology ; Movement/physiology ; Aged ; }, abstract = {Objective.This study examined the strength and stability of motor signals in low gamma and high gamma bands of vascular electrocorticograms (vECoG) recorded with endovascular stent-electrode arrays (Stentrodes) implanted in the superior sagittal sinus of two participants with severe paralysis due to amyotrophic lateral sclerosis.Approach.vECoG signals were recorded from two participants in the COMMAND trial, an Early Feasibility Study of the Stentrode brain-computer interface (BCI) (NCT05035823). The participants performed attempted movements of their ankles or hands. The signals were band-pass filtered to isolate low gamma (30-70 Hz) and high gamma (70-200 Hz) components. The strength of vECoG motor activity was measured as signal-to-noise ratio (SNR) and the percentage change in signal amplitude between the rest and attempted movement epochs, which we termed depth of modulation (DoM). We trained and tested classifiers to evaluate the accuracy and stability of detecting motor intent.Main results.Both low gamma and high gamma were modulated during attempted movements. For Participant 1, the average DoM across channels and sessions was 125.41 ± 17.53% for low gamma and 54.23 ± 4.52% for high gamma, with corresponding SNR values of 6.75 ± 0.37 dB and 3.69 ± 0.28 dB. For Participant 2, the average DoM was 22.77 ± 4.09% for low gamma and 22.53 ± 2.04% for high gamma, with corresponding SNR values of 1.72 ± 0.25 dB and 1.73 ± 0.13 dB. vECoG amplitudes remained significantly different between rest and move periods over the 3 month testing period, with >90% accuracy in discriminating attempted movement from rest epochs for both participants. For Participant 1, the average DoM was strongest during attempted movements of both ankles, while for Participant 2, the DoM was greatest for attempted movement of the right hand. The overall classification accuracy was 91.43% for Participant 1 and 70.37% for Participant 2 in offline decoding of multiple attempted movements and rest conditions.Significance.By eliminating the need for open brain surgery, the Stentrode offers a promising BCI alternative, potentially enhancing access to BCIs for individuals with severe motor impairments. This study provides preliminary evidence that the Stentrode can detect discriminable signals indicating motor intent, with motor signal modulation observed over the 3 month testing period reported here.}, }
@article {pmid40048117, year = {2025}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Increased risk of ischemic stroke in amyotrophic lateral sclerosis: a nationwide cohort study in South Korea.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40048117}, issn = {1590-3478}, support = {HI20C1073//Ministry of Health and Welfare/ ; }, abstract = {BACKGROUND: We investigated the risk of ischemic stroke in ALS and analyzed the effect of ALS-related physical disability using the Korean National Health Insurance Service database.<br><br>METHODS: A total of 2,251 ALS patients diagnosed between January 1, 2012, and December 31, 2015, and 1:10 age- and sex-matched control populations were included. Cases that participated in the national health check-up programs were selected. A Cox hazard regression model was used to examine the hazard ratios (HRs) for ischemic stroke in ALS after adjusting for potential confounders.<br><br>RESULTS: A total of 681 ALS patients and 10,934 non-ALS participants were selected. ALS patients were slightly younger than the control group (60.3&#x2009;&#xb1;&#x2009;10.1 years vs. 61.0&#x2009;&#xb1;&#x2009;10.5 years, p&#x2009;=&#x2009;0.105), and the proportion of male patients was similar between the two groups (61.6% vs. 60.9%, p&#x2009;=&#x2009;0.722). ALS patients were more likely to have a lower body mass index (23.1&#x2009;&#xb1;&#x2009;2.92 vs. 24.0&#x2009;&#xb1;&#x2009;3.1, p&#x2009;<&#x2009;0.001) and obstructive sleep apnea syndrome (0.59% vs. 0.06%, p&#x2009;<&#x2009;0.001) than the controls. In ALS patients, the incidence rate of ischemic stroke was 6.32 per 1,000 person-years, and the adjusted HR of ischemic stroke was 2.58 (95% confidence interval 1.38&#x2009;-&#x2009;4.82) compared with the matched group. The risk of ischemic stroke did not differ by the presence of disability in ALS patients.<br><br>CONCLUSIONS: Our findings suggest that ALS patients have an increased risk of ischemic stroke compared with controls, but the risk did not differ by the presence of disability in ALS.}, }
@article {pmid40047927, year = {2025}, author = {Ludolph, A and Klose, V and Dreyhaupt, J and Del Tredici, K and Braak, H}, title = {The deltoid muscle and the pattern of paresis in ALS.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {253}, pmid = {40047927}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications ; *Deltoid Muscle/physiopathology/pathology ; Male ; Female ; Middle Aged ; Aged ; *Paresis/etiology/physiopathology ; Adult ; Prospective Studies ; Muscle, Skeletal/physiopathology ; Pyramidal Tracts/physiopathology/pathology ; Electromyography ; Aged, 80 and over ; }, abstract = {There is neuroanatomical and clinical evidence that the corticospinal tract governs the patterns of pareses in sporadic ALS. These patterns are mirrored by phylogenetically young monosynaptic corticomotor neuronal connections. It is well known that, clinically, dysfunction of the deltoid muscle contributes considerably to the early disability of the ALS patient. In this study, we prospectively compared the degree of pareses of the deltoid muscle with the triceps and biceps brachii in N = 71 patients (426 muscles). We could show that the extent of involvement of the deltoid muscle early in the disease process resembles that of the biceps rather than the triceps brachii. This pattern is consistent with functional data of the corticospinal monosynaptic connectivity of all three muscles.}, }
@article {pmid40047382, year = {2025}, author = {Murray, D and Rooney, J and Meldrum, D and Al-Chalabi, A and Bunte, TM and Chiwera, T and Choudhury, M and Chio, A and Fenton, L and Fortune, J and Maidment, L and Manera, U and McDermott, CJ and Meyjes, M and Tattersall, R and Torrieri, MC and Van Damme, P and Vanderlinden, E and Wood, C and Van Den Berg, LH and Hardiman, O}, title = {Respiratory measurements, respiratory symptoms, and quality of life in ALS: results from the REVEALS study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2025.2471421}, pmid = {40047382}, issn = {2167-9223}, abstract = {Objective: Progressing respiratory weakness throughout the course of amyotrophic lateral sclerosis (ALS) is clinically associated with distressing symptoms, including dyspnea, orthopnea, and difficulty clearing secretions. Fatigue, poor sleep, and reduced quality of life are also considered to be associated with declining respiratory function. Respiratory measurements guide prescription of interventions, which aim to alleviate symptoms. The relationships between respiratory measurements and patient reported symptoms are currently unclear. Method: The REVEALS study was a longitudinal, observational, multisite study of decline in respiratory function in people with ALS attending six European centers. Respiratory measures (forced and slow vital capacity (F/SVC), sniff nasal inspiratory pressure (SNIP), and peak cough flow) were collected, as were the presence of respiratory symptoms and simple quality of life, fatigue and sleep measures. We used Bayesian's multivariate models to explore the associations of the respiratory measures with outcome variables. Results: Two hundred and eighty participants completed in-person assessments over a median of 8 (IQR 2.3, 14.1) months, with 974 data collection timepoints. The probability of reporting symptoms including dyspnea, orthopnea, and difficulty clearing secretions increased with decreasing respiratory measurement scores. The probability of reporting moderately low quality of life and moderate fatigue also increased with decreasing test scores, but reported sleep quality was not associated with respiratory scores. Conclusion: Respiratory weakness in people with ALS was associated with symptoms including dyspnea, orthopnea, and difficulty clearing secretions. The probability of reporting symptoms increased incrementally as respiratory weakness increased, supporting the use of both respiratory measurements and the presence of symptoms in making decisions about clinical interventions.}, }
@article {pmid40046336, year = {2025}, author = {Öztürk, MM and Emgård, J and García-Revilla, J and Fernández-Calle, R and Yang, Y and Deierborg, T and Roos, TT}, title = {The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.}, journal = {Brain communications}, volume = {7}, number = {2}, pages = {fcaf087}, pmid = {40046336}, issn = {2632-1297}, abstract = {Numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain's innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.}, }
@article {pmid40045432, year = {2025}, author = {Blair, K and Martinez-Serra, R and Gosset, P and Martín-Guerrero, SM and Mórotz, GM and Atherton, J and Mitchell, JC and Markovinovic, A and Miller, CCJ}, title = {Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {49}, pmid = {40045432}, issn = {2051-5960}, support = {MR/X021858/1//UK Research and Innovation/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Endoplasmic Reticulum/metabolism ; *Vesicular Transport Proteins/metabolism ; Animals ; *Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Protein Tyrosine Phosphatases/metabolism ; }, abstract = {Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.}, }
@article {pmid40044663, year = {2025}, author = {Abu-Rumeileh, S and Scholle, L and Mensch, A and Großkopf, H and Ratti, A and Kölsch, A and Stoltenburg-Didinger, G and Conrad, J and De Gobbi, A and Barba, L and Steinacker, P and Klafki, HW and Oeckl, P and Halbgebauer, S and Stapf, C and Posa, A and Kendzierski, T and Silani, V and Hausner, L and Ticozzi, N and Froelich, L and Weishaupt, JH and Verde, F and Otto, M}, title = {Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {2019}, pmid = {40044663}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; *tau Proteins/metabolism/blood ; Male ; Female ; Middle Aged ; Aged ; Phosphorylation ; *Biomarkers/blood ; *Alzheimer Disease/blood/metabolism/pathology/diagnosis ; Muscle, Skeletal/metabolism/pathology ; Case-Control Studies ; Biopsy ; Aged, 80 and over ; Adult ; Cohort Studies ; }, abstract = {Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood p-tau 181 is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum p-tau 181 and p-tau 217 in a multicentre cohort of ALS (n = 152), AD (n = 111) cases and disease controls (n = 99) recruited from four different centres. Further, we investigated the existence of both p-tau species using immunohistochemistry (IHC) and mass spectrometry (MS) in muscle biopsies of ALS cases (IHC: n = 13, MS: n = 5) and disease controls (IHC: n = 14, MS: n = 5) from one cohort. Serum p-tau 181 and p-tau 217 were higher in AD and ALS patients compared to disease controls. IHC and MS analyses revealed the presence of p-tau 181 and 217 in muscle biopsies from both ALS cases and disease controls, with ALS samples showing increased p-tau reactivity in atrophic muscle fibres. Blood p-tau species could potentially be used to diagnose both ALS and AD.}, }
@article {pmid40044193, year = {2025}, author = {Ross, WT and Buday, S and Yakel, E and Khabele, D and Balls-Berry, J and As-Sanie, S and Colditz, G and Baumann, AA}, title = {Does interdisciplinary group care for the treatment of endometriosis improve pain interference: protocol for a pilot randomised controlled trial at an urban academic medical centre.}, journal = {BMJ open}, volume = {15}, number = {3}, pages = {e097372}, pmid = {40044193}, issn = {2044-6055}, support = {K23 HD110710/HD/NICHD NIH HHS/United States ; KL2 TR002346/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; Pilot Projects ; *Endometriosis/complications/therapy ; *Quality of Life ; *Pelvic Pain/therapy/etiology ; Academic Medical Centers ; Pain Management/methods ; Adult ; Randomized Controlled Trials as Topic ; Patient Care Team/organization &amp; administration ; Pain Measurement ; }, abstract = {INTRODUCTION: Endometriosis affects 10-15% of people assigned female at birth and can cause chronic pelvic pain and impair many domains of quality of life, such as fertility, mood and bladder, bowel and sexual function. Current treatments often fail, leading to recurrent pain and the need for reintervention. As endometriosis negatively affects many domains of life, a variety of non-pharmacological treatments modestly improve symptoms. To bundle these interventions into accessible packaging, our interdisciplinary team developed a novel endometriosis intervention titled 'Peer-Empowered Endometriosis Pain Support (PEEPS)', an 8-week integrative group care intervention. Here, we present the protocol for a pilot randomised controlled trial (RCT) to evaluate the effectiveness and implementation of PEEPS for people with endometriosis-associated pain refractory to surgical management. We hypothesise that patients who complete the PEEPS programme will show a greater decrease in pain interference in daily activities at intervention completion as compared with baseline than those in the education arm.<br><br>METHODS AND ANALYSIS: This is a hybrid type 1 effectiveness-implementation mixed-methods RCT in which 60 participants will be randomised using computer-generated random numbers stratified by group in the ratio 1:1 to PEEPS plus usual versus educational handout plus usual care. The primary outcome is change in pain interference from baseline to intervention completion. Secondary outcomes include change in pain interference from baseline to 6 months and 12 months postintervention, as well as change in other quality-of-life measures as measured by nine validated questionnaires from baseline to completion, 6 months and 12&#x2009;months. Proctor et al's Implementation Outcomes Framework will be used to evaluate acceptability, appropriateness and feasibility of PEEPS implementation, and the Consolidated Framework for Implementation Research will be used to guide the evaluation of barriers and facilitators of PEEPS at the patient and provider levels. Primary data analyses will follow the intention-to-treat principle. Descriptive statistics and two-sample t-tests for normally distributed values and Wilcoxon Rank-Sum test were performed for non-normally distributed values. Frequency analysis and Fisher's exact or &#x3c7;[2] tests will be used for categoric variables as appropriate. Longitudinal analysis of the primary and secondary outcomes will be conducted with a mixed-effects model to investigate the effect of PEEPS compared with education. Least square means (LSMs) and the corresponding 95% CIs at each timepoint, as well as LSM differences and 95% CIs between any post-baseline and baseline will be provided for the outcomes. ORs and 95% CIs will be calculated for categorical outcomes. Qualitative data will be collected in the form of open-ended feedback, focus groups with programme completers and semistructured interviews with participants who complete two or fewer sessions. The analysis will use an embedded design-experimental model in which quantitative and qualitative outcomes will occur concurrently with weight priority given to quantitative data.<br><br>ETHICS AND DISSEMINATION: This trial was approved by the Washington University in St. Louis Institutional Review Board (protocol 202402082) on 27 March 2024 and has low risk of harm to participants. All deidentified data from this project will be shared via Digital Commons@Becker. The findings of this study will be disseminated via scientific meetings and peer-reviewed journals. The results and conclusions will be summarised for patients and the public in common language using infographics to make the findings accessible. This pilot RCT will yield the effect size for PEEPS and generate implementation context and outcomes data to guide PEEPS application to real-world practice. If PEEPS proves to be effective, this study will inform adaptation and scaling to improve the lives of people with endometriosis through a non-hormonal, fertility-preserving approach.<br><br>TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT06549985.}, }
@article {pmid40042459, year = {2025}, author = {Lee, SM and Yoon, SJ and Park, KW and Kim, A and Kim, HJ and Jung, NY and Jang, H and Seeley, WW and Kim, YE and Moon, SY and Kim, EJ and , }, title = {Semantic variant primary progressive aphasia with ANXA11 p.D40G.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {3}, pages = {e14566}, pmid = {40042459}, issn = {1552-5279}, support = {2021-ER1004-01//Korea National Institute of Health/ ; 2024-ER1001-00//Korea National Institute of Health/ ; RS-2024-00337993//Korea Dementia Research Project through the Korea Dementia Research Center, funded by the Ministry of Health &amp; Welfare and Ministry of Science and ICT, Republic of Korea/ ; }, mesh = {Humans ; *Aphasia, Primary Progressive/genetics/pathology ; Male ; Female ; Aged ; Middle Aged ; *Annexins/genetics ; *DNA-Binding Proteins/genetics ; Frontotemporal Dementia/genetics/pathology ; Republic of Korea ; Cohort Studies ; High-Throughput Nucleotide Sequencing ; }, abstract = {INTRODUCTION: Pathogenic variants of annexin A11 (ANXA11) have been identified in patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). We explored ANXA11 pathogenic variants in a Korean FTD cohort to investigate the prevalence and the role of ANXA11 variation in FTD.<br><br>METHODS: We used next-generation sequencing (NGS) to search for pathogenic variants in ANXA11 in two nationwide FTD cohorts in Korea.<br><br>RESULTS: We identified a pathogenic variant in ANXA11, c.119A&#xa0;>&#xa0;G (p.D40G), in six patients with semantic variant primary progressive aphasia (svPPA), representing 5.5% of the svPPA cohort (6/109), and representing 2.3% of the FTD cohort overall (6/259). Only one patient later developed features suggestive of ALS.<br><br>DISCUSSION: This study links a rare variant in ANXA11 to a sporadic clinical syndrome in which specific TAR DNA-binding protein-43 (TDP-43) forms an obligate co-fibril with annexin A11. The variant, p.D40G, lies within the N-terminal portion of annexin A11's TDP-43 type C interacting domain, suggesting that genetic variation in that region may promote co-fibrillization.<br><br>HIGHLIGHTS: The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.}, }
@article {pmid40041912, year = {2025}, author = {Dash, UC and Bhol, NK and Swain, SK and Samal, RR and Nayak, PK and Raina, V and Panda, SK and Kerry, RG and Duttaroy, AK and Jena, AB}, title = {Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {1}, pages = {15-34}, pmid = {40041912}, issn = {2211-3835}, abstract = {Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.}, }
@article {pmid40039939, year = {2024}, author = {Udhayakumar, R and Gopakumar, S and Rahman, S and Karmakar, C}, title = {Nonlinear Assessment of Gait Signal Complexity in Neurodegenerative Disorders.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781711}, pmid = {40039939}, issn = {2694-0604}, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology ; *Algorithms ; *Gait/physiology ; Nonlinear Dynamics ; Entropy ; Signal Processing, Computer-Assisted ; Male ; Female ; Middle Aged ; Aged ; }, abstract = {The human gait cycle undergoes discernible alterations upon the onset of neurodegenerative diseases (NDD) such as Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. Each specific neurodegenerative disorder imparts a distinct influence on human gait dynamics, and precise quantification of these changes holds the potential for accurate methods of NDD detection.Nonlinear entropy algorithms, such as sample entropy (SampEn), find widespread use in physiological signal analysis. SampEn gauges signal complexity by identifying pattern matches within windowed sub-segments of the signal. However, traditional SampEn is notably dependent on user-defined parameters, particularly the tolerance parameter r, leading to inaccuracies in complexity information.SampEn profiling emerges as an alternative concept, eliminating the need for an input r parameter. This data-driven algorithm autonomously generates a set of 'r' values based on the signal's dynamics, yielding a comprehensive SampEn profile. The SampEn profile, containing extensive information about the signal's complexity, serves as a valuable resource for extracting secondary entropy features.In this study, we have contrasted the efficacy of traditional SampEn with SampEn profile-based secondary features such as Total SampEn (TSE) and Median SampEn (MSE), in identifying neurological states. Our findings consistently reveal that secondary features derived from the reduced-parametric SampEn profiling method outperform the traditional parametric SE in distinguishing control cohorts from specific Neurodegenerative Disease (NDD) cohorts.}, }
@article {pmid40039399, year = {2024}, author = {Rechichi, I and Amprimo, G and Cicolin, A and Olmo, G}, title = {Predicting Amyotrophic Lateral Sclerosis Progression: an EMG-based Survival Analysis.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782485}, pmid = {40039399}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis/mortality ; Humans ; *Electromyography/methods ; *Disease Progression ; Male ; Female ; Middle Aged ; Survival Analysis ; Aged ; Sleep, REM ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease, ultimately leading to muscle inefficiency and death. A vast majority of people with ALS also suffer from sleep disorders. Previous studies highlighted the presence of REM Sleep Without Atonia (RSWA) in an ALS cohort, and suggested its strong correlation with the disease severity. This study investigates the ability of electromyography (EMG) parameters recorded during Rapid-eye Movement (REM) sleep to predict disease progress and outcome rapidity in ALS. Survival models trained on a cohort of 45 ALS patients undergoing a longitudinal study, revealed a promising predictive power for the proposed EMG-derived metrics (c-index ≥ 0.65) and encouraging goodness of fit (through c-index and χ[2]). These results suggest the possibility of employing the trained model in follow-up procedures, based on non-invasive, lightweight EMG metrics, which would significantly ease disease monitoring and help personalized symptomatic care.}, }
@article {pmid40039278, year = {2024}, author = {Murphy, EK and Doussan, A and Verga, S and Stommel, EW and McIlduff, C and Halter, RJ and Rutkove, SB}, title = {Assessing Pulmonary Function in ALS using Electrical Impedance Tomography.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10781742}, pmid = {40039278}, issn = {2694-0604}, mesh = {Humans ; *Electric Impedance ; *Tomography/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Respiratory Function Tests/methods ; Male ; Female ; Middle Aged ; Lung/diagnostic imaging/physiopathology ; Algorithms ; Case-Control Studies ; Aged ; Adult ; }, abstract = {This study aimed to determine an optimal model involving thoracic electrical impedance tomography (EIT) metrics and patient geometric information to best correlate to standard pulmonary function test (PFT) measures in a cohort of 32 ALS patients and 32 age-matched healthy controls. Thoracic EIT is a non-invasive technology in which an electrode belt chest allows for real-time impedance imaging of respiratory function. The optimal form of the model was determined via a genetic algorithm a novel technique for model generation in EIT applications. Combining multiple metrics yielded optimal r[2] values of 0.62 and 0.66 for 1- and 2-term regression models optimized. The results appear very promising and further refinement of the technology appears warranted.}, }
@article {pmid40038221, year = {2025}, author = {Mustafa, F and Mittal, S and Garg, D and Agarwal, A and Garg, A and Gupta, BK and Soneja, M and Srivastava, AK}, title = {HIV associated motor neuron disease (MND): A case series with systematic review of literature.}, journal = {Journal of neurovirology}, volume = {31}, number = {1}, pages = {1-15}, pmid = {40038221}, issn = {1538-2443}, mesh = {Humans ; *HIV Infections/drug therapy/complications/virology ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/virology/drug therapy/diagnostic imaging/pathology ; Female ; Adult ; *Motor Neuron Disease/virology/drug therapy ; Viral Load ; CD4 Lymphocyte Count ; Anti-HIV Agents/therapeutic use ; }, abstract = {Human immunodeficiency virus (HIV) associated motor neuron disease (MND) is very rare. HIV infection can cause an MND-like syndrome due to central nervous system (CNS) involvement de novo or during antiretroviral therapy (ART) due to CNS escape. We present two cases: one with a classic amyotrophic lateral sclerosis (ALS) phenotype, which was the manifestation of symptomatic CNS escape from ART, and the second with a primary lateral sclerosis (PLS) phenotype associated with underlying HIV infection. A systematic review of published literature of people living with HIV (PLHIV) who developed ALS/ MND was conducted using the PubMed, Embase, and Lilacs databases. A total of 91 cases were found, 89 of which were obtained from 37 articles, and two were included from our own case series. In patients with HIV-associated MND, 63 patients reviewed had a classic ALS phenotype followed by progressive muscular atrophy variant (12), progressive bulbar palsy (8), PLS (7) and bulbar onset ALS (1). Neuroimaging, electrophysiology, cerebrospinal fluid (CSF) analysis, CSF and serum HIV viral load, and CD4 count investigations were used for diagnosis. Following the initiation or modification of antiretroviral therapy (ART), approximately 70% exhibited an improvement or a stable disease course. HIV-associated MND is a rare condition that can occur in both ART-naive individuals and those on treatment. A proportion of cases (~ 70%) show improvement with ART. Accurate diagnosis requires the exclusion of opportunistic infections, which remains a critical yet challenging aspect of managing this condition.}, }
@article {pmid40037468, year = {2025}, author = {Peck, A and Dadi, A and Yavarow, Z and Alfano, LN and Anderson, D and Arkin, MR and Chou, TF and D'Ambrosio, ES and Diaz-Manera, J and Dudley, JP and Elder, AG and Ghoshal, N and Hart, CE and Hart, MM and Huryn, DM and Johnson, AE and Jones, KB and Kimonis, V and Kiskinis, E and Lee, EB and Lloyd, TE and Mapstone, M and Martin, A and Meyer, H and Mozaffar, T and Onyike, CU and Pfeffer, G and Pindon, A and Raman, M and Richard, I and Rubinsztein, DC and Schiava, M and Schütz, AK and Shen, PS and Southworth, DR and Staffaroni, AM and Taralio-Gravovac, M and Weihl, CC and Yao, Q and Ye, Y and Peck, N}, title = {2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy.}, journal = {Neurobiology of disease}, volume = {207}, number = {}, pages = {106861}, pmid = {40037468}, issn = {1095-953X}, support = {R01 CA293084/CA/NCI NIH HHS/United States ; Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Valosin Containing Protein/genetics/metabolism ; Humans ; Animals ; Myositis, Inclusion Body/genetics/therapy/metabolism ; Frontotemporal Dementia/genetics/therapy ; }, abstract = {Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the VCP gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach. The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.}, }
@article {pmid40037332, year = {2025}, author = {Belbasis, L and Morris, S and van Duijn, C and Bennett, D and Walters, R}, title = {Mendelian randomization identifies proteins involved in neurodegenerative diseases.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf018}, pmid = {40037332}, issn = {1460-2156}, support = {203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; //NIHR/ ; //NHS/ ; /DH_/Department of Health/United Kingdom ; }, abstract = {Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.}, }
@article {pmid40036711, year = {2025}, author = {Nguyen, ML and Haddad, A and Law-Ye, B and Hesters, A}, title = {Uncommon Spinal Cord MRI Findings in a Patient With Early-Onset Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Neurology}, volume = {104}, number = {7}, pages = {e213503}, doi = {10.1212/WNL.0000000000213503}, pmid = {40036711}, issn = {1526-632X}, }
@article {pmid40036368, year = {2025}, author = {Ervilha Pereira, P and De Bleecker, JL and Bogaert, E and Dermaut, B}, title = {Myopathic aggregation-prone variants in the TDP-43 prion-like domain: genetics paving the way.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf076}, pmid = {40036368}, issn = {1460-2156}, abstract = {While neuropathological and genetic studies have established the crucial involvement of TDP-43 proteinopathy in the pathogenesis of ALS (Amyotrophic Lateral Sclerosis), FTD (Frontotemporal Dementia) and related neurodegenerative disorders, multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies. In addition, TDP-43 has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury. However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing. In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology. We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity. Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of 'multisystem proteinopathy'.}, }
@article {pmid40034872, year = {2025}, author = {Wagner, H and Mlček, M and Krupičková, P and Popkova, M and Mejstrik, A and Boucek, T and Michálek, P and Kittnar, O and Belohlavek, J}, title = {Adrenaline has a limited effect on myocardial microvascular blood flow: A randomised experimental study in a porcine cardiac arrest model.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100893}, pmid = {40034872}, issn = {2666-5204}, abstract = {BACKGROUND: Adrenaline (ADR) is a cornerstone of advanced life support (ALS) in cardiac arrest (CA), although its neurologically favourable survival outcomes remain unclear. ADR increases coronary perfusion pressure (CPP), with levels >15 mmHg associated with successful defibrillation. This study aimed to elucidate the relationship between ADR, myocardial microvascular blood flow, and resuscitation outcomes using a porcine CA model simulating refractory ventricular fibrillation (VF).<br><br>METHODS: This study involved 24 domestic pigs. After instrumentation, intubation, and baseline measurements, the animals were randomised into the ADR or control (saline) groups. VF was induced, and cardiopulmonary resuscitation was initiated using continuous mechanical chest compressions and ventilation. ADR or saline was administered following ALS guidelines. After 21&#x202f;min of ALS, defibrillation was performed. Continuous measurements of arterial and venous blood pressures using an electrocardiogram and index of myocardial resistance (IMR) and transit mean time (Tmn) 1&#x202f;min before and after each injection or peak blood pressure were recorded and compared between the groups. CPP-IMR, amplitude spectrum area (AMSA)-IMR, CPP-Tmn, and AMSA-Tmn correlations were assessed.<br><br>RESULTS: Compared with six animals in the control group, three in the ADR group achieved a return of spontaneous circulation. No difference was observed in IMR or AMSA; however, significant increases in CPP and arterial end-diastolic blood pressure were observed at several time points. Tmn differed between groups only at two time points.<br><br>CONCLUSION: Repeated ADR doses during prolonged ALS simulating refractory VF did not improve myocardial microvascular blood flow, as measured using IMR, despite leading to an increase in CPP.}, }
@article {pmid40034089, year = {2025}, author = {Vaage, AM and Holmøy, T and Dahl, J and Stigum, H and Meyer, HE and Nakken, O}, title = {Statin Use and Amyotrophic Lateral Sclerosis Survival: A Population-Based Cohort Study.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70095}, pmid = {40034089}, issn = {1468-1331}, support = {//ALS Norway/ ; 2022050//Helse S&#xf8;r-&#xd8;st RHF/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology/drug therapy ; Female ; Male ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Middle Aged ; Cohort Studies ; Aged ; Norway/epidemiology ; Registries ; Adult ; }, abstract = {BACKGROUND: Dyslipidemia is common in amyotrophic lateral sclerosis (ALS). Statin use has been associated with both favorable and poor prognoses. We assessed whether statin use affects ALS survival.<br><br>METHODS: We linked four Norwegian health surveys (1972-2003) with mandatory national registries to obtain information on premorbid health, ALS diagnosis, and death. Using the Norwegian Prescribed Drug Registry, we identified participants who had dispensed statins pre- and post-diagnosis. We first compared pre-diagnosis statin discontinuation rates between ALS patients and matched controls. Flexible parametric models were then fitted to estimate the relationship between statin use and survival time in ALS, using restricted mean survival time and hazard ratio (HR) as effect measures.<br><br>RESULTS: A total of 524 patients (43% female) with ALS were included. Mean time from ALS diagnosis to death or end of study was 2.0 (SD 2.1) years. A substantial proportion of statin users (21%) discontinued statins during the year leading up to diagnosis. This group was characterized by poorer ALS prognosis compared to those adhering to statins and were included as statin users in our analysis. After adjusting for sex, age, birth year, riluzole use and premorbid smoking status, body mass index, and total cholesterol levels, statin use was not associated with ALS survival. The estimated mean survival difference comparing statin users to non-users was 0.74 (95% CI -5.98 to 7.47) months, corresponding to a HR of 0.97 (95% CI 0.77-1.23).<br><br>CONCLUSION: Statin use was not associated with ALS survival, suggesting that statins should not routinely be discontinued in ALS.}, }
@article {pmid40033997, year = {2025}, author = {Poulsen, NS and Kraglund, LR and Vissing, J}, title = {Physical training of wheelchair users with neuromuscular disorders: A systematic review.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602241313114}, doi = {10.1177/22143602241313114}, pmid = {40033997}, issn = {2214-3602}, abstract = {OBJECTIVE: Wheelchair users with neuromuscular disorders have symptoms related to the disease and complications to the sedentary lifestyle, such as constipation and lower back pain. Physical training might be beneficial. This systematic review investigates the potential benefits and harms of physical training for wheelchair users with neuromuscular disorders.<br><br>METHODS: We systematically searched PubMed including studies published until July 2024. Inclusion criteria: 1) participants with a neuromuscular disorder, 2) at least 60% of participants in a study were wheelchair users, 3) physical training and its effects were investigated, 4) studies were prospective, and 5) English language was used. Non-peer-reviewed articles were excluded. Search results were screened by title, abstract, and full text. Two independent authors assessed the quality with the Downs and Black Quality Index.<br><br>RESULTS: We included 14 studies of 140 patients from 5 types of neuromuscular disorders (Duchenne muscular atrophy, spinal muscular atrophy, limb-girdle muscular atrophy, facioscapulohumeral muscular dystrophy, and amyotrophic lateral sclerosis). The mean quality was low (16/32) due to flaws in study design, selection bias, and power. Even though many were of low quality and lacked descriptions of adverse events, they all showed positive effects. Most studies investigated physical training of mastication or respiration with improvements in both. Other findings were improvements in endurance, extremity strength, and range of motion.<br><br>CONCLUSIONS: Physical training of wheelchair users with neuromuscular disorders is not well investigated. Physical training seems safe and beneficial, but training of respiratory and masticatory muscles is the only well-documented exercise modality that can be advised in patients with Duchenne Muscular Dystrophy or Duchenne Muscular Dystrophy/Spinal Muscular Atrophy, respectively. Larger, high-quality trials, including other neuromuscular disorders, are needed to assess the effects and adverse events of physical training.}, }
@article {pmid40033457, year = {2025}, author = {Kallambettu, V and York, JD and Vasilopolous, T and Hutcheson, K and Plowman, E}, title = {Validation of the Dynamic Imaging Grade of Swallowing Toxicity for Amyotrophic Lateral Sclerosis.}, journal = {Neurogastroenterology and motility}, volume = {}, number = {}, pages = {e70008}, doi = {10.1111/nmo.70008}, pmid = {40033457}, issn = {1365-2982}, support = {/NS/NINDS NIH HHS/United States ; /CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Although dysphagia is prevalent in persons with amyotrophic lateral sclerosis (pALS) and is associated with morbidity and mortality, no validated outcomes currently exist for the gold standard videofluoroscopy (VF) exam. We therefore sought to psychometrically validate the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale in pALS.<br><br>METHODS: One hundred pALS attended a research evaluation and underwent a standardized VF and validated clinical outcomes of oral intake (FOIS), perceived swallowing impairment (EAT-10), and ALS disease progression (ALSFRS-Revised). Duplicate, independent, and blinded VF ratings were completed using the DIGEST and MBSImP scales. Weighted kappa, ANOVAs (Tukey's HSD, Welch's correction), and Chi-square analyses were performed to determine intra- and inter-rater reliability, criterion validity, and construct validity of the DIGEST scale for use in pALS.<br><br>RESULTS: The mean age was 64.4(SD&#x2009;=&#x2009;10.4), 50% were male, and the average ALS duration was 28.2&#x2009;months (SD&#x2009;=&#x2009;22.2). Excellent intra-rater (kappa&#x2009;=&#x2009;0.92-1.0) and inter-rater (kappa&#x2009;=&#x2009;0.94) reliability were noted for DIGEST ratings. DIGEST grades significantly discriminated pharyngeal pathophysiology (MBSImP, F(3,96)&#x2009;=&#x2009;24.7, p&#x2009;<&#x2009;0.0001), perceived dysphagia (EAT-10, F(3,40)&#x2009;=&#x2009;20.8, p&#x2009;<&#x2009;0.0001), oral intake (FOIS, X[2]:25.4, df&#x2009;=&#x2009;3, p&#x2009;<&#x2009;0.0001), ALS bulbar disease progression (ALSFRS-bulbar, F(3,93)&#x2009;=&#x2009;20.8, p&#x2009;<&#x2009;0.0001) with main effects noted for all analyses. Post hoc pairwise comparisons noted differences across all DIGEST grades with the exception of DIGEST 2 versus 3 (moderate vs. severe dysphagia), p&#x2009;>&#x2009;0.05.<br><br>CONCLUSIONS: These data confirm that the DIGEST scale is a reliable and valid VF outcome for use in pALS to distinguish normal versus impaired swallowing and mild versus moderate or severe dysphagia for use in clinical practice and as a clinical trial endpoint marker.}, }
@article {pmid40033250, year = {2025}, author = {Lu, C and Huang, XX and Huang, M and Liu, C and Xu, J}, title = {Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {82}, pmid = {40033250}, issn = {1471-2377}, mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Amyotrophic Lateral Sclerosis/genetics/blood ; *Proteomics/methods ; *Genome-Wide Association Study/methods ; *Biomarkers/blood ; Blood Proteins/genetics/analysis/metabolism ; Quantitative Trait Loci ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive.<br><br>OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment.<br><br>METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis.<br><br>RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.<br><br>CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.}, }
@article {pmid40032505, year = {2025}, author = {Callegaro, S and Manera, U and Canosa, A and Grassano, M and Palumbo, F and Cabras, S and Matteoni, E and Di Pede, F and De Mattei, F and De Marchi, F and Mazzini, L and Moglia, C and Calvo, A and Chiò, A and Vasta, R}, title = {Another brick in our knowledge of ALS causes: a population-based study of residential clustering.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335670}, pmid = {40032505}, issn = {1468-330X}, }
@article {pmid40032118, year = {2025}, author = {Dang, M and Wu, L and Zhang, X}, title = {Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.}, journal = {International journal of biological macromolecules}, volume = {306}, number = {Pt 3}, pages = {141677}, doi = {10.1016/j.ijbiomac.2025.141677}, pmid = {40032118}, issn = {1879-0003}, abstract = {Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.}, }
@article {pmid40031506, year = {2024}, author = {Guo, J and Chen, D and Zeng, X and Liu, X and Wang, X and Teng, S and Ye, K and Sun, X and Zhang, S and He, J and Fan, D and Liu, Y}, title = {A Multi-branch Attention-based Deep Learning Method for ALS Identification with sMRI Data.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2024}, number = {}, pages = {1-4}, doi = {10.1109/EMBC53108.2024.10782847}, pmid = {40031506}, issn = {2694-0604}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/diagnosis ; *Deep Learning ; Humans ; *Spinal Cord/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Algorithms ; Image Processing, Computer-Assisted/methods ; }, abstract = {The structural Magnetic resonance imaging (sMRI) of spinal cord plays a significant role in the clinical diagnosis of Amyotrophic Lateral Sclerosis (ALS). But due to small cross-sectional area in the axial plane and long sagittal/coronal expansion of spinal cord, the diagnosis of ALS using sMRI of spinal cord has remained largely at the stage of morphological observation. In this study, a Multi-branch attention-based deep learning method is proposed to solve this problem. Multi-branch framework is utilized to extract general features of all levels of spinal cord for challenging of long sagittal and coronal expansion of spinal cord, and attention module coupled with multi-scale module in each branch is applied to extract multi-scale features and pay more attention to the important regions of the spinal cord in the axial plane. Experiments show that the proposed method obtains better performance in ALS identification, which implies that the proposed method can extract features of important region in the spinal cord and could be helpful to find more regions sensitive for ALS disease identification.}, }
@article {pmid40030850, year = {2025}, author = {Hong, Z and Yi, S and Deng, M and Zhong, Y and Zhao, Y and Li, L and Zhou, H and Xiao, Y and Hu, X and Niu, L}, title = {Transcranial Focused Ultrasound Modifies Disease Progression in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on ultrasonics, ferroelectrics, and frequency control}, volume = {72}, number = {2}, pages = {191-201}, doi = {10.1109/TUFFC.2024.3525143}, pmid = {40030850}, issn = {1525-8955}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnostic imaging/genetics ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Superoxide Dismutase-1/genetics ; Disease Progression ; Muscle, Skeletal/physiopathology ; Male ; Motor Cortex ; Humans ; Elasticity Imaging Techniques ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressively worsening neurodegenerative condition with very few treatment options available. Ultrasound neuromodulation offers promising benefits for treating neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. However, the effects and underlying mechanisms of ultrasound neuromodulation on ALS remain unclear. A head-mounted ultrasound neuromodulation system was developed to noninvasively stimulate the motor cortex of symptomatic mice carrying the G93A human SOD1 mutation (SOD $1^{\text {G93A}}$) for four weeks. Motor performance was assessed through the rotarod locomotor test, grip strength test, and open field test. In addition, the effect of ultrasound stimulation on the elastic modulus of gastrocnemius muscle atrophy was measured using real-time shear wave elastography (SWE). Subsequently, the brain tissues of the mice were harvested. Gastrocnemius morphology was examined using hematoxylin-eosin and Gomori aldehyde-fuchsin (GAF) staining. The number of neurons and the phenotype of microglia in the motor cortex were observed by immunohistochemical analysis. Ultrasound therapy delayed disease onset by 10.7% and increased the lifespan by 6.7% in SOD $1^{\text {G93A}}$ mice by reduction of neuronal loss and enhancement of M2 microglia in the motor cortex. Furthermore, we found significant improvements in motor function for ultrasound-treated mice. More importantly, ultrasound stimulation ameliorated gastrocnemius muscle atrophy in the SOD $1^{\text {G93A}}$ mice. These results revealed the neuroprotective effects of ultrasound against the disease pathogenesis of SOD $1^{\text {G93A}}$ mice. Transcranial ultrasound neuromodulation provides an innovative tool for the intervention and treatment of neurodegenerative diseases.}, }
@article {pmid40030617, year = {2024}, author = {Jiang, Y and Li, K and Liang, Y and Chen, D and Tan, M and Li, Y}, title = {Daily Assistance for Amyotrophic Lateral Sclerosis Patients Based on a Wearable Multimodal Brain-Computer Interface Mouse.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3520984}, pmid = {40030617}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a chronic, progressive neurodegenerative disease that mainly causes damage to upper and lower motor neurons. This leads to a progressive deterioration in the voluntary mobility of the upper and lower extremities in ALS patients, which underscores the pressing need for an assistance system to facilitate communication and body movement without relying on neuromuscular function. In this paper, we developed a daily assistance system for ALS patients based on a wearable multimodal brain-computer interface (BCI) mouse. The system comprises two subsystems: a mouse system assisting the upper extremity and a wheelchair system based on the mouse system assisting the lower extremity. By wearing a BCI headband, ALS patients can control a computer cursor on the screen with slight head rotation and eye blinking, and further operate a computer and drive a wheelchair with specially designed graphical user interfaces (GUIs). We designed operating tasks that simulate daily needs and invited ALS patients to perform the tasks. In total, 15 patients with upper extremity limitations performed the mouse system task and 9 patients with lower extremity mobility issues performed the wheelchair system task. To our satisfaction, all the participants fully accomplished the tasks and average accuracies of 83.9% and 87.0% for the two tasks were achieved. Furthermore, workload evaluation using NASA Task Load Index (NASA-TLX) revealed that the participants experienced a low workload when using the system. The experimental results demonstrate that the proposed system provides ALS patients with effective daily assistance and shows promising long-term application prospects.}, }
@article {pmid40030616, year = {2024}, author = {Bista, S and Coffey, A and Mitchell, M and Fasano, A and Dukic, S and Buxo, T and Giglia, E and Heverin, M and Muthuraman, M and Carson, RG and Lowery, M and Manus, LM and Hardiman, O and Nasseroleslami, B}, title = {Abnormal EEG spectral power and coherence measures during pre-motor stage in Amyotrophic Lateral Sclerosis.}, journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TNSRE.2024.3523109}, pmid = {40030616}, issn = {1558-0210}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive motor decline. Studies of electroencephalographic (EEG) activity during rest and motor execution have captured network changes in ALS. However, the nature of network-level impairment in the pre-motor activity in ALS remains unclear. Assessing the (dys)function of motor networks engaged prior to motor output is essential for understanding the motor pathophysiology in ALS. We recorded EEG in 22 people with ALS (PwALS) and 16 age-matched healthy controls during rest and isometric pincer-grip tasks. EEG spectral power and coherence were calculated during rest, pre-motor stage, and motor execution. In PwALS, significantly higher event-related spectral perturbations were observed compared to controls over electrodes representing a) contralateral prefrontal and parietal regions in theta band during pre-motor stage, b) contralateral parietal and ipsilateral motor regions in high-beta band during motor execution. Similarly, spectral coherence revealed abnormal EEG connectivity within 1) sensorimotor network during rest in theta band, 2) (pre)motor networks during pre-motor stage in low-alpha and high-beta bands, 3) Fronto-parietal networks during execution in high-beta band. Furthermore, the abnormal EEG connectivity during rest and execution (but not during pre-motor stage) showed significant negative correlation with clinical ALS-functional-rating-scale scores. Combining abnormal EEG connectivity from rest, pre-motor, and execution stages provided more powerful discrimination between patients and controls with a uniquely higher contribution of measures pertaining to the pre-motor stage. The results indicate that pre-motor functional activity reflects a different and unique aspect of network impairment, with potential for inclusion as biomarker candidates in ALS.}, }
@article {pmid40030411, year = {2024}, author = {Mishra, S and Chatterjee, D and Kanekar, N}, title = {Topological Gait Analysis: A New Framework and Its Application to the Study of Human Gait.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7040-7053}, doi = {10.1109/JBHI.2024.3427700}, pmid = {40030411}, issn = {2168-2208}, mesh = {Humans ; *Gait Analysis/methods ; Adult ; Male ; Middle Aged ; Female ; Gait/physiology ; Aged ; Parkinson Disease/physiopathology ; Amyotrophic Lateral Sclerosis/physiopathology ; Signal Processing, Computer-Assisted ; Huntington Disease/physiopathology ; Algorithms ; }, abstract = {OBJECTIVE: This study introduces a physiologically driven topological gait analysis (TGA) framework to gain insights into pathological gait.<br><br>METHODS: A publicly available gait dataset consisting of four groups: healthy adults, people with Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) was used. The topological properties of the configuration space of three gait parameters were studied by approximating the underlying distribution through a Gaussian kernel-based density estimation technique. Thereafter, sublevel sets of the density estimate were analyzed using cubical persistence homology.<br><br>RESULTS: Three new features were constructed: 1. Probability density estimates (PDEs) that characterize the distribution of gait parameters over their configuration space. Healthy adults exhibited a unimodal distribution, while people with neurodegenerative disorders displayed a multi-modal distribution. 2. Persistence entropy plots that summarize changes in the PDEs and characterize the uncertainty in the underlying distribution. Gait of healthy adults was concentrated at higher entropy values as opposed to neurodegenerative gait. 3. A number that captures disease severity trends.<br><br>CONCLUSIONS: Topological features in PD and HD indicate a 'bias' to a certain set of gait configurations. This lack of exploration may reflect poor planning of the underlying topology, resulting in outward manifestations of impaired gait. The lower variegations in PDEs in ALS compared to PD and HD suggest that the planning of the topology of gait may occur at higher levels of the neural architecture.<br><br>SIGNIFICANCE: TGA offers characterization of gait at a hitherto uncharted level, potentially serving neuromotor markers for early diagnosis and personalized rehabilitation protocols.}, }
@article {pmid40029926, year = {2025}, author = {Panda, P and Mohanty, S and Gouda, SR and Baral, TC and Mohanty, A and Nayak, J and Mohapatra, R}, title = {Advanced strategies for enhancing the neuroprotective potential of curcumin: delivery systems and mechanistic insights in neurodegenerative disorders.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-26}, doi = {10.1080/1028415X.2025.2472773}, pmid = {40029926}, issn = {1476-8305}, abstract = {Background: Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant neuroprotective potential due to its diverse pharmacological properties.Objective: This review explores curcumin's role in modulating key pathological mechanisms underlying neurodegenerative disorders such as Alzheimer's, Parkinson's diseases, Amyotrophic Lateral Sclerosis, Huntington's Disease and Prion Disease.Methods: A comprehensive analysis of curcumin's molecular interactions, including its effects on amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal-induced neurotoxicity, was conducted. Additionally, strategies to overcome its low bioavailability and blood-brain barrier (BBB) permeability were evaluated.Results: Curcumin inhibits Aβ aggregation and promotes disaggregation, reducing amyloid plaque formation in Alzheimer's disease. It modulates glial cell activity, attenuating neuroinflammation and fostering a neuroprotective environment. By interacting with tau proteins, curcumin prevents hyperphosphorylation and neurofibrillary tangle formation. As a potent antioxidant, it scavenges reactive oxygen species, mitigating oxidative stress-related neuronal damage. Its metal-chelating properties further diminish neurotoxicity by sequestering iron and copper ions. Despite its limited bioavailability and BBB permeability, curcumin's therapeutic efficacy can be enhanced using nanocarriers such as nanoparticles, liposomes, and micelles, which improve solubility, stability, and brain penetration.Conclusion: Curcumin's multifaceted neuroprotective mechanisms make it a promising candidate for preventing or slowing neurodegenerative disease progression. Advanced drug delivery systems hold potential for overcoming its pharmacokinetic limitations, paving the way for future clinical applications.}, }
@article {pmid40029669, year = {2025}, author = {Carroll, E and Scaber, J and Huber, KVM and Brennan, PE and Thompson, AG and Turner, MR and Talbot, K}, title = {Drug repurposing in amyotrophic lateral sclerosis (ALS).}, journal = {Expert opinion on drug discovery}, volume = {20}, number = {4}, pages = {447-464}, pmid = {40029669}, issn = {1746-045X}, mesh = {*Drug Repositioning ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; *Drug Discovery/methods ; Translational Research, Biomedical/methods ; }, abstract = {INTRODUCTION: Identifying treatments that can alter the natural history of amyotrophic lateral sclerosis (ALS) is challenging. For years, drug discovery in ALS has relied upon traditional approaches with limited success. Drug repurposing, where clinically approved drugs are reevaluated for other indications, offers an alternative strategy that overcomes some of the challenges associated with de novo drug discovery.<br><br>AREAS COVERED: In this review, the authors discuss the challenge of drug discovery in ALS and examine the potential of drug repurposing for the identification of new effective treatments. The authors consider a range of approaches, from screening in experimental models to computational approaches, and outline some general principles for preclinical and clinical research to help bridge the translational gap. Literature was reviewed from original publications, press releases and clinical trials.<br><br>EXPERT OPINION: Despite remaining challenges, drug repurposing offers the opportunity to improve therapeutic options for ALS patients. Nevertheless, stringent preclinical research will be necessary to identify the most promising compounds together with innovative experimental medicine studies to bridge the translational gap. The authors further highlight the importance of combining expertise across academia, industry and wider stakeholders, which will be key in the successful delivery of repurposed therapies to the clinic.}, }
@article {pmid40029136, year = {2025}, author = {Revi, N and Nandeshwar, M and Harijan, D and Sankaranarayanan, SA and Joshi, M and Prabusankar, G and Rengan, AK}, title = {Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {6}, pages = {1103-1116}, doi = {10.1021/acschemneuro.4c00791}, pmid = {40029136}, issn = {1948-7193}, mesh = {*Microglia/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Animals ; *DNA-Binding Proteins/metabolism ; Benzimidazoles/pharmacology ; Neuroprotective Agents/pharmacology ; Mice ; Acridines/pharmacology ; Humans ; Molecular Docking Simulation ; }, abstract = {Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.}, }
@article {pmid40028680, year = {2025}, author = {Khosravi, S and Amini, E and Emamikhah, M and Alavi, A and Lang, AE and Rohani, M}, title = {Motor Neuron Involvement in Two ATP13A2-Related Families: ALS And HSP-Like Phenotypes.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70027}, pmid = {40028680}, issn = {2330-1619}, abstract = {BACKGROUND: Mutations in the ATP13A2 gene have been implicated in various neurodegenerative disorders, including Kufor-Rakeb syndrome (KRS), neuronal ceroid lipofuscinosis (NCL), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS). This report presents two Iranian families with ATP13A2 variants exhibiting atypical features of KRS.<br><br>CASES: We highlight four patients from two consanguineous Iranian families with mutations in the ATP13A2 gene presenting with variable features of motor neuron disease as well as juvenile-onset parkinsonism, and cognitive decline. The onset of symptoms ranged from 11 to 29&#x2009;years, with initial manifestations including gait disturbance, postural instability, and cognitive impairment. As the disease progressed, patients developed a range of neurological signs, such as dystonia, spasticity, and dysarthria.<br><br>CONCLUSION: This report expands the phenotypic spectrum of ATP13A2-related disorders, highlighting the potential overlap of symptoms associated with KRS, ALS, and HSP.}, }
@article {pmid40027730, year = {2025}, author = {Pant, DC and Lone, MA and Parameswaran, J and Ma, F and Dutta, P and Wang, Z and Park, J and Verma, S and Hornemann, T and Jiang, J}, title = {Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027730}, issn = {2692-8205}, support = {R01 AG068247/AG/NIA NIH HHS/United States ; UL1 TR000454/TR/NCATS NIH HHS/United States ; }, abstract = {Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 ΔExon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.}, }
@article {pmid40027671, year = {2025}, author = {Woo, E and Tasnim, F and Kawamata, H and Manfredi, G and Konrad, C}, title = {Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40027671}, issn = {2692-8205}, support = {R01 NS139141/NS/NINDS NIH HHS/United States ; R35 NS122209/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases and are associated with mutations in numerous genes. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1[A4V], TDP-43[N352S], FUS[R521G], CHCHD10[R15L], and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1[A4V], C9orf72, and TDP-43[N352S] iMN had increased mitochondrial membrane potential, while in CHCHD10[R15L] cells membrane potential was decreased. TDP-43[N352S] iMN displayed changes in mitochondrial morphology and increased motility. SOD1[A4V], TDP-43[N352S], and CHCHD10[R15L] iMN had increased oxygen consumption rates and altered extracellular acidification rates, reflecting a hypermetabolic state similar to the one described in sporadic ALS fibroblasts. FUS[R521G] mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. We then tested the viability of iMN and found decreases in survival in SOD1[A4V], C9orf72, and FUS[R521G], which were corrected by small molecules that target mitochondrial stress. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.}, }
@article {pmid40027590, year = {2025}, author = {Untalan, LGV and Malanog, JPD and Jamora, RDG}, title = {Evaluating YouTube as a source of information on amyotrophic lateral sclerosis.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251324439}, pmid = {40027590}, issn = {2055-2076}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that leads to progressive motor weakness and eventual death. Recent years have seen an increase in online information on ALS, with the popular video platform YouTube becoming a prominent source. We aimed to evaluate the quality, reliability, actionability, and understandability of ALS videos on YouTube.<br><br>METHODS: A search was performed using the keyword "Amyotrophic Lateral Sclerosis" on YouTube. A total of 240 videos were viewed and assessed by two independent raters. Video characteristics such as type of uploader, views, likes, comments, and Video Power Index were also collected.<br><br>RESULTS: Videos had moderate to low quality and reliability (Global Quality Scale [GQS] and modified DISCERN [mDISCERN] median 2.5), and poor understandability and actionability (PEMAT total median 8.5). Among the general video characteristics, only length of video showed a significant positive correlation across the tools (with mDISCERN [p&#x2009;<&#x2009;0.001]; with GQS [p&#x2009;<&#x2009;0.001]; with PEMAT [p&#x2009;<&#x2009;0.001]). Videos from physicians (p&#x2009;=&#x2009;0.024, sig <0.05), other healthcare professionals (p&#x2009;=&#x2009;0.017, sig <0.05), and educational channels (p&#x2009;=&#x2009;0.001, sig <0.05) had better quality when compared to others.<br><br>CONCLUSION: YouTube videos are a poor source of information for ALS as videos tend to have moderate to low quality and reliability and are poorly understandable and actionable. Longer videos, and videos uploaded by those in the healthcare and educational fields, were found to perform relatively better. Thus, when using YouTube, caution and careful attention to the video characteristics are recommended.}, }
@article {pmid40027570, year = {2025}, author = {Giorgio, A and Ciracì, E and De Luca, M and Stella, G and Giorgio, V}, title = {Hepatic abscess and hydatid liver cyst: European infectious disease point of view.}, journal = {World journal of hepatology}, volume = {17}, number = {2}, pages = {103325}, pmid = {40027570}, issn = {1948-5182}, abstract = {This manuscript is based on a recent study by Pillay et al that was published in recently. Liver abscesses can be caused by rare potentially life-threatening infections of either bacterial or parasitic origin. The incidence rate in Europe is lower than in developing countries, but it is a major complication with high morbidity, particularly in immunocompromised patients. They are most frequently caused by Enterobacterales infections, but hypervirulent Klebsiella strains are an emerging problem in Western countries. Amoebiasis has been a public health problem in Europe, primarily imported from other endemic foci. At the same time, this infection is becoming an emerging disease, as the number of infected patients who have not traveled to endemic areas is rising. Treatment options for hydatid liver cyst include chemotherapy, open or laparoscopic surgery, percutaneous treatment (percutaneous aspiration, re-aspiration and injection and its modification) and ''wait and watch'' strategy. Most hydatid liver cyst patients in Pillay et al's study received surgical treatment, but several studies have confirmed the safety and efficacy of percutaneous aspiration, re-aspiration and injection.}, }
@article {pmid40025671, year = {2025}, author = {Wang, Y and Li, C and Yang, Y and Ma, C and Zhao, X and Li, J and Wei, L and Li, Y}, title = {A Surface-Enhanced Raman Spectroscopy Platform Integrating Dual Signal Enhancement and Machine Learning for Rapid Detection of Veterinary Drug Residues in Meat Products.}, journal = {ACS applied materials &amp; interfaces}, volume = {17}, number = {10}, pages = {16202-16212}, doi = {10.1021/acsami.4c21938}, pmid = {40025671}, issn = {1944-8252}, mesh = {*Spectrum Analysis, Raman/methods ; *Veterinary Drugs/analysis ; *Machine Learning ; *Drug Residues/analysis ; *Meat Products/analysis ; Animals ; Metal Nanoparticles/chemistry ; Food Contamination/analysis ; }, abstract = {The detection and quantification of veterinary drug residues in meat remain a significant challenge due to the complex background interference inherent to the meat matrix, which compromises the stability and accuracy of spectroscopic analysis. This study introduces an advanced label-free surface-enhanced Raman spectroscopy (SERS) platform for the precise identification and quantification of veterinary drugs. By employing a dual enhancement strategy involving sodium borohydride activation and calcium ion-deuterium oxide guidance, this platform achieves the efficient capture and signal amplification of drug molecules on highly active nanoparticles. High-quality SERS spectra were obtained for carprofen, doxycycline hydrochloride, chloramphenicol, and penicillin G sodium salt, enabling accurate classification and interference suppression. In addition, the application of machine learning algorithms, including PCA-LDA, heatmap, and decision tree modeling, allows for accurate differentiation of mixed drug samples. Quantitative analyses in meat samples were achieved through Raman intensity ratios and multivariate curve resolution-alternate least-squares (MCR-ALS) analysis, with results showing high consistency with high-performance liquid chromatography (HPLC) measurements. These findings highlight the potential of this SERS-based platform for accurate and rapid detection of multicomponent veterinary drug residues in complex food matrices.}, }
@article {pmid40025240, year = {2025}, author = {Maier, A and Kettemann, D and Weyen, U and Grehl, T and Schulte, PC and Steinbach, R and Rödiger, A and Weydt, P and Petri, S and Wolf, J and Grosskreutz, J and Koch, JC and Weishaupt, JH and Rosseau, S and Norden, J and Körtvélyessy, P and Koch, B and Holm, T and Hildebrandt, B and Schumann, P and Walter, B and Riitano, A and Münch, C and Meyer, T and Spittel, S}, title = {Provision, cough efficacy and treatment satisfaction of mechanical insufflation-exsufflation in a large multicenter cohort of patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7360}, pmid = {40025240}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Cough ; Male ; Female ; *Insufflation/methods ; Middle Aged ; Aged ; *Patient Satisfaction ; Longitudinal Studies ; Treatment Outcome ; Germany ; }, abstract = {In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p < 0.05). Most patients who received MI-E used it daily (n = 290 of 370; 78.4%). Self-assessed cough deficiency correlated with clinical measurements, especially for patients with higher deficits. At follow-up visits, patients reported reduced cough deficiency (p < 0.001). Frequent MI-E use was linked to greater symptom relief and higher likelihood of recommending the therapy. This study highlights the symptomatic and palliative potential of MI-E therapy for ALS patients.}, }
@article {pmid40025162, year = {2025}, author = {Hiew, JY and Lim, YS and Liu, H and Ng, CS}, title = {Integrated transcriptomic profiling reveals a STING-mediated Type II Interferon signature in SOD1-mutant amyotrophic lateral sclerosis models.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {347}, pmid = {40025162}, issn = {2399-3642}, support = {#SED000125//Monash University Malaysia (Monash Malaysia)/ ; #PM010CNI000148//International Brain Research Organization (IBRO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/immunology ; Animals ; Humans ; Mice ; *Membrane Proteins/genetics/metabolism ; *Gene Expression Profiling ; *Disease Models, Animal ; *Superoxide Dismutase-1/genetics/metabolism ; Mutation ; Transcriptome ; Interferon-gamma/metabolism/genetics ; }, abstract = {Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS), particularly in cases with SOD1 mutations. Using integrative transcriptomics, we analyzed gene expression changes in mouse models throughout progression, human induced-pluripotent stem cells (hiPSCs), and post-mortem spinal cord tissue from ALS patients. We identified a conserved upregulation of interferon (IFN) genes and IFN-stimulating genes (ISGs) in both mouse models and human ALS, with a predominance Type I IFNs (IFN-α/β) in mice and Type II IFNs (IFN-γ) in humans. In mouse models, we observed robust and sustained upregulation of Type I and II ISGs, including ATF3, beginning at disease onset stage and persisting throughout disease progression. Single-cell transcriptomics further pinpointed vascular endothelial cells as a major source of ISGs. Furthermore, we found that the STING-TBK1 axis is essential for the induction of Type II ISGs in ALS, as its deletion impaired their expression. Our study uncovers a conserved ISGs signature across ALS models and patients, highlighting the potential role of innate immune activation in ALS pathogenesis. These findings suggest that ISGs may serve as potential biomarkers and therapeutic targets for ALS.}, }
@article {pmid40024955, year = {2025}, author = {Masood, S and Almas, MS and Hassan, SSU and Tahira, S and Fiaz, MH and Minhas, UEA and Zafar, HMQ and Masood, M}, title = {Safety and efficacy of arimoclomol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {40024955}, issn = {1590-3478}, abstract = {OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disorder characterized by muscle weakness, atrophy, and spasticity. This meta-analysis aims to assess the safety and efficacy of Arimoclomol in patients with ALS.<br><br>METHOD: A comprehensive literature search was conducted on 3 databases to discover articles published up to August 2024. Included studies were randomized controlled trials (RCTs). Data was analysed using Review Manager (v5.4). Cochrane Risk of Bias-2 (RoB-2) was adopted to assess the quality of RCTs.<br><br>RESULTS: A total of 359 patients were analysed, with 239 individuals in the Arimoclomol group and 120 individuals in the placebo group. The pooled analysis of the primary outcome, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score from baseline, did not demonstrate a statistically significant difference favoring the Arimoclomol group (MD&#x2009;=&#x2009;0.4495; 95% CI: -0.39, 1.27; p&#x2009;=&#x2009;0.30). Similarly, secondary outcomes, including the Combined Assessment of Function and Survival (CAFS) rank score (MD&#x2009;=&#x2009;1.00; 95% CI: -2.68, 4.67; p&#x2009;=&#x2009;0.60), increase in transaminases (RR&#x2009;=&#x2009;1.05; 95% CI: 0.19, 5.70; p&#x2009;=&#x2009;0.95), mortality rate (RR&#x2009;=&#x2009;0.86; 95% CI: 0.55, 1.34; p&#x2009;=&#x2009;0.50), and adverse events (RR&#x2009;=&#x2009;0.86; 95% CI: 0.55, 1.34; p&#x2009;=&#x2009;0.50), showed no statistically significant differences between the groups.<br><br>CONCLUSION: This study does not conclusively demonstrate that Arimoclomol has beneficial effects on ALS patients' physical functionality but shows promise for safety. Further clinical trials are needed to explore the neuroprotective effects of Arimoclomol in the treatment of ALS.}, }
@article {pmid40024058, year = {2025}, author = {Baumgarten, BR and Freye, CE}, title = {Use of Fisher's Ratio assisted multivariate curve resolution- alternating least squares for discovery-based analysis using ultrahigh pressure liquid chromatography-high resolution mass spectrometry.}, journal = {Journal of chromatography. A}, volume = {1747}, number = {}, pages = {465812}, doi = {10.1016/j.chroma.2025.465812}, pmid = {40024058}, issn = {1873-3778}, mesh = {Chromatography, High Pressure Liquid/methods ; Least-Squares Analysis ; Multivariate Analysis ; *Mass Spectrometry/methods ; Pharmaceutical Preparations/analysis/chemistry ; }, abstract = {Non-targeted analysis of complex chemical mixtures can be difficult considering the convoluted nature of the matrix and the potential unknown chemical differences between samples or classes of samples. Ultrahigh pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF) is an ideal technique to probe chemical differences for a wide variety of samples. While UHPLC-QTOF can discover minute chemical differences down to low part per billion (ppb) concentrations with a high degree of confidence, the application of high-resolution mass spectrometry can yield massive amounts of information (∼ 10 gb per sample) that cannot be analyzed manually. Therefore, the application of chemometric techniques is mandatory for the interrogation of complex samples. Fisher's ratio (FR) assisted multivariate curve resolution-alternating least squares (MCR-ALS) was used to the discover and identify the chemical differences between two classes of materials: 1) a pond water matrix and 2) the matrix spiked with a pharmaceutical standard mix containing 17 compounds. Thirteen of the seventeen spiked compounds were discovered using FR analysis, and then five were successfully deconvoluted using MCR-ALS wherein the number of curves chosen were automatically determined using singular value decomposition (SVD). The use of an automated FR assisted MCR-ALS will aid in discovering trace levels of chemical components without the need for the researcher to provide potentially biased input which will aid in non-targeted workflow.}, }
@article {pmid40022663, year = {2025}, author = {Buckett, LE and Holdom, CJ and Howe, SL and McCombe, PA and Henderson, RD and Al-Chalabi, A and Steyn, FJ and Ngo, ST}, title = {Persistent high levels of perceived fatigue are not associated with hypermetabolism in patients with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2471429}, pmid = {40022663}, issn = {2167-9223}, abstract = {Objective: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Little is known about factors that contribute to fatigue, and whether levels of fatigue change throughout disease course. We aimed to determine associations between self-reported perceived fatigue and metabolic and clinical features of ALS, and perceived fatigue over the course of disease. Methods: This prospective study was conducted between July 2017 and March 2024. Baseline measures of self-reported perceived fatigue, metabolic rate, and clinical measures of disease were assessed in 117 participants with clinically definite or probable ALS. For comparison, fatigue and metabolic rate were collected from 107 control participants. Perceived fatigue was determined using the Fatigue Severity Scale (FSS). Metabolic rate was assessed using indirect calorimetry. Functional capacity and clinical progression were assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Results: Baseline levels of perceived fatigue were greater in people living with ALS (plwALS) when compared to controls (5.44 vs. 2.55; p < 0.01). Perceived fatigue was higher in plwALS with lower ALSFRS-R scores and was not associated with measures of metabolism. For most plwALS, perceived fatigue remained high as functional capacity worsened. Conclusion: Our findings confirm higher prevalence of perceived fatigue in plwALS, with persistently high FSS scores reported by most patients during follow-up. High levels of fatigue were not associated with hypermetabolism, suggesting that metabolic rate is unlikely to be a primary contributor. Results highlight a need for further research to identify factors that contribute to fatigue in ALS, and options for improved fatigue management.}, }
@article {pmid40022581, year = {2025}, author = {Galvin, M and Heverin, M and Mac Domhnaill, &#xc9; and Mcfarlane, R and Meldrum, D and Murray, D and Bolger, A and Connelly, J and Flynn, K and Fox, E and Gibbons, F and Hederman, L and Impey, S and O'Keefe, I and O'Meara, C and McKibben, D and Nicholson, M and Stephens, G and Van Dijk, J and Van Den Berg, L and Hardiman, O}, title = {Challenges and solutions to complex data governance issues in cross-national, cross-sectoral, multidisciplinary real world health research: a descriptive overview.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2428927}, pmid = {40022581}, issn = {2167-9223}, abstract = {Real-world clinical data is generated during clinical engagements. The collection and further processing and mining of clinical information requires consents and navigation of necessary and important data governance processes. PRECISION ALS is an academic industry programme that collects, collates and analyses clinical and para-clinical data from patients with ALS across 10 European sites. The infrastructure of PRECISION ALS represents a complex interplay of the clinical, governance, and technical frameworks. Incorporation of infrastructural and operational measures enables sophisticated cross-national, cross-sectoral and cross disciplinary health research. PRECISION ALS has established a range of domain expertise, technologies, governance and clinical data management practices that can be applied throughout the life cycle of patient data from generation, collation, delivery and secure storage for advanced analytics. PRECISION ALS is designed to move the field of ALS research to a true Precision Medicine based approach toward new and more effective therapeutics.}, }
@article {pmid40021952, year = {2025}, author = {Hao, Y and Li, Z and Du, X and Xie, Q and Li, D and Lei, S and Guo, Y}, title = {Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {31}, number = {1}, pages = {82}, pmid = {40021952}, issn = {1528-3658}, support = {92478109//National Natural Science Foundation of China/ ; 82471451//National Natural Science Foundation of China/ ; ZR2024QB108//Shandong Provincial Natural Science Foundation/ ; 7222082//Beijing Municipal Natural Science Foundation&#xff0c;China/ ; }, mesh = {Animals ; *Disease Models, Animal ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mice ; *Mice, Transgenic ; *Proteomics/methods ; *Acetylglucosamine/metabolism ; *Spinal Cord/metabolism ; Glycosylation ; Superoxide Dismutase-1/metabolism/genetics ; Protein Processing, Post-Translational ; Humans ; Proteome/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been found to affect the processing of several important proteins implicated in ALS. However, the overall level and cellular localization of O-GlcNAc during ALS progression are incompletely understood, and large-scale profiling of O-GlcNAcylation sites in this context remains unexplored.<br><br>METHODS: By using immunostaining analysis and chemoenzymatic labeling-based quantitative chemoproteomics, we assayed O-GlcNAcylation dynamics of lumbar spinal cords from SOD-G93A mice and their non-transgenic (NTG) littermates, the most widely used animal model for studying ALS pathogenesis.<br><br>RESULTS: We discovered that the global O-GlcNAcylation was significantly reduced at the disease end stage. Correlatively, a great increase of OGA was observed. Immunohistochemistry and immunofluorescence analysis showed a higher proportion of O-GlcNAc-positive neurons in the NTG group, while O-GlcNAc colocalization with astrocytes/microglia was elevated in SOD1-G93A mice. Moreover, we reported the identification of 568 high-confidence O-GlcNAc sites from end-stage SOD1-G93A and NTG mice. Of the 568 sites, 226-many of which occurred on neuronal function and structure-related proteins-were found to be dynamically regulated.<br><br>CONCLUSION: These data provide a valuable resource for dissecting the functional role of O-GlcNAcylation in ALS and shed light on promising therapeutic avenues for ALS. The chemoenzymatic labeling-based chemoproteomic approach is applicable for probing O-GlcNAc dynamics in various pathological processes.}, }
@article {pmid40020551, year = {2025}, author = {Tafuri, B and Giugno, A and Nigro, S and Zoccolella, S and Barone, R and Tamburrino, L and Gnoni, V and Urso, D and Rollo, E and De Blasi, R and Logroscino, G}, title = {Radiomic alterations and clinical correlates of hypothalamic nuclei in ALS.}, journal = {Computers in biology and medicine}, volume = {189}, number = {}, pages = {109906}, doi = {10.1016/j.compbiomed.2025.109906}, pmid = {40020551}, issn = {1879-0534}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; *Hypothalamus/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; Retrospective Studies ; Body Mass Index ; Adult ; Image Processing, Computer-Assisted/methods ; Radiomics ; }, abstract = {OBJECTIVE: The aim of this study is to analyze hypothalamic changes and clinical/metabolic correlates with a radiomic approach in Amyotrophic Lateral Sclerosis (ALS).<br><br>METHODS: We retrospectively identified 54 sporadic ALS patients and 53 matched controls. We compared radiomics features over hypothalamic subunits in T1-weighted. Semi-partial correlation (Spearman's correlation) assessed the relationship between Body Mass Index (BMI) and clinical scores with radiomics features. We considered only moderate correlations (rho>|0.4|).<br><br>RESULTS: Compared to HC, individuals with ALS showed significantly higher values of radiomic measures in the left Anterior-Inferior, Posterior and Inferior-Tubular hypothalamic subunits. Similarly, right hypothalamic nuclei reported significant differences in Anterior-Superior, Posterior and Inferior-Tubular nuclei. Two radiomics measures of randomness of the intensities in left Anterior-Inferior subunit showed highly significant correlation with greater BMI values. Higher local homogeneity of the right Inferior-Tubular subunit corresponded to higher ALS Functional Rating Scale-Revised (ALSFRS-r), while finer textures of the left Anterior-Superior subunit were negatively related with disease progression rate.<br><br>CONCLUSIONS: These results support the hypothesis that a degenerative process affecting hypothalamus in ALS extends beyond the atrophy process. Intriguingly, the close relationship between the entropy of left Anterior-Inferior nucleus and the higher BMI may further demonstrate the critical role of hypothalamus in eating abnormalities. Furthermore, the inhomogeneity of the right Inferior-Tubular subunit reflects a more severe clinical condition by ALSFRS-R. This work represents a significant advancement in the study of ALS and its association with hypothalamic changes through a novel radiological approach, uncovering new associations between sub-hypothalamic radiomic changes, anthropometric measures, and disease outcomes.}, }
@article {pmid40019593, year = {2025}, author = {Dobroniak, CC and Lesche, V and Olgemöller, U and Beck, P and Lehmann, W and Spering, C}, title = {Surgical strategy for chest wall reconstruction secondary to cardiopulmonary resuscitation versus post-traumatic.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {51}, number = {1}, pages = {122}, pmid = {40019593}, issn = {1863-9941}, mesh = {Humans ; *Cardiopulmonary Resuscitation/methods ; Male ; Female ; Retrospective Studies ; Middle Aged ; *Thoracic Wall/injuries/surgery ; *Flail Chest/surgery/etiology ; *Rib Fractures/surgery ; *Sternum/injuries/surgery ; Germany ; Plastic Surgery Procedures/methods ; Aged ; Fracture Fixation, Internal/methods ; Adult ; Length of Stay/statistics &amp; numerical data ; Bone Plates ; }, abstract = {PURPOSE: In mechanically cardiopulmonary resuscitated (CPR) patients, chest compressions at the level of the 3rd to 5th rib on the sternum result in reproducibly similar injury patterns: parasternal osteochondral dissociation (OCS) on both sides in combination with a sternal fracture with or without an additional serial rib fracture in the anterolateral column (ALS). This injury biomechanically impairs physiological breathing, resulting in an inverse breathing pattern. Trauma patients, on the other hand, often show a mixed pattern depending on the location of the main energy. The aim of the study was to evaluate the surgical technique of chest wall reconstruction (CWR) using transsternal refixation of the 5th rib on both sides in combination with plate osteosynthesis of the sternum and to analyze its success in comparison to the surgical strategy of CWR in the context of a traumatic genesis.<br><br>METHOD: Data acquisition was performed using medical records of a Level I Trauma Centre in Germany and compare patients with radiologically or clinically diagnosed flail chest as a result of cardiopulmonary mechanical resuscitation (CPR). The retrospective study included patients in the period 2018-2023 after surgical CWR. The patients were either post-CPR (n&#x2009;=&#x2009;29; CPR) or trauma patients (n&#x2009;=&#x2009;36; trauma). The collective was described and analyzed using the digital patient file, as well as data on ICU stay and duration of ventilation or conversion to assisted ventilation modes, reason for chest wall instability, time of surgery, length of stay and mortality. As a long-term follow-up, body plethysmography was analyzed comparatively. Primary endpoints were mean length of stay in ICU, time to surgery, ventilator dependency and mortality rate. Secondary endpoints were time to transfer to rehabilitation, ventilation disorders and long term outcome.<br><br>RESULTS: In the period 65 patients (48&#xa0;m, 17w) were included, 29 of whom had been mechanically resuscitated (CPR), 36 formed to post-traumatic cohort (trauma). The CPR were significantly older (69 vs. 58 years; p-value 0.003). The duration from CPR to surgery was on average significantly longer than trauma to surgery (16.76 vs. 4.11 days). The mean length of stay in ICU were 30 days (trauma) and 45 days for CPR (significantly longer, p-value 0.0008). The mean duration of ventilation was 188&#xa0;h for trauma and 593&#xa0;h for CPR. Extubation or conversion to assisted, relevant de-escalating ventilation modes was possible in both groups after a mean of 38&#xa0;h post-OP. Among the CPR patients, 4 died in hospital (hospital mortality: CPR 20.7% vs. trauma 5.6%), 7 (30%) were transferred to an early clinical rehabilitation and 10 were discharged to home or follow-up treatment. In the case of trauma, 5 (14.7%) were transferred to an early clinical rehabilitation and 20 were discharged to home or follow-up treatment. Bodyplethysmography 6 months after CPR / trauma showed no differences in both collectives with regard to ventilation disorders. Diffusion was prolonged in both groups, presumably due to the healing process of lungs contusion. Both showed no restriction disorders.<br><br>CONCLUSION: Chest wall reconstruction, including plate osteosynthesis of the sternum in combination with transsternal fixation of the 5th rib on both sides can largely restore physiological respiratory mechanics immediately after surgery and accelerate the weaning success. In the management of patients after CPR, the initial diagnosis which had indicated resuscitation, is the main focus and can often be an obstacle to extubation. Nevertheless, independent breathing can be accelerated by restoring the biomechanics through early surgical treatment using CWR and saves long-term ICU stays with the potential for further complication and resource consumption. CWR forms the essential basis for early rehabilitation of the underlying cause of resuscitation. Ventilation disorders do not occur after surgical CWR, even during the course of the procedure.}, }
@article {pmid40019589, year = {2025}, author = {Shaw, SK and Sravani, N and Sharma, A and Anand, J}, title = {Assessment of probable zones of agricultural land suitability based on MCDM, probabilistic, and data-driven approach in Krishna District, India.}, journal = {Environmental monitoring and assessment}, volume = {197}, number = {3}, pages = {339}, pmid = {40019589}, issn = {1573-2959}, mesh = {*Agriculture/statistics &amp; numerical data ; Conservation of Natural Resources/methods ; Decision Making ; *Decision Support Techniques ; Ecosystem ; Geographic Information Systems ; India ; Meteorological Concepts ; Remote Sensing Technology ; }, abstract = {Agricultural land evaluation is essential for crop cultivation for fostering a sustainable and productive agricultural system. To address this issue, this current study implements geographic information system (GIS)-based analytical hierarchy process (AHP), frequency ratio (FR), Shannon entropy (SE), and evidential belief function (EBF) models for possible identification of agricultural land in Krishna district, India. Eight thematic layers viz. rainfall, temperature, soil texture, slope, soil moisture index, organic matter content, groundwater level, and land use/land cover (LULC) exhibit their relative contribution toward the agricultural land suitability (ALS) assessment. A total of 56 groundwater wells are considered to prepare well inventory map. Then, 70% (40) and 30% (16) wells are taken to perform accuracy assessment of the proposed methods in training and validation phase respectively by receiver operating characteristics (ROC) curve and Seed Cell Area Index (SCAI) method. Four distinct classes of ALS have been delineated by each model viz. poor, moderate, high, and very high. AHP (79.05%) and SE (89.94%) showcases their effectiveness in delineating highly suitable agricultural land constituting higher area. Whereas EBF and FR model identifies 33.35% and 27% area of this district as moderate to poor ALS respectively. AUC value reveals that AHP (AUC = 0.701) method can be highly convenient in training phase, whereas EBF (AUC = 0.626) model evaluates average predictive strength for ALS assessment in validation phase for this study area. Outcomes of SCAI method demonstrate higher classification accuracy of SE model indicating higher suitability of bivariate approaches in accurate prediction. Results of this research significantly develop useful perception for the sustainable use and management of agricultural land of Krishna district with higher crop production. This will also help the Agricultural and Irrigation department of this district to build applicative plan for effective utilization of agricultural land with optimized use of available water resources.}, }
@article {pmid40019378, year = {2025}, author = {Li, X and Jin, S and Wang, D and Wu, Y and Tang, X and Liu, Y and Yao, T and Han, S and Sun, L and Wang, Y and Hou, SX}, title = {Accumulation of Damaging Lipids in the Arf1-Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2414260}, doi = {10.1002/advs.202414260}, pmid = {40019378}, issn = {2198-3844}, support = {2023YFA1800202//National Key Research and Development Program of China/ ; 82450108//National Natural Science Foundation of China/ ; 82203511//National Natural Science Foundation of China/ ; 82472817//National Natural Science Foundation of China/ ; }, abstract = {Lipid metabolism disorders in both neurons and glial cells have been found in neurodegenerative (ND) patients and animal models. However, the pathological connection between lipid droplets and NDs remains poorly understood. The recent work has highlighted the utility of a neuron-specific Arf1-knockout mouse model and corresponding cells for elucidating the nexus between lipid metabolism disorders and amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, it is found that Arf1 deficiency first induced surplus fatty acid synthesis through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further caused mitochondrial DNA (mtDNA) to be released into cytoplasm. Concurrently, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons might also induce accumulation of sphingolipids in lysosomes that caused dysfunction of autophagy and lysosomes, which further promoted lysosomal stress and mitochondria-derived extracellular vesicles (MDEVs) release. The released MDEVs carried mtDNA into microglia to activate the inflammatory pathways and neurodegeneration. The studies on neuronal lipid droplets (LDs) and recent studies of microglial LDs suggest a unified pathological function of LDs in NDs: activating the inflammatory pathways in microglia. This finding potentially provides new therapeutic strategies for NDs.}, }
@article {pmid40017821, year = {2025}, author = {Dierksen, F and Geibel, JS and Albrecht, J and Hofer, S and Dechent, P and Hesse, AC and Frahm, J and Bähr, M and Koch, JC and Liman, J and Maier, IL}, title = {T1-relaxation times along the corticospinal tract as a diagnostic marker in patients with amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroimaging}, volume = {4}, number = {}, pages = {1549727}, pmid = {40017821}, issn = {2813-1193}, abstract = {BACKGROUND AND PURPOSE: In the differential diagnostic workup of amyotrophic lateral sclerosis (ALS), magnetic resonance imaging (MRI) is primarily used to rule out significant differential diagnoses. So far, whole-brain T1-mapping has not been assessed as a diagnostic tool in this patient population.<br><br>METHODS: We investigated the diagnostic potential of a novel T1-mapping method based on real-time MRI with 0.5 mm in-plane resolution and 4s acquisition time per slice. The study included patients aged 18 to 90 years who met the revised El Escorial criteria for at least possible ALS. T1-relaxation times were measured along the corticospinal tract in predefined regions of interest.<br><br>RESULTS: Twenty-nine ALS-patients and 43 control group patients (CG) were included in the study. Median ALS Functional Rating Scale revised (ALSFRS-R) was 37 (IQR, 35-44) points and the mean duration from symptom onset to MRI was 21 &#xb1; 17 (SD) months. ALS patients showed significantly higher T1-relaxation times in all ROIs compared to CG with mean differences in the hand knob of 50 ms (p < 0.001), corona radiata 24 ms (p = 0.034), internal capsule 27 ms (p = 0.002) and midbrain peduncles 48 ms (p < 0.001). There was a consistent negative correlation between the ALSFRS-R and T1-relaxation times in all ROIs.<br><br>CONCLUSIONS: T1-relaxation times along the corticospinal tract are significantly elevated in ALS patients compared to CG and associated with lower ALSFRS-R. These results imply the analysis of T1-relaxation times as a promising diagnostic tool that can distinguish ALS patients from the control group. Ongoing longitudinal studies may provide deeper insights into disease progression and the effects of therapeutic interventions.}, }
@article {pmid40017539, year = {2025}, author = {Mengistu, DY and Terribili, M and Pellacani, C and Ciapponi, L and Marzullo, M}, title = {Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular medicine}, volume = {5}, number = {}, pages = {1530719}, pmid = {40017539}, issn = {2674-0095}, abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.}, }
@article {pmid40017137, year = {2025}, author = {Lovett, A and Chary, S and Babu, S and Bruneteau, G and Glass, JD and Karlsborg, M and Ladha, S and Mayl, K and McDermott, C and Bucelli, RC and Chiò, A and Ferguson, TA and Cochrane, T and Fradette, S and Smirnakis, K and Inra, J and Malek, S and Fanning, L}, title = {Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28372}, pmid = {40017137}, issn = {1097-4598}, support = {//Biogen/ ; }, abstract = {INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.<br><br>METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.<br><br>RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.<br><br>DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.}, }
@article {pmid40016300, year = {2025}, author = {Xia, Y and Gregory, JM and Waldron, FM and Spence, H and Vallejo, M}, title = {Improving ALS detection and cognitive impairment stratification with attention-enhanced deep learning models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {7045}, pmid = {40016300}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/complications ; *Deep Learning ; *Cognitive Dysfunction/diagnosis ; Female ; Male ; Aged ; Middle Aged ; Attention ; Neural Networks, Computer ; Brain/diagnostic imaging/pathology ; Neuroimaging/methods ; Frontotemporal Dementia/diagnosis/diagnostic imaging/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease marked by motor deterioration and cognitive decline. Early diagnosis is challenging due to the complexity of sporadic ALS and the lack of a defined risk population. In this study, we developed Miniset-DenseSENet, a convolutional neural network combining DenseNet121 with a Squeeze-and-Excitation attention mechanism, using 190 autopsy brain images from the Gregory Laboratory at the University of Aberdeen. The model distinguishes controls, ALS patients with no cognitive impairment, and ALS patients with cognitive impairment (ALS-frontotemporal dementia) with 97.37% accuracy, addressing a significant challenge in overlapping neurodegenerative disorders involving TDP-43 proteinopathy. Miniset-DenseSENet outperformed other transfer learning models, achieving a sensitivity of 1 and specificity of 0.95. These findings suggest that integrating transfer learning and attention mechanisms into neuroimaging can enhance diagnostic accuracy, enabling earlier ALS detection and improving patient stratification. This model has the potential to guide clinical decisions and support personalied therapeutic strategies.}, }
@article {pmid40015858, year = {2025}, author = {Vijayarajan, VBA and Torra, J and Runge, F and de Jong, H and van de Belt, J and Hennessy, M and Forristal, PD}, title = {Confirmation and characterisation of ALS inhibitor resistant Poa trivialis from Ireland.}, journal = {Pesticide biochemistry and physiology}, volume = {208}, number = {}, pages = {106266}, doi = {10.1016/j.pestbp.2024.106266}, pmid = {40015858}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/antagonists &amp; inhibitors/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Ireland ; *Sulfonylurea Compounds/pharmacology ; Mutation ; Sulfonamides/pharmacology ; Plant Proteins/genetics/antagonists &amp; inhibitors ; Plant Weeds/drug effects ; Poaceae/drug effects ; Isoxazoles ; Sulfones ; }, abstract = {Relying on one broad-spectrum product to control grass weeds has resulted in cases of resistance to acetolactate synthase (ALS) inhibitors in species that were not the primary target such as Poa trivialis (POATR), in wheat fields in Ireland. In this study, we have characterised ALS inhibitor resistance in two populations of POATR-R, suspected of being resistant, to (i) sulfonylurea (SUs)-mesosulfuron + iodosulfuron (the selecting agent), (ii) SU + sulfonylamino‑carbonyl-triazolinone (SCT)-mesosulfuron + propoxycarbazone, and (iii) triazolopyrimidine (TP)-pyroxsulam ALS chemistries. Resistant POATR-R populations showed ALS inhibitor cross-resistance associated with target-site resistance (TSR) mutations. Combined mutations (Pro-197 and Trp-574) were found in POATR-R plants; Trp-574-Leu in POATR-R1 conferring greater SUs, SU + SCT and TP (resistance index, RI >214) resistance, while Pro-197-Thr in POATR-R2 (RI >37) was associated with less resistance. The high levels of ALS inhibitor cross-resistance in POATR-R populations caused by TSR mutations are consistent with the ploidy status, as cytogenetic tests revealed that both the R and S populations were diploid (2n = 2× = 14). Cytochrome P450 inhibitor assays did not detect metabolism-based ALS resistance in POATR-R. Alternative herbicide modes of action, including acetyl-CoA carboxylase (pinoxaden, fenoxaprop, propaquizafop, cycloxydim or clethodim) and 5-enolpyruvylshikimate-3-phosphate synthase (glyphosate) inhibitors applied at the recommended label rate were highly effective on these resistant populations. Residual herbicides and cultural methods, as well as the judicious use of alternative in-crop herbicide options, should be prioritized as sustainable options for managing these ALS-resistant populations. This is first worldwide characterisation of resistance mechanisms in P. trivialis to ALS inhibitor chemistries.}, }
@article {pmid40015855, year = {2025}, author = {Xu, Y and Xu, F and Li, Y and Wang, X and Han, Y and Zheng, M}, title = {Effects of Pro197 resistance mutations occurring in different acetolactate synthase (ALS) isozymes on Descurainia sophia L. resistance to tribenuron-methyl.}, journal = {Pesticide biochemistry and physiology}, volume = {208}, number = {}, pages = {106263}, doi = {10.1016/j.pestbp.2024.106263}, pmid = {40015855}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Arylsulfonates/pharmacology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Isoenzymes/genetics ; *Mutation ; Plant Proteins/genetics/metabolism ; Plant Weeds/drug effects/genetics ; }, abstract = {Descurainia sophia L. is one of the most problematic broad-leaf weed infesting winter wheat in China, and have evolved resistance to acetolactate synthase (ALS)-inhibiting herbicide of tribenuron-methyl. At least four ALS isozymes (ALS1 ∼ ALS4) exist in D. sophia, but these four ALS isozymes are not present in all D. sophia. In addition, amino acid mutations in ALS are mainly responsible for D. sophia resistance to tribenuron-methyl. In this study, D. sophia populations carrying homozygous mutation of Pro197Ser/Thr/Leu/Ala/His in ALS1 or in ALS2 were purified, respectively. Resistant D. sophia populations carrying mutant ALS exhibited 17 ∼ 694 folds resistance to tribenuorn-methyl. In addition, tribenuron-methyl resistance in D. sophia carrying ALS1 mutation was about 2.3 ∼ 11.4 folds higher than D. sophia with the same mutation in ALS2. The reduced binding affinity of ALS to tribenuron-methyl was mainly responsible for D. sophia resistance to tribenuron-methyl. However, the increase in resistance of D. sophia was not linear with the decrease of binding affinity of ALS to tribenuron-methyl. These results indicate that the effects of resistance mutations on ALS1 and ALS2 isozymes are not the same, and the ALS1 and ALS2 function differently in resistance evolution of D. sophia to tribenuron-methyl.}, }
@article {pmid40015643, year = {2025}, author = {Hasumi, M and Ito, H and Machida, K and Niwa, T and Taminato, T and Nagai, Y and Imataka, H and Taguchi, H}, title = {Dissecting the mechanism of NOP56 GGCCUG repeat-associated non-AUG translation using cell-free translation systems.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {4}, pages = {108360}, doi = {10.1016/j.jbc.2025.108360}, pmid = {40015643}, issn = {1083-351X}, abstract = {The repeat expansion in the human genome contributes to neurodegenerative disorders such as spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis. Transcripts with repeat expansions undergo noncanonical translation called repeat-associated non-AUG (RAN) translation. The NOP56 gene, implicated in SCA36, contains a GGCCTG repeat in its first intron. In tissues of patients with SCA36, poly (Gly-Pro) and poly (Pro-Arg) peptides, likely produced through NOP56 RAN translation in (NOP56-RAN), have been detected. However, the detailed mechanism underlying NOP56-RAN remains unclear. To address this, we used cell-free translation systems to investigate the mechanism of NOP56-RAN and identified the following features. (i) Translation occurs in all reading frames of the sense strand of NOP56 intron 1. (ii) Translation is initiated in a 5' cap-dependent manner from near-cognate start codons upstream of the GGCCUG repeat in each frame. (iii) Longer GGCCUG repeats enhance NOP56-RAN. (iv) A frameshift occurs within the GGCCUG repeat. These findings provide insights into the similarities between NOP56-RAN and other types of RAN translation.}, }
@article {pmid40015332, year = {2025}, author = {Tavares de Sousa, M and Hergert, B and Crispi, F and Gomez, O and Hecher, K}, title = {Imaging the fetal aortic arch and its branching pattern in a midtrimester screening population.}, journal = {Ultraschall in der Medizin (Stuttgart, Germany : 1980)}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2548-2411}, pmid = {40015332}, issn = {1438-8782}, abstract = {UNLABELLED: Purpose Variants of the aortic arch branching have recently been found to have an impact for neonates undergoing surgical interventions of the thoracic aorta such as repair of aortic coarctation. They have been described prenatally in 6%, whereas they occur in up to 26% postnatally. To explore whether the branching variations might have been under-diagnosed in utero, we comprehensively assessed the aortic arch and its branching patterns in a low-risk population between 19 and 22 weeks of gestation. Material and Methods This prospective cohort study included 139 low-risk singleton pregnancies. During a standardized fetal echocardiography we investigated the aortic arch in a sagittal view according to predefined landmarks. Based on video clips, its branching pattern was categorized in normal branching or branching variants by two operators who were blinded to each other. Results Classification of the aortic arch branching was achieved in 127/139 (91.4%) cases. 103 cases (81.1%) showed a normal pattern and 24 cases (18.9%) a branching variant. Both operators agreed on 18 brachiobicephalic trunks "(THE SO CALLED BOVINE ARCH)": , 4 aberrant left vertebral arteries, one aortic arch with five branching vessels and in one case there was disagreement on the type of the variant. Conclusion Prenatal targeted echocardiography could identify a 18.9% prevalence of aortic arch branching variants in a low-risk population. Future studies are warranted to assess the clinical impact of our findings on neonates with congenital heart defects.<br><br>HINTERGRUND: Gef&#xe4;&#xdf;varianten der thorakalen Aortenabg&#xe4;nge wurden als Risikofaktoren f&#xfc;r Neugeborene identifiziert, die eine Intervention der Aorta, zum Beispiel bei Aortenisthmusstenose, vor sich haben. Pr&#xe4;natal wurde die H&#xe4;ufigkeit mit bis zu 6% beschrieben, w&#xe4;hrend sie postnatal in bis zu 26% gefunden wurden. Um zu untersuchen, ob die Varianten bisher in utero unterdiagnostiziert wurden, untersuchten wir den Aortenbogen und die Abg&#xe4;nge in einer Niedrigrisikogruppe zwischen 19 und 22 Schwangerschaftswochen.<br><br>MATERIAL UND METHODEN: Diese prospektive Kohortenstudie umfasste 139 Einlingsschwangerschaften mit niedrigem Risiko. W&#xe4;hrend einer standardisierten fetalen Echokardiografie untersuchten wir den Aortenbogen in sagittaler Ebene. Anhand von Videoclips wurden die Abg&#xe4;nge des Aorta von zwei Untersuchenden, die zueinander verblindet waren, entweder als normales Abgangsmuster oder als Variante klassifiziert.<br><br>ERGEBNISSE: Die Klassifizierung des Abg&#xe4;nge der fetalen Aorta gelang in 127/139 (91,4 %) der F&#xe4;lle. In 103 F&#xe4;llen (81,1 %) wurde ein normales Abgangsmuster beobachtet, w&#xe4;hrend in 24 F&#xe4;llen (18,9 %) eine Variante vorlag. In 18 F&#xe4;llen wurde ein Truncus brachiocephalicus (SOGENANNTER BOVINER AORTENBOGEN),: in 4 F&#xe4;llen eine aberrante linke Vertebralarterie und in einem Fall ein Aortenbogen mit f&#xfc;nf abgehenden Gef&#xe4;&#xdf;en gefunden. In einem Fall waren die Untersuchenden bez&#xfc;glich der Variante uneinig.<br><br>SCHLUSSFOLGERUNG: Die gezielte pr&#xe4;natale Echokardiografie konnte in einer Niedrigrisikopopulation eine Pr&#xe4;valenz von 18,9 % f&#xfc;r Varianten der Abg&#xe4;nge des Aortenbogen identifizieren. Zuk&#xfc;nftige Studien sind erforderlich, um die klinischen Auswirkungen unserer Ergebnisse auf Neugeborene mit angeborenen Herzfehlern zu bewerten.}, }
@article {pmid40014834, year = {2025}, author = {Gusovsky Chevalier, AV and Lin, CC and Kerber, K and Reynolds, EL and Callaghan, BC and Burke, JF}, title = {Cost Trends of New-To-Market Neurologic Medications: An Insurance Claims Database Analysis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213428}, pmid = {40014834}, issn = {1526-632X}, support = {T32 HS029590/HS/AHRQ HHS/United States ; }, mesh = {Humans ; Male ; Female ; United States ; Middle Aged ; *Databases, Factual ; Aged ; Adult ; Nervous System Diseases/drug therapy/economics ; Insurance Claim Review/trends ; Drug Costs/trends ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: Costs for neurologic medications have increased considerably in recent years. Since 2014, more than 30 neurologic medications have been approved by the US Food and Drug Administration (FDA) for neurologic conditions. This study aims to characterize recent trends in annual costs and aggregate spending from 2012 to 2021 for new-to-market (NTM) medications for 9 neurologic conditions.<br><br>METHODS: We used the Merative MarketScan commercial and Medicare supplemental databases to observe patients seen by a neurologist with neurologic diseases with newly FDA-approved medications from 2014 to 2021: amyotrophic lateral sclerosis (ALS), transthyretin amyloidosis (ATTR), Duchenne muscular dystrophy (DMD), Huntington disease (HD), myasthenia gravis (MG), migraine, orthostatic hypotension (OH), tardive dyskinesia (TD), and spinal muscular atrophy (SMA). Patients were included if they had &#x2265;1 disease-related prescription medication fill from 2012 to 2021. NTM (medications approved from 2014 to 2021) and older evidence-based guideline-supported medications were observed annually. Outcomes examined were annual and aggregate out-of-pocket (OOP) and total medication costs.<br><br>RESULTS: We identified 2,687 unique individuals with ALS, 38 with ATTR, 69 with DMD, 884 with HD, 9,984 with MG, 441,099 with migraine, 4,723 with OH, 1,266 with TD, and 17 with SMA. The youngest population was DMD (mean = 25 years [SD = 7]), and the oldest was TD (mean = 66 years [SD = 14]). For DMD, the population was 99% male and for migraine, the population was 84% female, and the other conditions had more relatively even sex divides. Collectively, migraine medications had the largest increase in aggregate costs (1993%) and had a substantial increase in OOP costs on average by 234% ($86-$288). Eculizumab for MG was an extreme outlier, with OOP costs increasing by 4,099% ($413-$17,359) and aggregate OOP costs by 7,005% ($5,375-$381,894). OOP costs of edaravone ($304-$5,707) and deutetrabenazine ($670-$7,170) sharply increased by 1,775% and 971%, respectively.<br><br>DISCUSSION: NTM medications for neurologic conditions have substantial and increasing individual and societal costs, which was not observed for older generic medications. These data suggest a need for policies to limit the financial burden of NTM medications on patients with neurologic conditions.}, }
@article {pmid40013906, year = {2025}, author = {Howard, J and Bekker, HL and McDermott, CJ and McNeill, A}, title = {Exploring the needs and preferences of people with amyotrophic lateral sclerosis (ALS) when making genomic testing decisions: an interview study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2469727}, pmid = {40013906}, issn = {2167-9223}, abstract = {Objective: Whole Genome Sequencing (WGS) for amyotrophic lateral sclerosis (ALS) (also known as motor neuron disease, MND) raises multiple considerations and has a range of implications for individuals and their family. However, it is unclear what needs people with ALS have when making genomic testing decisions. This study explores the experiences, needs and preferences of these individuals when considering WGS and going through the process. Methods: A semi-structured interview study was carried out with 14 people with ALS from across the UK who had, or were considering, WGS. Participants were recruited from a local ALS care center and MND Association/MND Scotland channels. Data were analyzed using framework analysis. Results: Findings indicate variation in (a) how WGS and access to pretest genetic counseling is provided, (b) the perceived adequacy of information to support decision-making and prepare people with ALS for their test result and its consequences, and (c) preferences for making decisions with family and health professionals that best meets their clinical and life needs along the care pathway. Conclusions: There is an urgent need for people with ALS to have relevant, accurate and accessible information that supports proactively their decision-making around WGS, particularly in the context of genetically-targeted treatments and clinical trials. These findings will contribute to the development of a shared decision-making intervention supporting people with ALS to make genomic testing decisions with their family and neurology services.}, }
@article {pmid40012994, year = {2025}, author = {Sabetta, E and Ferrari, D and Massimo, L and Kõks, S}, title = {Tandem repeat expansions and copy number variations as risk factors and diagnostic tools for amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1522445}, pmid = {40012994}, issn = {1664-2295}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder leading to upper and lower motoneurons degeneration. Although several mechanisms potentially involved in disease development have been identified, its pathogenesis is not fully understood. From the patient side, ALS diagnosis, still based on clinical criteria, can be difficult and may take up to 1 year. More than 30 genes have been associated to genetically inherited ALS, among which four (C9ORF72, SOD1, TARDBP and FUS) would explain around 60-70% of cases. However, familial ALS represents only 5-10% of ALS cases while the remaining are sporadic, with genetics explaining 6-10% of such cases only. In this context, short tandem repeats (STRs) expansions, have recently been found in clinically diagnosed ALS patients. In this review, we discuss the recent discoveries on ALS associated STRs and their potential as biomarkers as well as prognosis and therapy targets.}, }
@article {pmid40012862, year = {2024}, author = {Tang, MB and Liu, YX and Hu, ZW and Luo, HY and Zhang, S and Shi, CH and Xu, YM}, title = {Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1454735}, pmid = {40012862}, issn = {1663-4365}, abstract = {Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.}, }
@article {pmid40012679, year = {2025}, author = {Glashutter, M and Wijesinghe, P and Matsubara, JA}, title = {TDP-43 as a potential retinal biomarker for neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1533045}, pmid = {40012679}, issn = {1662-4548}, abstract = {TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation of the TDP-43 protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and others. TDP-43 in the eye shows promise as a biomarker for these NDDs. Several studies have identified cytoplasmic TDP-43 inclusions in retinal layers of donors with ALS, FTLD, AD, CTE, and other conditions using immunohistochemistry. Our findings suggest that pathological aggregates of TDP-43 in the human retina are most prevalent in FTLD-TDP, ALS, and CTE, suggesting these diseases may provide the most reliable context for studying the potential of TDP-43 as a retinal biomarker. Animal model studies have been pivotal in exploring TDP-43's roles in the retina, including its nuclear and cytoplasmic localization, RNA binding properties, and interactions with other proteins. Despite these advances, more research is needed to develop therapeutic strategies. A major limitation of human autopsy studies is the lack of corresponding brain pathology assessments to confirm TDP-43 proteinopathy diagnosis and staging. Other limitations include small sample sizes, lack of antemortem eye pathology and clinical histories, and limited comparisons across multiple NDDs. Future directions for the TDP-43 as a retinal biomarker for NDDs include retinal tracers, hyperspectral imaging, oculomics, and machine learning development.}, }
@article {pmid40012394, year = {2025}, author = {Kumar, P and Kumar, A and Keerthipriya, M and H, C and Nalini, A and Vengalil, S and Sitani, K and Nagaraj, C and Dey, S and Debnath, M and K, V and Satyaprabha, TN}, title = {A New Approach to Synthesizing Carbon-11-PBR28 and its Clinical Validation in ALS Patients.}, journal = {Current radiopharmaceuticals}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118744710341203250220042349}, pmid = {40012394}, issn = {1874-4729}, abstract = {BACKGROUND: Many studies have reported Translocator Protein (TSPO) overexpression in many neurological disorders. Carbon-11[11C]PBR28 is a widely used TSPO Positron Emission Tomography (PET) radiopharmaceutical. We have compared HPLC-based purification with cartridge-based purification and performed PET-MR imaging in ALS patients.<br><br>METHODS: [11C]PBR28 has been synthesized using an HPLC-based and cartridge-based purification technique in the FX2C chemistry module. All necessary quality controls were performed and compared. We injected 350 &#xb1; 20 MBq of the [11C]PBR28 intravenously into human patients (n = 6) diagnosed with amyotrophic lateral syndrome (ALS) and performed simultaneous PETMR dynamic imaging.<br><br>RESULTS: The radiochemical purity was greater than 95% with both methods. The radiochemical yield was 11.8 &#xb1; 3.3%, and molar activity was 253 &#xb1; 20.9 GBq/&#x3bc;mol with a total synthesis time of 25 &#xb1; 2 min in the HPLC-based purification method. Whereas the radiochemical yield was 53.0 &#xb1; 3.6%, and molar activity was 885 &#xb1; 17.7 GBq/&#x3bc;mol with a total synthesis time of 12 &#xb1; 2 min in the cartridge-based purification method. We have compared PET-MR imaging of ALS limb onset (n =3) with ALS bulbar and limb onset (n =3), and there was a difference in time activity curves. The activity was higher in the precentral gyrus and cerebellum at 2.5 &#xb1; 0.5 min in bulbar cases with an SUV of 2.3 &#xb1; 0.3, whereas ALS limb onset showed the highest uptake at 0.5 &#xb1; 0.2 min with an SUV of 1.5 &#xb1; 0.2.<br><br>CONCLUSION: The cartridge-based method provided higher radiochemical yield and molar activity.}, }
@article {pmid40012174, year = {2025}, author = {Rajamanickam, G and Hu, Z and Liao, P}, title = {Targeting the TRPM4 Channel for Neurologic Diseases: Opportunity and Challenge.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {}, number = {}, pages = {10738584251318979}, doi = {10.1177/10738584251318979}, pmid = {40012174}, issn = {1089-4098}, abstract = {As a monovalent cation channel, the transient receptor potential melastatin 4 (TRPM4) channel is a unique member of the transient receptor potential family. Abnormal TRPM4 activity has been identified in various neurologic disorders, such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, pathologic pain, and epilepsy. Following brain hypoxia/ischemia and inflammation, TRPM4 up-regulation and enhanced activity contribute to the cell death of neurons, vascular endothelial cells, and astrocytes. Enhanced ionic influx via TRPM4 leads to cell volume increase and oncosis. Depolarization of membrane potential following TRPM4 activation and interaction between TRPM4 and N-methyl-d-aspartate receptors exacerbate excitotoxicity during hypoxia. Importantly, TRPM4 expression and activity remain low in healthy neurons, making it an ideal drug target. Current approaches to inhibit or modulate the TRPM4 channel have various limitations that hamper the interpretation of TRPM4 physiology in the nervous system and potentially hinder their translation into therapy. In this review, we discuss the pathophysiologic roles of TRPM4 and the different inhibitors that modulate TRPM4 activity for potential treatment of neurologic diseases.}, }
@article {pmid40011745, year = {2025}, author = {Rödström, KEJ and Eymsh, B and Proks, P and Hayre, MS and Cordeiro, S and Mendez-Otalvaro, E and Madry, C and Rowland, A and Kopec, W and Newstead, S and Baukrowitz, T and Schewe, M and Tucker, SJ}, title = {Cryo-EM structure of the human THIK-1 K2P K[+] channel reveals a lower Y gate regulated by lipids and anesthetics.}, journal = {Nature structural &amp; molecular biology}, volume = {}, number = {}, pages = {}, pmid = {40011745}, issn = {1545-9985}, abstract = {THIK-1 (KCNK13) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K[+] channel implicated in microglial activation and neuroinflammation, and a current target for the treatment of neurodegenerative disorders, for example Alzheimer's disease and amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little is known about the structural and functional properties of THIK-1. Here we present a 3.16-Å-resolution cryo-EM structure of human THIK-1 that reveals several distinct features, in particular, a tyrosine in M4 that contributes to a lower 'Y gate' that opens upon activation by physiologically relevant G-protein-coupled receptor and lipid signaling pathways. We demonstrate that linoleic acid bound within a modulatory pocket adjacent to the filter influences channel activity, and that halothane inhibition involves a binding site within the inner cavity, both resulting in conformational changes to the Y gate. Finally, the extracellular cap domain contains positively charged residues that line the ion exit pathway and contribute to the distinct biophysical properties of this channel. Overall, our results provide structural insights into THIK-1 function and identify distinct regulatory sites that expand its potential as a drug target for the modulation of microglial function.}, }
@article {pmid40011708, year = {2025}, author = {Yang, C and Lee, GB and Hao, L and Hu, F}, title = {TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43[Q331K] knock-in mouse model.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {315}, pmid = {40011708}, issn = {2399-3642}, support = {R01 NS088448/NS/NINDS NIH HHS/United States ; R21 AG078741/AG/NIA NIH HHS/United States ; R01NS088448//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS121608/NS/NINDS NIH HHS/United States ; R21AG078741//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01NS121608//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; Mice ; *Membrane Proteins/genetics/metabolism ; *Lipid Metabolism/genetics ; *Nerve Tissue Proteins/genetics/metabolism ; *Disease Models, Animal ; *Obesity/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism/deficiency ; Gene Knock-In Techniques ; Male ; Mice, Inbred C57BL ; }, abstract = {The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. TMEM106B has been identified as a risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate the role of TMEM106B in TDP-43 proteinopathy, we ablated TMEM106B in the TDP-43[Q331K] knock-in mouse line, which expresses an ALS-linked TDP-43 mutation at endogenous levels. We found that TMEM106B deficiency leads to glial activation, Purkinje cell loss, and behavioral deficits in TDP-43[Q331K] mice without inducing typical TDP-43 pathology. Interestingly, ablation of TMEM106B results in significant body weight gain, increased fat deposition, and hepatic triglyceride (TG) accumulation in TDP-43[Q331K] mice. In addition, lipidomic and transcriptome analysis shows a profound alteration in lipid metabolism in the liver of TDP-43[Q331K]Tmem106b[-/-] mice. Our studies reveal a novel function of TMEM106B and TDP-43 in lipid metabolism and provide new insights into their roles in neurodegeneration.}, }
@article {pmid40011434, year = {2025}, author = {Gao, G and Shi, Y and Deng, HX and Krainc, D}, title = {Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1982}, pmid = {40011434}, issn = {2041-1723}, support = {R21 NS114765/NS/NINDS NIH HHS/United States ; NS114765//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 NS099623/NS/NINDS NIH HHS/United States ; R35 NS122257/NS/NINDS NIH HHS/United States ; NS122257//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS099623//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Animals ; *Lipid Peroxidation ; *Ketoglutarate Dehydrogenase Complex/metabolism/genetics ; Humans ; *Mitochondria/metabolism ; *Parkinson Disease/metabolism/genetics ; Male ; Mice ; *alpha-Synuclein/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Dopaminergic Neurons/metabolism/pathology ; Thioctic Acid/metabolism ; Transcription Factors/metabolism/genetics ; Mitochondrial Proteins/metabolism/genetics ; Mice, Knockout ; Ketoglutaric Acids/metabolism ; Brain/metabolism ; }, abstract = {Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.}, }
@article {pmid40010009, year = {2025}, author = {Mikuriya, S and Takegawa-Araki, T and Tamura, M}, title = {Edaravone mitigates TDP-43 mislocalization in human amyotrophic lateral sclerosis neurons with potential implication of the SIRT1-XBP1 pathway.}, journal = {Free radical biology &amp; medicine}, volume = {230}, number = {}, pages = {283-293}, doi = {10.1016/j.freeradbiomed.2025.01.012}, pmid = {40010009}, issn = {1873-4596}, mesh = {Humans ; *Edaravone/pharmacology ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *X-Box Binding Protein 1/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; *Motor Neurons/metabolism/drug effects/pathology ; *Sirtuin 1/metabolism/genetics ; Signal Transduction/drug effects ; Free Radical Scavengers/pharmacology ; Neuroprotective Agents/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss along with pathological mislocalization of TAR DNA-binding protein 43 (TDP-43), a protein implicated in RNA metabolism. Although edaravone, a free-radical scavenger, has been approved for ALS treatment, its precise mechanism of action is not fully understood, particularly in relation to TDP-43 pathology. Here, we investigated the effects of edaravone on induced pluripotent stem cell (iPSC)-derived motor neurons in a patient with ALS harboring a TDP-43 mutation. Our results demonstrated that edaravone significantly attenuated neurodegeneration, as evidenced by neurite preservation, neuronal cell death reduction, and correction of aberrant cytoplasmic localization of TDP-43. These neuroprotective effects were not observed with vitamin C, indicating a unique mechanism of action for edaravone, distinct from its antioxidative properties. RNA sequencing revealed that edaravone rapidly modulated gene expression, including protein quality control pathway, such as the ubiquitin-proteasome system. Further analysis identified X-box binding protein (XBP1), a key regulator of the endoplasmic reticulum stress response, as a critical factor in the therapeutic effects of edaravone. This study suggests that edaravone may offer a multifaceted therapeutic approach for ALS by targeting oxidative stress and TDP-43 mislocalization through distinct molecular pathways.}, }
@article {pmid40009859, year = {2025}, author = {Chung, J and Lim, F}, title = {Effect of Nurse Residency Programs on New Graduate Nurses Entering the Critical Care Setting: An Integrative Review.}, journal = {Critical care nursing quarterly}, volume = {48}, number = {2}, pages = {120-142}, pmid = {40009859}, issn = {1550-5111}, mesh = {Humans ; *Clinical Competence ; *Critical Care Nursing/education ; *Preceptorship ; Education, Nursing, Baccalaureate ; Critical Care ; Internship, Nonmedical/organization &amp; administration ; }, abstract = {The transition period from undergraduate nursing education to professional practice is a time of uncertainty and great difficulty for new graduate nurses (NGNs). Nurse residency programs (NRPs) provide structured education, simulation-based learning, and preceptorship to ease the transition. Although its effect on improving retention of NGNs is well established in the literature, the effect on clinical competency has not been documented as well. The purpose of this integrative review is to appraise the available literature and synthesize the evidence that demonstrates the effect of NRPs on clinical competency of NGNs entering the critical care setting. Inclusion criteria were quantitative and qualitative studies, peer-reviewed studies published after 2004 and in English, identified through a systematic literature search using the CINAHL database. Critical appraisal of the articles was completed using Law et al's Critical Review Form. Eight articles (4 quantitative, 3 mixed method, and 1 qualitative study) met the inclusion criteria. The themes identified were common tools used to assess the efficacy of NRPs, improved clinical competency of NGNs, improved self-confidence, improved retention rates, and peer support among NGNs. Implications for nursing education and practice include applying evidence-based NRPs, incorporating simulation, enhancing sustainability, and reducing NRP variability through accreditation.}, }
@article {pmid40009787, year = {2025}, author = {Mondesert, E and Delaby, C and De La Cruz, E and Kuhle, J and Benkert, P and Pradeilles, N and Duchiron, M and Morchikh, M and Camu, W and Cristol, JP and Hirtz, C and Esselin, F and Lehmann, S}, title = {Comparative Performances of 4 Serum NfL Assays, pTau181, and GFAP in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {6}, pages = {e213400}, pmid = {40009787}, issn = {1526-632X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Female ; *Glial Fibrillary Acidic Protein/blood ; Male ; *Neurofilament Proteins/blood ; Aged ; *tau Proteins/blood ; Middle Aged ; *Biomarkers/blood ; Phosphorylation ; Cohort Studies ; Prognosis ; }, abstract = {BACKGROUND AND OBJECTIVES: Selecting the most appropriate blood tests is crucial for the management of patients with amyotrophic lateral sclerosis (ALS). This study evaluates the diagnostic and prognostic performance of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 181 (pTau181) biomarkers in ALS to establish their clinical relevance and cutoff values.<br><br>METHODS: In a cohort of patients from the ALS center in Montpellier, we conducted a head-to-head comparison of 4 different technologies and 3 distinct serum analytes: NfL was tested using the ultrasensitive Simoa and the microfluidic Ella platforms, along with 2 assays recently set up on clinical-grade platforms: Lumipulse and Elecsys. We also used Elecsys to assess serum GFAP and pTau181.<br><br>RESULTS: Our cohort included 139 patients with ALS and 70 non-ALS patients, with a mean age of 66.1 &#xb1; 11.4 years and 47.4% of women. The mean follow-up was 42 &#xb1; 26.3 months for patients with ALS and 141.6 &#xb1; 106.3 months for non-ALS patients, with a mortality rate of 85.5% vs 7.7%. There was a high correlation between all methods tested for serum NfL quantification (R[2] = 0.939 to 0.963). The area under the curve (AUC) for ALS diagnosis was 0.889 (0.827-0.932) for NfL Simoa, 0.906 (0.847-0.944) for Ella, 0.912 (0.853-0.948) for Lumipulse, and 0.910 (0.851-0.946) for Elecsys. Serum pTau181 and GFAP showed poor diagnostic performance with AUCs of 0.565 (0.472-0.649) and 0.546 (0.461-0.636), respectively. Kaplan-Meier survival analysis revealed significant hazard ratios (4.4-5.4) for blood NfL. Patients with ALS had a 40%-50% chance of surviving 50 weeks below the prognostic cutoff values while survival rates dropped to near zero above. NfL and GFAP levels were associated with age and body mass index, considered confounding factors. pTau181 levels varied significantly in patients with ALS depending on the site of onset.<br><br>DISCUSSION: This study demonstrates the consistent performance of 4 immunoassays for serum NfL quantification in ALS. NfL showed high diagnostic and prognostic accuracy, making it suitable for individual assessment, unlike GFAP or pTau181. We propose diagnostic and prognostic cutoff values for serum NfL, providing a basis for wider implementation, especially with the clinically accredited Lumipulse and Elecsys platforms, which are becoming standard practice.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum NfL levels are useful in identifying over 80% of patients with ALS and predicting survival in patients with ALS compared with pTau181 and GFAP levels.}, }
@article {pmid40009417, year = {2025}, author = {Oliveira Santos, M and Pinto, S and Silveira, F and Gromicho, M and Alves, I and Castro, J and Castro, I and de Carvalho, M}, title = {Amyotrophic Lateral Sclerosis Associated With Severe Sensory Neuronopathy: Case Series.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {133-139}, doi = {10.1097/CND.0000000000000520}, pmid = {40009417}, issn = {1537-1611}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; Male ; Middle Aged ; Female ; Aged ; Disease Progression ; Sensation Disorders/etiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system. However, an association with sensory neuronopathy has been scarcely described. We described 3 unrelated patients (2 males) with sporadic spinal-onset ALS and sensory neuronopathy. Mean onset age was 63.7 years and mean Revised Amyotrophic Lateral Sclerosis Functional Rating Scale at diagnosis was 42. Sensory disturbances emerged before or overlap with motor symptoms in the same onset region and followed the same pattern of lower motor neuron involvement over disease progression. Two patients have also bilateral trigeminal sensory fibers affection. None had cognitive abnormalities. Genetic testing for the most common ALS-associated genes was unrevealing. Mean disease duration and ALS functional rating scale-revised at last visit was 47 months and 27, respectively. One patient is still alive, dependent on nocturnal noninvasive ventilation. Motor neuron disease is now considered a multisystem neurodegenerative disorder, and sensory neuronopathy, although very rare, should not be neglected as a possible part of the disease spectrum.}, }
@article {pmid40009414, year = {2025}, author = {Hamad, AA}, title = {Tofersen for Amyotrophic Lateral Sclerosis: Genetic Treatment With Precision Medicine: The Future of ALS Treatment.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {117-119}, doi = {10.1097/CND.0000000000000517}, pmid = {40009414}, issn = {1537-1611}, }
@article {pmid40009412, year = {2025}, author = {Finsterer, J}, title = {Before Trapezius RNS Can Be Recommended as an Additional Tool for the Diagnosis of ALS, Well-Powered Prospective Studies Are Required.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {3}, pages = {114-115}, doi = {10.1097/CND.0000000000000515}, pmid = {40009412}, issn = {1537-1611}, }
@article {pmid40009238, year = {2025}, author = {Ruffo, P and Traynor, BJ and Conforti, FL}, title = {Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {233}, pmid = {40009238}, issn = {1432-1459}, support = {ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/diagnosis ; Humans ; Genetic Therapy/methods ; }, abstract = {This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.}, }
@article {pmid40008462, year = {2025}, author = {Huertas-Alonso, AJ and González-Serrano, DJ and Salgado-Ramos, M and Hadidi, M and Sánchez-Verdú, P and Cabañas, B and Chuck, CJ and Clark, JH and Moreno, A}, title = {Sustainable Microwave-Assisted Synthesis of Medium- and Long-Chain Alkyl Levulinates from Biomass-Derived Levulinic Acid.}, journal = {ChemSusChem}, volume = {}, number = {}, pages = {e202402508}, doi = {10.1002/cssc.202402508}, pmid = {40008462}, issn = {1864-564X}, support = {SBPLY/17/180501/000522//Junta de Comunidades de Castilla-La Mancha/ ; RTI2018-099503-B-I00//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; }, abstract = {Alkyl levulinates (ALs) represent a family of bio-compounds derived from levulinic acid (LA), a platform chemical obtained from lignocellulosic biomass. Medium- and long-chain ALs (pentyl levulinate or longer) have shown potential as biofuel and fuel additives due to their relatively low oxygen content and resemblance to biodiesel. This study reports a fast and environmentally friendly method for synthesizing ALs via microwave (MW)-assisted LA esterification, laying emphasis on medium- and long-chain ALs. By combining p-toluenesulfonic acid (5 wt % loading) as catalyst and MW radiation as heating source for a short time (5 minutes), excellent yields of ALs (≥89 mol %) were achieved for a wide range of primary and secondary alcohols (2-10 carbons), overcoming the expected lower reactivity of long chain alcohols. Additionally, formation of undesired side products, such as dialkyl ethers or LA aldol condensation products, was significantly minimized. The feasibility of recovering the unreacted alcohol was successfully proved by simple distillation (88 wt % recovery). The green chemistry metrics assessment proved that this approach aligns with the green chemistry principles and the United Nations Sustainable Development Goals, offering a more sustainable pathway for biofuel and fuel additive production.}, }
@article {pmid40008327, year = {2025}, author = {van Eijk, RPA and Steyn, FJ and Janse van Mantgem, MR and Schmidt, A and Meyjes, M and Allen, S and Daygon, DV and Loeffler, JP and Al-Chalabi, A and van den Berg, LH and Henderson, RD and Ngo, ST}, title = {An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcaf063}, pmid = {40008327}, issn = {2632-1297}, abstract = {Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.}, }
@article {pmid40008320, year = {2025}, author = {Wulterkens, D and Coumou, F and Slagt, C and Waalewijn, RA and Mommers, L}, title = {Defibrillation pad placement accuracy among Advanced Life Support instructors: A manikin-based observational study examining experience, self-evaluation, and actual performance.}, journal = {Resuscitation plus}, volume = {22}, number = {}, pages = {100886}, pmid = {40008320}, issn = {2666-5204}, abstract = {BACKGROUND: Ventricular fibrillation is common in patients with out-of-hospital cardiac arrest. Early and effective defibrillation is important for their survival. Effective defibrillation depends highly on correct positioning of the defibrillation pads. Teaching this correctly by ALS instructors is therefore crucial.<br><br>METHODS: Fifty certified advanced life support instructors were recruited from a large training institute. Participants were asked to place defibrillation pads on an anatomically and real-weight (90&#xa0;kg) manikin. Primary outcome was the placement of defibrillation pads placed in the sternal-apical and anterior-posterior positions. Secondary outcomes were performance self-assessment, defibrillation experience, self-perceived competence and self-efficacy in teaching defibrillation. These measures were evaluated using an 11-point Likert scale.<br><br>RESULTS: A total of 31 medical doctors and 19 registered nurses were enrolled in this study. Defibrillation pads were placed (mean&#xa0;&#xb1;&#xa0;SD) 42&#xa0;&#xb1;&#xa0;21&#xa0;mm, 38&#xa0;&#xb1;&#xa0;23&#xa0;mm, 35&#xa0;&#xb1;&#xa0;19&#xa0;mm and 61&#xa0;&#xb1;&#xa0;48&#xa0;mm from the reference point for the sternal, apical, anterior and posterior pads respectively, resulting in a respectively correct placement of 18%, 20%, 32% and 28%. The average number of correctly applied pads per instructor was 0.98&#xa0;&#xb1;&#xa0;0.74 out of four.Self-assessment of defibrillation pads placed by the participants were 8.56&#xa0;&#xb1;&#xa0;1.33 and 7.88&#xa0;&#xb1;&#xa0;1.64 for the sternal-apical and anterior-posterior positions respectively. Personal defibrillation experience showed that the majority had applied over 20 standard defibrillations. Experience with anterior-posterior pad placement was less and experience with bi-axillary and double sequential external defibrillation positions were absent in most participants. Self-perceived competence for the sternal-apical, anterior-posterior, bi-axillary and dual external synchronized positions were 8.68&#xa0;&#xb1;&#xa0;1.06, 8.08&#xa0;&#xb1;&#xa0;1.37, 5.57&#xa0;&#xb1;&#xa0;2.95 and 5.11&#xa0;&#xb1;&#xa0;2.67 respectively. Self-efficacy score for teaching defibrillation was 8.59&#xa0;&#xb1;&#xa0;0.81. No association was found between the number of correctly applied pads and any of the participants' variables.<br><br>CONCLUSION: This study corroborates and expands upon existing knowledge regarding the challenges of defibrillator pad placement, revealing substantial variation in placement accuracy among instructors. Our novel analysis of pad angles and anterior-posterior analysis demonstrates that a significant portion of pads are incorrectly placed. These findings highlight the need for standardized approaches and improved training methodologies in defibrillator pad placement.}, }
@article {pmid40008198, year = {2025}, author = {Garetto, B and Cao, N and Finelli, V and Aunan, E and Signorile, M and Olsbye, U and Bordiga, S and Nova, A and Borfecchia, E}, title = {Pinpointing Cu-Coordination Motifs in Bio-Inspired MOFs by Combining DFT-Assisted XAS Analysis and Multivariate Curve Resolution.}, journal = {The journal of physical chemistry. C, Nanomaterials and interfaces}, volume = {129}, number = {7}, pages = {3570-3582}, pmid = {40008198}, issn = {1932-7447}, abstract = {In recent years, X-ray absorption spectroscopy (XAS) has emerged as an essential technique for investigating the structure and composition of heterogeneous catalysts, providing valuable insights into the nature of active sites within these systems. However, the average nature of the XAS signal, inherently merged over all the absorber-containing species forming during in situ/operando experiments, often complicates the interpretation of the data. Nonetheless, advanced analysis methods have been developed to address this problem. In particular, herein we employed in situ XAS spectroscopy together with multivariate curve resolution-alternating least squares (MCR-ALS) and wavelet transform (WT) analysis to monitor the evolution of distinct Cu species in histidine-modified Cu-UiO-66 MOFs and to obtain detailed structural insights about the Cu sites. A novel approach adopted in this work was the application of density functional theory (DFT)-assisted extended X-ray absorption fine structure (EXAFS) fitting to quantitatively refine the local structure of the MCR-derived pure Cu species. This approach revealed the preferential redox activity of Cu[II] ions coordinated within the defective Zr clusters of the MOF, compared to Cu[II] ions bound to both the histidine molecule and the defective site during a standard redox reaction protocol.}, }
@article {pmid40007904, year = {2025}, author = {Esteruelas, G and Ettcheto, M and Haro, I and Herrando-Grabulosa, M and Gaja-Capdevila, N and Gomara, MJ and Navarro, X and Espina, M and Souto, EB and Camins, A and García, ML and Sánchez-López, E}, title = {Novel Tissue-Specific Multifunctionalized Nanotechnological Platform Encapsulating Riluzole Against Motor Neuron Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {2273-2288}, pmid = {40007904}, issn = {1178-2013}, mesh = {*Riluzole/pharmacokinetics/pharmacology/chemistry/administration &amp; dosage ; Animals ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neuron Disease/drug therapy ; Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/administration &amp; dosage ; Motor Neurons/drug effects ; Humans ; Nanoparticles/chemistry ; Polyethylene Glycols/chemistry/pharmacokinetics ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Mice ; Drug Carriers/chemistry/pharmacokinetics ; Blood-Brain Barrier/drug effects/metabolism ; Drug Delivery Systems/methods ; Tissue Distribution ; Peptides/chemistry/pharmacokinetics/administration &amp; dosage ; }, abstract = {BACKGROUND: Motor neuron diseases are neurological disorders characterized by progressive degeneration of upper and/or lower motor neurons. Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron diseases, where patients suffer progressive paralysis, muscle atrophy and finally death. Despite ALS severity, no treatment is safe and fully effective. In this area, Riluzole was the first drug approved and it constitutes the gold-standard for this pathology. However, to obtain suitable therapeutic efficacy, Riluzole requires high doses that are associated with severe adverse effects in other tissues. To attain Riluzole therapeutic efficacy avoiding other organs side-effects, new therapeutic strategies to enhance the delivery of Riluzole specifically to motor neurons constitute an unmet medical need. In this area, we have developed a novel multifunctional nanostructurated carrier to selectively deliver Riluzole to motor neurons.<br><br>RESULTS: This work develops and characterizes at in vitro and in vivo levels a tissue-targeted formulation of peptide and PEG-labelled PLGA nanoparticles encapsulating Riluzole. For this purpose, pVEC, a cell penetrating peptide able to increase transport through the blood-brain barrier, was attached to the nanoparticles surface. The multifunctionalized nanoparticles show suitable characteristics for the release of Riluzole in the central nervous system and were detected in motor neurons within 1 h after administration while significantly reducing the concentration of Riluzole in non-therapeutic organs responsible of side effects.<br><br>CONCLUSION: A novel drug delivery system has been developed and characterized, demonstrating enhanced CNS biodistribution of riluzole, which shows promise as efficient therapeutic tool for motor neuron diseases, including amyotrophic lateral sclerosis.}, }
@article {pmid40006958, year = {2025}, author = {Mielcarska, MB and Rouse, BT}, title = {Viruses and the Brain-A Relationship Prone to Trouble.}, journal = {Viruses}, volume = {17}, number = {2}, pages = {}, pmid = {40006958}, issn = {1999-4915}, mesh = {Humans ; *Brain/virology ; Animals ; Viruses/pathogenicity/genetics ; Antiviral Agents/therapeutic use/pharmacology ; Virus Diseases/virology ; Neurodegenerative Diseases/virology ; }, abstract = {Neurological disorders, some of which are associated with viral infections, are growing due to the aging and expanding population. Despite strong defenses of the central nervous system, some viruses have evolved ways to breach them, which often result in dire consequences. In this review, we recount the various ways by which different viruses can enter the CNS, and we describe the consequences of such invasions. Consequences may manifest as acute disease, such as encephalitis, meningitis, or result in long-term effects, such as neuromuscular dysfunction, as occurs in poliomyelitis. We discuss evidence for viral involvement in the causation of well-known chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as vascular dementia in the elderly. We also describe the approaches currently available to control a few of the neural viral infections. These include antivirals that are effective against human immunodeficiency virus and herpes simplex virus, as well as vaccines valuable for controlling rabies virus, poliomyelitis virus, and some flavivirus infections. There is an urgent need to better understand, at a molecular level, how viruses contribute to acute and, especially, chronic neurological diseases and to develop more precise and effective vaccines and therapies.}, }
@article {pmid40006784, year = {2025}, author = {Ji, M and Yu, H and Cui, H and Chen, J and Yu, J and Li, X}, title = {A New Pro-197-Ile Mutation in Amaranthus palmeri Associated with Acetolactate Synthase-Inhibiting Herbicide Resistance.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {4}, pages = {}, pmid = {40006784}, issn = {2223-7747}, support = {CARS25//China Agriculture Research System/ ; }, abstract = {Palmer amaranth (Amaranthus palmeri S. Watson), native to North America, is one of the most prominent invasive weed species on agricultural land. Acetolactate synthase (ALS)-resistant A. palmeri (Amaranthus palmeri) is widespread, while the research focus on resistance pattern and molecular basis of A. palmeri to imazethapyr is seldom documented in China. An A. palmeri population that survived the recommended rate of imazethapyr was collected in Shandong Province, China. The resistant mechanism and pattern of A. palmeri to imazethapyr was investigated. Dose-response assay showed that the resistant (R) population displayed a high resistance level (292.5-fold) to imazethapyr compared with the susceptible (S) population. Sequence analysis of the ALS gene revealed that nucleotide mutations resulted in three resistance-conferring amino acid substitutions, Pro-197-Ile, Trp-574-Leu, and Ser-653-Asp, in the individual plants of the R population. An in vitro enzyme assay indicated that the ALS was relatively unsusceptible to imazethapyr in the R population, showing a resistance index of 88.6-fold. ALS gene expression and copy number did not confer resistance to imazethapyr in the R population. Pro-197-Ile is the first reported amino acid substitution conferring ALS resistance to A. palmeri. This is the first case of an imazethapyr-resistant A. palmeri biotype in China.}, }
@article {pmid40004464, year = {2025}, author = {Liu, Z and Song, SY}, title = {Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases.}, journal = {Genes}, volume = {16}, number = {2}, pages = {}, pmid = {40004464}, issn = {2073-4425}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/diagnosis ; *Transcriptome/genetics ; Prognosis ; *Genome-Wide Association Study/methods ; Genomics/methods ; Gene Expression Profiling/methods ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Genetic Predisposition to Disease ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches.}, }
@article {pmid40004056, year = {2025}, author = {Yan, B and Suen, MC and Xu, N and Lu, C and Liu, C and Zhu, G}, title = {G-Quadruplex Structures Formed by Human Telomere and C9orf72 GGGGCC Repeats.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {40004056}, issn = {1422-0067}, support = {32071188//National Scientific Foundation of China/ ; 16101120, 161011121, AoE/M-403-16, AoE/M-401/20//Research Grants Council of the Hong Kong Special Administrative Region, China/ ; BGF.2023.019//Hong Kong University of Science and Technology, China/ ; 2021A1515220104//Guangdong Basic and Applied Basic Research Foundation, China/ ; 32301012//Young Scientists Fund of the National Natural Science Foundation of China/ ; }, mesh = {*G-Quadruplexes ; Humans ; *Telomere/genetics ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {G-quadruplexes (G4s) are unique nucleic acid structures composed of guanine-rich (G-rich) sequences that can form diverse topologies based on the arrangement of their four strands. G4s have attracted attention for their potential roles in various biological processes and human diseases. In this review, we focus on the G4 structures formed by human telomeric sequences, (GGGTTA)n, and the hexanucleotide repeat expansion, (GGGGCC)n, in the first intron region of the chromosome 9 open reading frame 72 (C9orf72) gene, highlighting their structural diversity and biological significance. Human telomeric G4s play crucial roles in telomere retention and gene regulation. In particular, we provide an in-depth summary of known telomeric G4s and focus on our recently discovered chair-type conformation, which exhibits distinct folding patterns. The chair-type G4s represent a novel folding pattern with unique characteristics, expanding our knowledge of telomeric G4 structural diversity and potential biological functions. Specifically, we emphasize the G4s formed by the (GGGGCC)n sequence of the C9orf72 gene, which represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The thorough structural analysis in this review advances our comprehension of the disease mechanism and provides valuable insights into developing targeted therapeutic strategies in ALS/FTD.}, }
@article {pmid40002740, year = {2025}, author = {Meng, K and Jia, H and Hou, X and Zhu, Z and Lu, Y and Feng, Y and Feng, J and Xia, Y and Tan, R and Cui, F and Yuan, J}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.}, journal = {Biomedicines}, volume = {13}, number = {2}, pages = {}, pmid = {40002740}, issn = {2227-9059}, support = {600791001//the Research Start-up Fund of Jining Medical University/ ; JYHL2021MS13//Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University/ ; 81700055//the National Natural Science Foundation of China/ ; Grant No. D2016021//Outstanding Talent Research Funding of Xuzhou Medical University/ ; BK20160229//Natural Science Foundation of Jiangsu Province/ ; tsqn201909147//Taishan Scholars Program of Shandong Province/ ; G2Y-kJS-SD-2023-097//Co-construction of Science and Technology Projects by the Science and Technology Department of the State Administration of Traditional Chinese Medicine/ ; }, abstract = {Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.}, }
@article {pmid40002527, year = {2025}, author = {Eisen, A and Kiernan, MC}, title = {The Neonatal Microbiome: Implications for Amyotrophic Lateral Sclerosis and Other Neurodegenerations.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002527}, issn = {2076-3425}, abstract = {Most brain development occurs in the "first 1000 days", a critical period from conception to a child's second birthday. Critical brain processes that occur during this time include synaptogenesis, myelination, neural pruning, and the formation of functioning neuronal circuits. Perturbations during the first 1000 days likely contribute to later-life neurodegenerative disease, including sporadic amyotrophic lateral sclerosis (ALS). Neurodevelopment is determined by many events, including the maturation and colonization of the infant microbiome and its metabolites, specifically neurotransmitters, immune modulators, vitamins, and short-chain fatty acids. Successful microbiome maturation and gut-brain axis function depend on maternal factors (stress and exposure to toxins during pregnancy), mode of delivery, quality of the postnatal environment, diet after weaning from breast milk, and nutritional deficiencies. While the neonatal microbiome is highly plastic, it remains prone to dysbiosis which, once established, may persist into adulthood, thereby inducing the development of chronic inflammation and abnormal excitatory/inhibitory balance, resulting in neural excitation. Both are recognized as key pathophysiological processes in the development of ALS.}, }
@article {pmid40002476, year = {2025}, author = {Raymond, J and Howard, IM and Berry, J and Larson, T and Horton, DK and Mehta, P}, title = {Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002476}, issn = {2076-3425}, support = {n/a/CC/CDC HHS/United States ; }, abstract = {Background/Objectives: To examine if head injury (HI) is associated with age at ALS diagnosis in the United States. Methods: In this cross-sectional populationf-based analysis, we identified patients with ALS who were registered from 2015 to 2023 who completed the Registry's head trauma survey module. The association between HI and age at ALS diagnosis was assessed using multivariate analysis. Results: Of the 3424 respondents, 56.6% had experienced a HI. The adjusted odds ratio (aOR) for an ALS diagnosis before age 60 years for patients with a HI was 1.24 (95% CI, 1.07-1.45). One or two HIs had an aOR of 1.15 (95% CI, 0.97-1.36), and five or more HIs had an aOR of 1.58 (95% CI, 1.19-2.09). HI before age 18 years yielded an aOR of 2.03 (95% CI, 1.53-2.70) as well as HI between the ages of 18 and 30 years (aOR = 1.48, 95% CI: 1.06-2.06)). When narrowing the analysis to patients with HI before age 18 compared with patients with no HI, we found an association with HI that led to an emergency department or hospital visit (aOR = 1.50 (95% CI: 1.21-1.86)). Conclusions: In this cross-sectional analysis of ALS patients, HIs occurring in childhood and early adulthood and the number of HIs increased the odds of being diagnosed before age 60 years. These results suggest that HI continues to be a risk factor for ALS and could be associated with a younger age of diagnosis.}, }
@article {pmid40002468, year = {2025}, author = {Dawoody Nejad, L and Pioro, EP}, title = {Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002468}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a terminal complex neurodegenerative disease, with 10-15% of cases being familial and the majority being sporadic with no known cause. There are no animal models for the 85-90% of sporadic ALS cases. More creative, sophisticated models of ALS disease are required to unravel the mysteries of this complicated disease. While ALS patients urgently require new medications and treatments, suitable preclinical in vitro models for drug screening are lacking. Therefore, human-derived induced pluripotent stem cell (hiPSC) technology offers the opportunity to model diverse and unreachable cell types in a culture dish. In this review, we focus on recent hiPSC-derived ALS neuronal and non-neuronal models to examine the research progress of current ALS 2D monocultures, co-cultures, and more complex 3D-model organoids. Despite the challenges inherent to hiPSC-based models, their application to preclinical drug studies is enormous.}, }
@article {pmid40002444, year = {2025}, author = {Okoh, C and Mayall, L and Makin, SM and Chen, C and Zarotti, N}, title = {Non-Pharmacological Interventions for Caregivers of People with Motor Neurone Disease: A Scoping Review of Psychosocial Outcomes.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, pmid = {40002444}, issn = {2076-3425}, abstract = {Objective: Caregivers of individuals with motor neurone disease (MND) face a wide range of psychosocial difficulties. To address these, non-pharmacological interventions have been trialled, showing promising results. However, no clear characterisation of the breadth of psychosocial constructs examined by the interventions is currently available, resulting in the lack of a core outcome set (COS). The present review explored the types of psychosocial outcomes investigated in studies that adopted non-pharmacological interventions with caregivers of people with MND. Methods: A scoping review was conducted across four major databases (Academic Search Ultimate, CINAHL, PsycINFO, and MEDLINE) from inception to the 1 March 2024. Results: From an initial return of 4802 citations, 10 were considered eligible for inclusion. A total of 10 main psychosocial outcomes were identified: anxiety and depression, psychological distress, resilience, caregiver burden, caregiver preparedness, self-efficacy, quality of life, spiritual wellbeing, and mindfulness. Conclusions: Caregiver burden and symptoms of anxiety and depression represent pivotal outcomes, but caution is advised with regard to caregiver burden's potential multidimensional structure. Psychological distress and quality of life are also commonly investigated, but clearer consensus is needed on their conceptualisation. There is a paucity of studies characterising important psychosocial outcomes such as resilience, problem-solving, self-efficacy, and mindfulness, while no investigations are available for relevant outcomes such as coping, isolation, and loneliness. Further research is warranted to address these gaps to improve our insight into non-pharmacological support for MND caregivers and ultimately lead to the development of a core psychosocial outcome set in this population.}, }
@article {pmid40001624, year = {2025}, author = {Ma, B and Ren, J and Qian, X}, title = {Study on the Polarization of Astrocytes in the Optic Nerve Head of Rats Under High Intraocular Pressure: In Vitro.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {40001624}, issn = {2306-5354}, support = {12472309 12072210//National Natural Science Foundation of China/ ; }, abstract = {Astrocytes, the most common glial cells in the optic nerve head (ONH), provide support and nutrition to retinal ganglion cells. This study aims to investigate the polarization types of astrocytes in the ONH of rats under high intraocular pressure (IOP) and explore signaling pathways potentially associated with different types of polarized astrocytes. The rat models with chronic high IOP were established. High IOP lasted for 2, 4, 6, and 8 weeks. Astrocytes were extracted from the ONH of rats using the tissue block cultivation method. Western blot was used to detect the expression of proteins associated with astrocyte polarization. Proteomics was employed to identify differential proteins associated with astrocyte polarization. Astrocytes polarized into A2 astrocytes after 2, 4, 6, and 8 weeks of high IOP, while polarization into A1 astrocytes began only after 8 weeks of high IOP. The differential proteins associated with A1 astrocyte polarization are primarily enriched in pathways of neurodegeneration with respect to multiple diseases, while the differential proteins associated with A2 astrocyte polarization are primarily enriched in pathways of spliceosome in amyotrophic lateral sclerosis. Our findings could provide a better understanding of the role of ONH astrocytes in the pathogenesis of glaucoma and offer new perspectives for glaucoma treatment.}, }
@article {pmid40001529, year = {2025}, author = {Onu, CJ and Adu, M and Chakkour, M and Kumar, V and Greenberg, ML}, title = {Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, pmid = {40001529}, issn = {2218-273X}, support = {R01 GM125082/GM/NIGMS NIH HHS/United States ; R35 GM149271/GM/NIGMS NIH HHS/United States ; GM149271/GF/NIH HHS/United States ; GM125082/GF/NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Inositol Phosphates/metabolism ; Animals ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Signal Transduction ; Inositol/metabolism ; }, abstract = {Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson's disease, Alzheimer's disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington's disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.}, }
@article {pmid40001370, year = {2025}, author = {Silva Ortíz, YL and de Sousa, TC and Kruklis, NE and Galeano García, P and Brango-Vanegas, J and Soller Ramada, MH and Franco, OL}, title = {The Role of Amphibian AMPs Against Oxidative Stress and Related Diseases.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {40001370}, issn = {2079-6382}, abstract = {Amphibians use their skin as an effective defense mechanism against predators and microorganisms. Specialized glands produce antimicrobial peptides (AMPs) that possess antioxidant properties, effectively reducing reactive oxygen species (ROS) levels. These peptides are promising candidates for treating diseases associated with oxidative stress (OS) and redox imbalance, including neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), as well as age-related conditions, like cardiovascular diseases and cancer. This review highlights the multifaceted roles of AMPs and antioxidant peptides (AOPs) in amphibians, emphasizing their protective capabilities against oxidative damage. They scavenge ROS, activate antioxidant enzyme systems, and inhibit cellular damage. AOPs often share structural characteristics with AMPs, suggesting a potential evolutionary connection and similar biosynthetic pathways. Peptides such as brevinin-1FL and Cath-KP demonstrate neuroprotective effects, indicating their therapeutic potential in managing oxidative stress-related diseases. The antioxidant properties of amphibian-derived peptides pave the way for novel therapeutic developments. However, a deeper understanding of the molecular mechanisms underlying these peptides and their interactions with oxidative stress is essential to addressing ROS-related diseases and advancing therapeutic strategies in clinical practice.}, }
@article {pmid40000803, year = {2025}, author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM}, title = {Neuronal polyunsaturated fatty acids are protective in ALS/FTD.}, journal = {Nature neuroscience}, volume = {28}, number = {4}, pages = {737-747}, pmid = {40000803}, issn = {1546-1726}, support = {NS132836//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS123242//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Fatty Acids, Unsaturated/metabolism ; Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Neurons/metabolism ; C9orf72 Protein/genetics ; Induced Pluripotent Stem Cells/metabolism ; Drosophila ; Disease Models, Animal ; Fatty Acid Desaturases/metabolism/genetics ; Animals, Genetically Modified ; Male ; Brain/metabolism ; }, abstract = {Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.}, }
@article {pmid40000618, year = {2025}, author = {Ru, Q and Li, Y and Zhang, X and Chen, L and Wu, Y and Min, J and Wang, F}, title = {Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.}, journal = {Bone research}, volume = {13}, number = {1}, pages = {27}, pmid = {40000618}, issn = {2095-4700}, support = {82071970//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072506//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970689//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32330047//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024AFB971//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Homeostasis ; *Iron/metabolism ; *Muscular Diseases/metabolism/therapy/pathology/physiopathology ; Animals ; }, abstract = {The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.}, }
@article {pmid39999835, year = {2025}, author = {Saxena, S and Liebscher, S}, title = {Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {3}, pages = {844-846}, pmid = {39999835}, issn = {1525-0024}, }
@article {pmid39999167, year = {2025}, author = {Wang, HV and Xiang, JF and Yuan, C and Veire, AM and Gendron, TF and Murray, ME and Tansey, MG and Hu, J and Gearing, M and Glass, JD and Jin, P and Corces, VG and McEachin, ZT}, title = {pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {9}, pages = {e2419818122}, pmid = {39999167}, issn = {1091-6490}, support = {F32 ES031827/ES/NIEHS NIH HHS/United States ; RM1 HG008935/HG/NHGRI NIH HHS/United States ; U01 MH116441/MH/NIMH NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; R35 GM139408/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Prefrontal Cortex/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; *DNA-Binding Proteins/metabolism/genetics ; Female ; Middle Aged ; Aged ; DNA Repeat Expansion/genetics ; Neurons/metabolism/pathology ; Phosphorylation ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.}, }
@article {pmid39998997, year = {2025}, author = {García-Casanova, PH and Vázquez-Costa, JF}, title = {Advances in the early diagnosis of amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {415-425}, doi = {10.1080/14737175.2025.2471556}, pmid = {39998997}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Early Diagnosis ; *Biomarkers ; Disease Progression ; Delayed Diagnosis ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Despite rapid disease progression, diagnostic delay of 10-16 months persists, influenced by disease-specific factors and healthcare systems. Reducing it is crucial for early intervention, multidisciplinary care planning, and patient participation in clinical trials.<br><br>AREAS COVERED: The authors review relevant studies identified through PubMed from 1990 to 2024. The article explores factors contributing to diagnostic delay, the importance of early diagnosis, and strategies for improvement, including the role of diagnostic criteria and biomarkers.<br><br>EXPERT OPINION: Diagnosis of ALS remains clinical, with clinical expertise as the main modifiable factor in the diagnostic delay. Some biomarkers may be useful to speed up diagnosis at an earlier stage of the disease and in patients with atypical presentations or co-morbidities. However, the use of biomarkers for ALS diagnosis in clinical practice is far from being established and poses considerable challenges, including the lack of disease-specific biomarkers and the potential for delayed results. Until disease-specific biomarkers become available, early referral to ALS specialists, together with physician education programs, will remain the main tools to reduce diagnostic delay in the next years.}, }
@article {pmid39998694, year = {2025}, author = {Paramasivan, NK and Sarker, P and Zekeridou, A and Staff, NP and Klein, CJ and McKeon, A and Pittock, SJ and Dubey, D}, title = {Upper motor neuron-predominant motor neuron disease: a novel immunotherapy-responsive association of GAD65 autoimmunity.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {230}, pmid = {39998694}, issn = {1432-1459}, support = {MN OHE#15//Minnesota Office of Higher Education/ ; }, mesh = {Humans ; *Glutamate Decarboxylase/immunology ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Motor Neuron Disease/immunology/physiopathology/therapy ; *Immunotherapy/methods ; Autoantibodies/blood/cerebrospinal fluid ; Adult ; Autoimmunity ; Amyotrophic Lateral Sclerosis/immunology/therapy/physiopathology ; }, abstract = {BACKGROUND: Autoimmune disorders can present as motor neuronopathies and need to be excluded prior to the diagnosis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the clinical phenotypes of patients with motor neuron disease (MND) in the context of high-titer serum/CSF GAD65 antibodies (radioimmunoassay).<br><br>METHODS: A retrospective review of all Mayo patients (between 1/1/2003 and 12/31/2023) with motor neuronopathy and co-existing high-titer GAD65 antibodies (&#x2265;&#x2009;20&#xa0;nmol/L in serum [equivalent to&#x2009;>&#x2009;10,000&#xa0;IU, ELISA] or detection in CSF) was performed. Clinical phenotypes and outcomes were compared with ALS patients diagnosed in the last 5&#xa0;years (1/1/2019-12/31/2023) who tested negative for GAD65 IgG.<br><br>RESULTS: We identified 12 patients with high-titer GAD65 IgG and motor neuronopathy, who often had lower back spasms, history of an exaggerated startle response with immunotherapy responsiveness as compared to ALS patients. On further analysis, a subgroup of these patients with neurogenic changes on EMG, had an upper motor neuron (UMN) predominant syndrome (58%), with history of exaggerated startle (57%), lower back spasms (43%), tandem gait impairment (86%) and UMN bladder symptoms (71%) that were significantly different from the ALS controls. The UMN predominant GAD65 MN responded favorably to immunotherapy with stable electromyography; significantly lesser worsening in mRS and mortality on long-term follow-up.<br><br>DISCUSSION: An upper motor neuron predominant motor neuronopathy is a distinct manifestation of GAD65 autoimmunity. Co-existing symptoms like exaggerated startle response, lower back spasms, impaired tandem gait, and UMN bladder signs might warrant consideration of an immunotherapy trial, which could yield favorable results.}, }
@article {pmid39998031, year = {2025}, author = {Burke, KM and Shea, C and Arulanandam, V and Sullivan, S and Ellrodt, AS and MacAdam, C and Carney, K and Casagrande, G and Christiansen, E and Paganoni, S}, title = {Cervical Collar Satisfaction and Functional Impact in Amyotrophic Lateral Sclerosis: A Survey Study.}, journal = {American journal of physical medicine &amp; rehabilitation}, volume = {}, number = {}, pages = {}, doi = {10.1097/PHM.0000000000002716}, pmid = {39998031}, issn = {1537-7385}, abstract = {OBJECTIVES: Many people with amyotrophic lateral sclerosis (ALS) develop cervical muscle weakness, often managed with cervical collars. Finding supportive and comfortable collars can be challenging. This study aimed to evaluate satisfaction with various collars and their impact on activities of daily living.<br><br>DESIGN: This electronic survey study collected demographic information, clinical status, and participant experiences with commonly used cervical collars.<br><br>RESULTS: Thirty-four participants (33 with ALS, 1 with primary lateral sclerosis) completed the survey, with 79% reporting neck weakness and 38% experiencing neck pain. Among those who tried cervical collars (65%), many had tried multiple options. The mean satisfaction across all collar types was 5.03 (SD = 2.92) out of 10.<br><br>CONCLUSION: These findings suggest current collars do not fully meet the needs of people living with ALS, emphasizing the importance of improved treatment options. Future research should explore innovative technologies to improve cervical support, function, and quality of life.}, }
@article {pmid39997929, year = {2025}, author = {Newell, ME and Aravindan, A and Babbrah, A and Halden, RU}, title = {Epigenetic Biomarkers Driven by Environmental Toxins Associated with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the United States: A Systematic Review.}, journal = {Toxics}, volume = {13}, number = {2}, pages = {}, pmid = {39997929}, issn = {2305-6304}, support = {GF000000002135//Glen Swette Memorial Fund/ ; }, abstract = {Environmental toxins and epigenetic changes have been linked to neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). This paper aimed to (i) identify environmental toxins associated with AD, PD, and ALS, (ii) locate potential industrial sources of toxins in the United States (U.S.), and (iii) assess epigenetic changes driven by exposure to toxins reported by patients. Environmental factors and epigenetic biomarkers of neurodegeneration were compiled from 69 studies in the literature using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) and geographic information system approaches. Some 127 environmental toxins have been associated or putatively associated with AD, PD, or ALS, with four toxic metals (As, Cd, Mn, and Hg) common to all three of these neurodegenerative diseases. Environmental toxins associated with epigenetic changes (e.g., DNA methylation) in patients include air pollutants, metals, and organic chemicals (e.g., pesticides, mycotoxins, and cyanotoxins). Geographic analysis showed that study locations (e.g., U.S., Europe, and East Asia) were selected by researchers based on convenience of access rather than exposure risk and disease prevalence. We conclude that several toxins and epigenetic markers shared among neurodegenerative diseases could serve as attractive future targets guiding environmental quality improvements and aiding in early disease detection.}, }
@article {pmid39996748, year = {2025}, author = {Yang, HM}, title = {Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996748}, issn = {2073-4409}, support = {2020R1A2C1011311//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress ; Mitochondrial Dynamics ; Mitophagy ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.}, }
@article {pmid39996723, year = {2025}, author = {Deecke, L and Ohlei, O and Goldeck, D and Homann, J and Toepfer, S and Demuth, I and Bertram, L and Pawelec, G and Lill, CM}, title = {Peripheral Immune Profiles in Individuals at Genetic Risk of Amyotrophic Lateral Sclerosis and Alzheimer's Disease.}, journal = {Cells}, volume = {14}, number = {4}, pages = {}, pmid = {39996723}, issn = {2073-4409}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; LI 2654/4-1//German Research Foundation/ ; #16SV5536K, #16SV5537, #16SV5538, #16SV5837, #01UW0808,01GL1716A, and 01GL1716B//Bundesministerium f&#xfc;r Bildung und Forschung/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology ; *Alzheimer Disease/genetics/immunology ; Male ; Female ; *Genetic Predisposition to Disease ; Middle Aged ; Aged ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide/genetics ; Multifactorial Inheritance/genetics ; CD8-Positive T-Lymphocytes/immunology ; }, abstract = {The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD). Using multicolor flow cytometry, we analyzed 92 immune cell phenotypes in the blood of 448 healthy participants from the Berlin Aging Study II. We calculated polygenic risk scores (PGSs) using genome-wide significant SNPs from recent large genome-wide association studies on ALS and AD. Linear regression analyses were then performed of the immune cell types on the PGSs in both the overall sample and a subgroup of older participants (>60 years). While we did not find any significant associations between immune cell subtypes and ALS and AD PGSs when controlling for the false discovery rate (FDR = 0.05), we observed several nominally significant results (p < 0.05) with consistent effect directions across strata. The strongest association was observed with CD57+ CD8+ early-memory T cells and ALS risk (p = 0.006). Other immune cell subtypes associated with ALS risk included PD-1+ CD8+ and CD57+ CD4+ early-memory T cells, non-classical monocytes, and myeloid dendritic cells. For AD, naïve CD57+ CD8+ T cells and mature NKG2A+ natural killer cells showed nominally significant associations. We did not observe major immune cell changes in individuals at high genetic risk of ALS or AD, suggesting they may arise later in disease progression. Additional studies are required to validate our nominally significant findings.}, }
@article {pmid39996599, year = {2025}, author = {Chowdhury, RN and Azam, MA and Azam, SA and Lana, S and Culver, EN and Garruto, RM and Wander, K}, title = {Elevated Serum MCP-2 and TARC Associated With Increased Risk of Death in Guamanian ALS Patients.}, journal = {European journal of neurology}, volume = {32}, number = {3}, pages = {e70088}, pmid = {39996599}, issn = {1468-1331}, support = {//Sigma Xia/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality ; Female ; Male ; Middle Aged ; Aged ; Guam/epidemiology ; Biomarkers/blood ; Adult ; Chemokine CCL2/blood ; }, abstract = {BACKGROUND: This study explores the relationship between inflammation and longevity in a high-incidence focus of amyotrophic lateral sclerosis (ALS) in post-WWII Guam. Characteristics of this focus include the sudden appearance of the disease in high numbers and the unusually long lifespan (without medical interventions) seen in some cases. We used bio-banked specimens to evaluate the relationship between serum immunoregulators and survival time.<br><br>METHODS: We evaluated sera from 69 Guam ALS cases collected within 2&#x2009;years of symptom onset by NIH researchers from 1950 to 1983 for 11 immunoregulators via ELISA (CRP, eotaxin-1, RANTES, IL-6, IL-8, IL-10, IFN-&#x3b3;, IP-10, MCP-1, MCP-2 and TARC). Factor analysis identified two factors responsible for ~68% of the variation in the data. We estimated Cox proportional hazards models to identify immunoregulators associated with time to death.<br><br>RESULTS: Each 10-unit increase in factor 2 cytokines (MCP-2 and TARC) was associated with a 38% increase in the risk of death (HR: 1.38; 95% CI: 1.19, 1.65; p: 0.00).<br><br>DISCUSSION: Like sporadic ALS cases worldwide, inflammation is associated with a shortened lifespan in Guamanian ALS; more specifically, our findings suggest serum levels of MCP-2 and TARC at onset may predict disease duration. Further investigation is needed to determine the role of these immunoregulators in disease prognosis and as targets for diagnostic and therapeutic interventions.}, }
@article {pmid39996130, year = {2025}, author = {Dilliott, AA and Costanzo, MC and Bandres-Ciga, S and Blauwendraat, C and Casey, B and Hoang, Q and Iwaki, H and Jang, D and Kim, JJ and Leonard, HL and Levine, KS and Makarious, M and Nguyen, TT and Rouleau, GA and Singleton, AB and Smadbeck, P and Solle, J and Vitale, D and Nalls, M and Flannick, J and Burtt, NP and Farhan, SMK}, title = {The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.}, journal = {Neurology. Genetics}, volume = {11}, number = {2}, pages = {e200246}, pmid = {39996130}, issn = {2376-7839}, abstract = {Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.}, }
@article {pmid39995927, year = {2025}, author = {McDonald, TS and Cui, CS and Lerskiatiphanich, T and Marallag, J and Lee, JD}, title = {Metabolic rate and insulin-independent glucose uptake increase in a TDP-43[Q331K] mouse model of amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e42482}, pmid = {39995927}, issn = {2405-8440}, abstract = {Impaired glucose regulation is increasingly recognised in amyotrophic lateral sclerosis (ALS), yet the precise mechanisms remain unclear. Here, we investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)[Q331K] mice, a model of ALS, at both the early and late symptomatic stages of disease. Mutant TDP-43[Q331K] mice and non-transgenic controls underwent indirect calorimetry, as well as intraperitoneal glucose, insulin, and glucagon tolerance testing. We also examined plasma hormone levels and quantified α- and β-cell areas in pancreatic islets. Throughout disease progression, TDP-43[Q331K] mice exhibited elevated metabolic rates, with a transient increase in food intake at the early stages. At the later stages of disease, heightened glucose uptake was observed despite unchanged insulin secretion or tolerance, indicating mechanisms independent of insulin. Notably, TDP-43[Q331K] mice maintained fasting blood glucose levels even when circulating glucagon levels were reduced, suggesting that alternative pathways contribute to preserving euglycemia. These findings reveal a distinct metabolic profile in TDP-43[Q331K] mice, underscoring the complexity of glucose dyshomeostasis in ALS.}, }
@article {pmid39995125, year = {2025}, author = {Kalinin, AP and Zubkova, ES and Menshikov, MY and Parfyonova, YV}, title = {ISR Modulators in Neurological Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X361653250213114821}, pmid = {39995125}, issn = {1875-6190}, abstract = {The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.}, }
@article {pmid39995102, year = {2025}, author = {Perdikakis, M and Papadimitrakis, D and Floros, N and Tzavellas, E and Piperi, C and Gargalionis, AN and Papavassiliou, AG}, title = {Diagnostic role of circulating cell-free DNA in schizophrenia and neuro-degenerative disorders.}, journal = {Biomarkers in medicine}, volume = {19}, number = {5}, pages = {165-176}, pmid = {39995102}, issn = {1752-0371}, mesh = {Humans ; *Cell-Free Nucleic Acids/blood ; *Schizophrenia/diagnosis/blood/genetics ; *Neurodegenerative Diseases/diagnosis/blood/cerebrospinal fluid/genetics ; *Biomarkers/blood/cerebrospinal fluid ; Amyotrophic Lateral Sclerosis/diagnosis/blood/genetics/cerebrospinal fluid ; Huntington Disease/diagnosis/blood/genetics/cerebrospinal fluid ; Parkinson Disease/diagnosis/blood/genetics/cerebrospinal fluid ; Alzheimer Disease/diagnosis/blood/cerebrospinal fluid/genetics ; Multiple Sclerosis/diagnosis/blood/cerebrospinal fluid/genetics ; }, abstract = {Over the past few years, circulating cell-free DNA (cfDNA) research has grown exponentially. Several studies have associated the release of cfDNA in the bloodstream, cerebrospinal fluid, and other body fluids with increased apoptosis and cell death. Therefore, their possible use as biomarkers for cancer and other diseases has emerged. The diagnosis of pathological entities such as schizophrenia and neurodegenerative diseases involves many challenges and requires ruling out conditions with similar symptoms. In this context, cfDNA could serve as a valuable diagnostic biomarker. This study encompasses the recent bibliography and research regarding the utilization of circulating cfDNA for diagnostic purposes in schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. This minimally invasive method has provided important evidence regarding the diagnosis of the aforementioned diseases although further research is necessary.}, }
@article {pmid39995075, year = {2025}, author = {Manco, C and Righi, D and Primiano, G and Romano, A and Luigetti, M and Leonardi, L and De Stefano, N and Plantone, D}, title = {Peripherin, A New Promising Biomarker in Neurological Disorders.}, journal = {The European journal of neuroscience}, volume = {61}, number = {4}, pages = {e70030}, pmid = {39995075}, issn = {1460-9568}, mesh = {Humans ; *Peripherins/metabolism/genetics ; *Biomarkers/metabolism ; Animals ; *Nervous System Diseases/metabolism ; }, abstract = {Peripherin is a class III intermediate filament protein that has recently gained attention as a potential biomarker for axonal damage in the peripheral nervous system. This review examines peripherin gene expression, protein structure, and its functions in both healthy and diseased states. Peripherin is predominantly expressed in the peripheral nervous system, especially in motor and sensory neurons, and plays a critical role in neurite growth, stability, and axonal transport during myelination. Its expression is regulated by various cytokines and undergoes several post-transcriptional modifications. Peripherin interacts with multiple proteins, including neurofilaments and kinases, influencing cytoskeletal dynamics and neuronal functions. The review also explores peripherin involvement in several neurological disorders, such as Amyotrophic Lateral Sclerosis, where its abnormal expression and aggregation contribute to disease pathology. Additionally, peripherin has been linked to polyneuropathies, traumatic axonal injury, and diabetic neuropathy, suggesting its broader relevance as a biomarker in these conditions. The potential of peripherin as a biomarker is further supported by recent studies using ultrasensitive detection methods, which have identified elevated peripherin levels in the serum of patients with neurological diseases. Despite the promising findings, the application of peripherin as a biomarker in clinical settings remains limited, primarily due to challenges in its detection and the need for further validation in diverse patient populations. Future research directions include the development of more sensitive assays and the exploration of peripherin's role in non-neuronal tissues, which may expand its diagnostic and therapeutic potential.}, }
@article {pmid39994742, year = {2025}, author = {Djukic, S and Zhao, Z and Jørgensen, LMH and Bak, AN and Jensen, DB and Meehan, CF}, title = {TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {42}, pmid = {39994742}, issn = {2051-5960}, support = {R370-2021-1109//The Lundbeck Foundation/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/metabolism/physiopathology/genetics ; Animals ; *Motor Neurons/pathology/metabolism/physiology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; *Disease Models, Animal ; *Neuronal Plasticity/physiology ; *Axon Initial Segment/metabolism/physiology ; Spinal Cord/pathology/metabolism ; Mice ; Male ; Humans ; Female ; Action Potentials/physiology ; Mice, Inbred C57BL ; }, abstract = {A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all (~97%) cases (familial and sporadic) have in common are cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs. We used the TDP-43(ΔNLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.}, }
@article {pmid39994160, year = {2025}, author = {Dubey, PR and Kaur, G and Shukla, R}, title = {Nano-mediated Management of Metal Toxicity-induced Neurodegeneration: A Critical Review.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39994160}, issn = {1559-1182}, abstract = {Heavy metals, omnipresent in the environment, though imperative in trace quantities for human physiology, become a serious health hazard due to their toxicity. Copper, arsenic, lead, iron, and mercury are some examples of the heavy metals responsible for oxidative stress, which is one of the primary factors behind neurodegenerative diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Neurodegeneration is caused by toxicity due to environmental exposure to these toxic substances or genetic variation. Conventional therapies, relying on chelation and antioxidants, suffer from the broader perspective of metal removal in a non-selective manner and poor targeting of the brain. In this respect, treatments based on nanotechnology that employ nanoparticles such as dendrimers, micelles, and liposomes constitute a promising interest in enhancing drug delivery with minimal neurotoxicity. The present review outlines the heavy metals responsible for neurodegenerative diseases, their pathophysiology, management strategies available at present, and the scope of nanotechnology intervention in overcoming shortcomings of conventional therapies. The genetic influence of heavy metals on neurological health is also part of this article.}, }
@article {pmid39993605, year = {2025}, author = {David Wu, CH and Whelan, TJ and Swaminath, A}, title = {Response to: Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {206}, number = {}, pages = {110804}, doi = {10.1016/j.radonc.2025.110804}, pmid = {39993605}, issn = {1879-0887}, }
@article {pmid39993604, year = {2025}, author = {Huertas, A and Moghanaki, D and Siva, S}, title = {Comment on Wu et al's article on toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {206}, number = {}, pages = {110805}, doi = {10.1016/j.radonc.2025.110805}, pmid = {39993604}, issn = {1879-0887}, }
@article {pmid39992908, year = {2025}, author = {Nemeth, T and Zarnocki, A and Ladanyi, A and Papp, C and Ayaydin, F and Szebeni, GJ and Gacser, A}, title = {PCR-based CRISPR/Cas9 system for fluorescent tagging: A tool for studying Candida parapsilosis virulence.}, journal = {PloS one}, volume = {20}, number = {2}, pages = {e0312948}, doi = {10.1371/journal.pone.0312948}, pmid = {39992908}, issn = {1932-6203}, mesh = {*CRISPR-Cas Systems ; Mice ; *Candida parapsilosis/genetics/pathogenicity ; Animals ; Virulence/genetics ; Polymerase Chain Reaction/methods ; Macrophages/microbiology ; Humans ; }, abstract = {Candida parapsilosis is persistent in a hospital environment hence it is often associated with nosocomial infections especially amongst low-birth weight neonates. Genetic modification is therefore important to characterise the physiological and virulence related properties of this fungus. A PCR-based CRISPR/Cas9 system has been adopted to facilitate the generation of fluorescent tagged prototroph isolates. We examined a total of eight fluorescent protein coding genes, out of which three were found to be applicable for simultaneous utilisation. We investigated three clinical isolates of C. parapsilosis in terms of their adherence to silicone and their uptake by J774.2 murine macrophages in competition assays. Interestingly, we found significant differences between them in both experiments where GA1 isolate was significantly less resistant to macrophage uptake and CDC317 was significantly more adherent to silicone material. In silico analysis of the agglutinin-like sequences (Als) exposed remarkable diversity in this protein family and additionally, the thorough analysis of the ALS genes revealed evidence of formation of a new gene by intrachromosomal recombination in the GA1 isolate. Finally, we provide a step by step protocol for the application of the PCR-based CRISPR/Cas9 system for fluorescently labelling C. parapsilosis isolates.}, }
@article {pmid39992655, year = {2025}, author = {Liu, X and Shang, H and Wei, Q and Yao, X and Lian, L and Dang, J and Jia, R and Wu, Z and Li, H and Niu, Q and Cheng, X and Zou, Z and Chen, S and Zhang, M and Liu, Y and Liu, Y and Liu, Q and Huang, X and Wang, H and Feng, H and Wang, S and Fan, D and , }, title = {Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2461055}, pmid = {39992655}, issn = {2574-3805}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Pyrazines/therapeutic use/adverse effects ; Double-Blind Method ; Aged ; Treatment Outcome ; China ; Nitrogen Oxides ; }, abstract = {IMPORTANCE: Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).<br><br>OBJECTIVE: To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS.<br><br>This phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial was conducted from December 24, 2020, through July 14, 2023, in 11 centers in China, with a 180-day follow-up. Patients aged 45 to 70 years, with ALS onset within 2 years, ALS Functional Rating Scale-Revised (ALSFRS-R) scores of at least 2 points on each item, and forced vital capacity (FVC) of at least 80% were included. Patients experienced a 1- to 4-point decrease in ALSFRS-R score during a 3-month screening period.<br><br>INTERVENTIONS: Patients were randomly assigned 1:1:1 to receive low-dose tetramethylpyrazine nitrone (600 mg twice daily), high-dose tetramethylpyrazine nitrone (1200 mg twice daily), or placebo (twice daily) for 180 days.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was change in ALSFRS-R score (range of 0-48, with lower scores indicating worse function) from baseline to 180 days. The secondary outcomes were changes in FVC, grip strength, ALS Assessment Questionnaire-40 (ALSAQ-40) score, and end point events. Safety outcomes included adverse events.<br><br>RESULTS: A total of 155 patients (mean [SD] age, 55.0 [6.5] years; 115 men [74.2%]) were randomized (51 [32.9%] to the low-dose tetramethylpyrazine nitrone group, 52 [33.6%] to the high-dose tetramethylpyrazine nitrone group, and 52 [33.6%] to the placebo group). No significant differences were observed in ALSFRS-R score changes between low-dose tetramethylpyrazine nitrone (least squares [LS] mean difference, -0.89 points; 95% CI -3.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, -0.20 points; 95% CI -2.48 to 2.07 points) compared with placebo. High-dose tetramethylpyrazine nitrone showed a significantly slower decline in grip strength at day 180 (LS mean difference, 2.46 kg; 95% CI, 0.15-4.76 kg). In a subgroup of patients younger than 65 years with slower disease progression, tetramethylpyrazine nitrone significantly attenuated the decline in grip strength (LS mean difference, 3.63 kg; 95% CI, 0.84-6.41 kg), bulbar scores (LS mean difference, 0.66 points; 95% CI, 0.03-1.29 points), and respiratory scores (LS mean difference, 0.54 points; 95% CI, 0.03-1.06 points). Adverse events were mostly mild or moderate, with no severe treatment-related adverse events or deaths.<br><br>CONCLUSIONS AND RELEVANCE: This randomized clinical trial demonstrates that tetramethylpyrazine nitrone is safe and well-tolerated in patients with ALS. There was no difference in the primary end point across the low-dose, high-dose, and placebo groups, with significant benefits in a subgroup of younger patients with slower disease progression.<br><br>TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2000039689.}, }
@article {pmid39991082, year = {2025}, author = {Chen, G and Cao, Y and Du, X and Cui, J and Zeng, X and Yang, H and Ren, Z and Xu, K}, title = {The Clinical Research Landscape of Intracranial Nicardipine for Aneurysmal Subarachnoid Hemorrhage: Insights From Bibliometric Analysis.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {1129-1146}, pmid = {39991082}, issn = {1177-8881}, mesh = {Humans ; *Bibliometrics ; *Nicardipine/administration &amp; dosage/therapeutic use ; *Subarachnoid Hemorrhage/drug therapy ; Biomedical Research ; }, abstract = {BACKGROUND: The 2023 American Heart Association/American Stroke Association guideline and Wessels et al's 2024 randomized controlled trial highlight the potential benefits of intracranial nicardipine for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to systematically identify the publication trends and research hotspots in this field through bibliometric analysis.<br><br>METHODS: Relevant publications were sourced from the Web of Science Core Collection (WoSCC). Bibliometric and visualization analyses were conducted using the online tools of the WoSCC database and CiteSpace 6.2.R6.<br><br>RESULTS: Analysis of 28 articles published by 158 researchers from 55 institutions across 8 countries revealed an intermittent small-scale growth in annual publication volume from 1994 to 2024, with a continuous rise in annual citation volume since 2005, indicating growing interest in the field. Japan, Germany, and the United States of America (USA) were the most prolific and influential countries. Institutions such as Tokyo Women's Medical University showed particularly significant contributions. Kasuya Hidetoshi was the most prolific author. There was little global collaboration among countries, institutions, and authors, with distinct regional research characteristics: Japan and Germany focused on intracranial implants, while the USA concentrated on intrathecal injections. Major publishing and co-cited journals included Neurocritical Care, Acta Neurochirurgica, Journal of Neurosurgery, and Stroke. Popular keywords in 2024 included "preventing cerebral vasospasm", "delayed cerebral ischemia", "outcome events", and "clinical trials", revealing current research hotspots.<br><br>CONCLUSION: This study maps the global clinical research landscape of intracranial application of nicardipine for aSAH from 1994 to 2024, providing valuable references and guidance for future research.}, }
@article {pmid39990425, year = {2025}, author = {Chakraborty, A and Mitra, J and Malojirao, VH and Kodavati, M and Mandal, SM and Gill, SK and Sreenivasmurthy, SG and Vasquez, V and Mankevich, M and Krishnan, B and Ghosh, G and Hegde, M and Hazra, T}, title = {Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.13.623464}, pmid = {39990425}, issn = {2692-8205}, abstract = {TAR DNA-binding protein 43 (TDP-43) proteinopathy plays a critical role in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). In our recent discovery, we identified that TDP-43 plays an essential role in DNA double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. Here, we found persistent DNA damage in the brains of ALS/FTD patients, primarily in the transcribed regions of the genome. We further investigated the underlying mechanism and found that polynucleotide kinase 3'-phosphatase (PNKP) activity was severely impaired in the nuclear extracts of both patient brains and TDP-43-depleted cells. PNKP is a key player in DSB repair within the transcribed genome, where its 3'-P termini processing activity is crucial for preventing persistent DNA damage and neuronal death. The inactivation of PNKP in ALS/FTD was due to reduced levels of its interacting partner, phosphofructo-2-kinase fructose 2,6 bisphosphatase (PFKFB3), and its biosynthetic product, fructose-2,6-bisphosphate (F2,6BP), an allosteric modulator of glycolysis. Recent work from our group has shown that F2,6BP acts as a positive modulator of PNKP activity in vivo. Notably, exogenous supplementation with F2,6BP restored PNKP activity in nuclear extracts from ALS/FTD brain samples and patient-derived induced pluripotent stem (iPS) cells harboring pathological mutations. Furthermore, we demonstrate that supplementation of F2,6BP restores genome integrity and partially rescues motor phenotype in a Drosophila model of ALS. Our findings underscore the possibility of exploring the therapeutic potential of F2,6BP or its analogs in TDP-43 pathology-associated motor neuron diseases.}, }
@article {pmid39990107, year = {2025}, author = {Zhao, S and Chen, R and An, Y and Zhang, Y and Ma, C and Gao, Y and Lu, Y and Yang, F and Bai, X and Zhang, J}, title = {Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1522073}, pmid = {39990107}, issn = {1663-4365}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons (MNs). Genetic mutations in Optineurin (OPTN) and Superoxide Dismutase 1 (SOD1) have been identified as causal factors for ALS. OPTN immunopositive inclusions have been confirmed in the cases of ALS with SOD1 mutations. However, the role of the OPTN gene in ALS caused by SOD1 mutations is ambiguous.<br><br>METHODS: The murine Optn lentivirus and empty vector lentivirus were injected into SOD1 [G93A] mice after discovering variations in Optn expression over time. The phenotype onset date, life span, locomotor activity, and pathological changes in the spinal cord were determined and recorded subsequently. In addition, the influences on cellular apoptosis, mitochondrial dynamics, mitophagy, and neuroinflammation were further investigated.<br><br>RESULTS: Optn expression was increased in the spinal cord of SOD1 [G93A] mice at the pre-symptomatic phase, but decreased after disease onset. Optn overexpression led to a 9.7% delay in the onset of disease and improved motor performance in SOD1 [G93A] mice. Optn overexpression also ameliorated the MNs loss by 46.8%. Moreover, all these ameliorating effects induced by Optn overexpression might be due to the inhibition of cellular apoptosis, improvement of mitochondrial quality, regulation of mitochondrial dynamics, promotion of mitophagy, and anti-inflammatory properties.<br><br>CONCLUSION: Our data demonstrate that Optn overexpression protects MNs, inhibites cellular apoptosis, improves mitochondrial quality and regulates neuroinflamation in SOD1 [G93A] mice at the pre-symptomatic stage.}, }
@article {pmid39989851, year = {2025}, author = {Rea, D and Tham, C and Tham, TC}, title = {Endoscopic calabash technique for gastric mesenchymal tumours: A low hanging fruit or a novel endoscopic technique?.}, journal = {World journal of gastrointestinal endoscopy}, volume = {17}, number = {2}, pages = {101676}, pmid = {39989851}, issn = {1948-5190}, abstract = {The term subepithelial lesions encompasses a wide array of pathology of which numerous benign and malignant pathologies are grouped. A subset of these lesions are termed gastric mesenchymal tumours of which some have innate malignant potential. Currently there is various guidance on the recommended approach to the investigation and management of these lesions and there exists multiple methods of resection. Lin et al have developed and proposed a new method of resection of these gastric mesenchymal tumours within the field of endoscopy, a procedure they have termed endoscopic calabash ligation and resection. This editorial aims to outlay the current landscape for gastric mesenchymal tumours with regards to the various guidelines and resection techniques while comparing Lin et al's new technique to those that are already established in the field of endoscopy. Advancements in endoscopy that maintain or improve patient outcomes compared to the gold standard approach are exciting developments. Lin et al's study suggests that their technique is comparable in regard to patient outcomes while simultaneously being more efficient in its use of hospital resources including procedural time. Whilst the data and analysis proposed in the study is promising, there are areas that need to be addressed before advocating the procedure for widespread use. However, with further studies and analysis this may be foreseeable in the future.}, }
@article {pmid39989811, year = {2025}, author = {Marzi, I and Pieraccini, G and Bemporad, F and Chiti, F}, title = {Detection of an Intermediate in the Unfolding Process of the N-Terminal Domain of TDP-43.}, journal = {ACS omega}, volume = {10}, number = {6}, pages = {5616-5633}, pmid = {39989811}, issn = {2470-1343}, abstract = {TAR DNA-binding protein 43 (TDP-43) is a nuclear protein accumulating in intraneuronal cytoplasmic inclusions associated with amyotrophic lateral sclerosis, frontotemporal lobar degeneration with tau-negative/ubiquitin-positive inclusions, and limbic-predominant age-related TDP-43 encephalopathy. Oligomerization of full-length TDP-43, driven by its N-terminal domain (NTD), is essential for its function, but aberrant self-assembly also promotes liquid-liquid phase separation and formation of solid inclusions. Building on recent all-atom molecular dynamics simulations and using various biophysical approaches, we identified a partially unfolded state accumulating during unfolding of TDP-43 NTD, before the major energy barrier of unfolding is crossed. Intrinsic fluorescence spectroscopy coupled to a stopped-flow device at high urea concentration reveals that the intermediate state has a fluorescence emission distinct from those of the native and unfolded states and forms within the 14 ms dead time. Conventional fluorescence spectroscopy shows it still accumulates at moderate urea concentration. Circular dichroism and H/D exchange results show a species with an intermediate content of secondary structure and a distorted β-sheet, whereas SYPRO orange fluorescence indicates an open conformation with more exposed hydrophobic regions compared to the native state. Importantly, this intermediate is observed even at low protein concentration, when TDP-43 NTD is largely monomeric, indicating that its formation is independent of the initial TDP-43 NTD oligomeric state. Dynamic light scattering at high protein concentration shows that the intermediate is a partially folded dimer. The intermediate forms upon chemical denaturation and does not occur under thermal unfolding. Overall, the findings highlight the presence of one more partially folded state for TDP-43 NTD, underlining its high structural plasticity and suggesting that its distinct unfolding pathway may play a critical role in both its functional and pathological behaviors.}, }
@article {pmid39989203, year = {2025}, author = {Wu, J and Sun, C and Xu, Y and Fan, D and Ye, S}, title = {The contralateral co-movement test in a Chinese population with amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2467959}, pmid = {39989203}, issn = {2167-9223}, abstract = {INTRODUCTION: Mirror movements (MMs) are often overlooked in patients with amyotrophic lateral sclerosis (ALS). Although the contralateral co-movement (COMO) test can be used to evaluate MMs in patients with ALS, it lacks a systematic evaluation. The aim of this study was to validate the effectiveness of the Chinese version of the COMO test in a Chinese ALS population.<br><br>METHODS: We prospectively enrolled 173 patients with ALS as the disease group and 28 healthy individuals as controls. All participants were evaluated using the Chinese version of the COMO test. Univariate analysis and multiple linear regression were used to compare differences between groups. Subgroup analysis of the COMO scores was performed based on different disease characteristics.<br><br>RESULTS: The COMO score in the ALS group was significantly greater (5.00% [1.67-10.00]) than that in the healthy control group (1.67% [0.00-3.33]). After adjusting for confounders, this difference remained significant. Multivariate linear analysis suggested that the upper motor neuron (UMN) score independently predicted the COMO score (P&#x2009;<&#x2009;0.001). The COMO score was not affected by different onset regions or lateralizations. Propensity score matching revealed no significant difference in COMO scores between uninvolved limb segments and the corresponding limb segments in other patients. The Cronbach's &#x3b1; of the Chinese COMO test was 0.621.<br><br>CONCLUSION: The Chinese COMO test can serve as a potential tool for assessing MMs in Chinese patients with ALS. The UMN score is a factor influencing the COMO score. The COMO test can provide objective evidence for ALS characteristics and the severity of UMN damage.}, }
@article {pmid39987720, year = {2025}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Usefulness of the Gold Coast criteria in diagnosing fast-progressing amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {471}, number = {}, pages = {123418}, doi = {10.1016/j.jns.2025.123418}, pmid = {39987720}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Disease Progression ; Retrospective Studies ; Aged ; *Electromyography/methods ; Sensitivity and Specificity ; Adult ; }, abstract = {The Gold Coast criteria are reportedly more sensitive for diagnosing amyotrophic lateral sclerosis (ALS) than the previously used criteria; however, the sensitivity of these sets of criteria among groups classified according to their prognosis has not been compared. In this study, we examined the difference in the sensitivity for ALS diagnosis among these criteria, especially in patients with fast-progression ALS. We enrolled 95 patients diagnosed with ALS and retrospectively classified them into three groups based on the interval between disease onset and death or tracheostomy. We retrospectively examined the number of patients meeting the Gold Coast, Awaji, or revised El Escorial criteria (rEEC) (definite/probable/possible) at initial clinical examination and electromyography and compared the rates of diagnosis according to each set of criteria among the three groups. The sensitivity of the Gold Coast criteria was significantly higher than that of the Awaji and rEEC criteria (sensitivity, 92.6 % vs. 71.8 % vs. 71.7 %, p < 0.001). The sensitivity of the Gold Coast criteria in patients with fast progression (n = 30) was significantly higher than that of the Awaji and rEEC criteria (sensitivity, 100 % vs. 73.3 % vs. 73.3 %, p = 0.001). Most patients diagnosed only based on the Gold Coast criteria had lower motor signs. Hence, the Gold Coast criteria are particularly useful for diagnosing fast-progression ALS.}, }
@article {pmid39987392, year = {2025}, author = {Liu, Y and Xiang, J and Gong, H and Yu, T and Gao, M and Huang, Y}, title = {The Regulation of TDP-43 Structure and Phase Transitions: A Review.}, journal = {The protein journal}, volume = {44}, number = {2}, pages = {113-132}, pmid = {39987392}, issn = {1875-8355}, support = {22477022//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Phase Transition ; Protein Processing, Post-Translational ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mutation ; Frontotemporal Dementia/metabolism/genetics/pathology ; }, abstract = {The transactive response DNA binding protein 43 (TDP-43) is an RNA/DNA-binding protein that is involved in a number of cellular functions, including RNA processing and alternative splicing, RNA transport and translation, and stress granule assembly. It has attracted significant attention for being the primary component of cytoplasmic inclusions in patients with amyotrophic lateral sclerosis or frontotemporal dementia. Mounting evidence suggests that both cytoplasmic aggregation of TDP-43 and loss of nuclear TDP-43 function contribute to TDP-43 pathology. Furthermore, recent studies have demonstrated that TDP-43 is an important component of many constitutive or stress-induced biomolecular condensates. Dysregulation or liquid-to-gel transition of TDP-43 condensates can lead to alterations in TDP-43 function and the formation of TDP-43 amyloid fibrils. In this review, we summarize recent research progress on the structural characterization of TDP-43 and the TDP-43 phase transition. In particular, the roles that disease-associated genetic mutations, post-translational modifications, and extrinsic stressors play in the transitions among TDP-43 monomers, liquid condensates, solid condensates, and fibrils are discussed. Finally, we discuss the effectiveness of available regulators of TDP-43 phase separation and aggregation. Understanding the underlying mechanisms that drive the pathological transformation of TDP-43 could help develop therapeutic strategies for TDP-43 pathology.}, }
@article {pmid39987285, year = {2025}, author = {Fang, M and Zhou, Y and He, K and Lu, Y and Tao, F and Huang, H}, title = {Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39987285}, issn = {1559-1182}, support = {82204651//National Natural Science Foundation of China/ ; }, abstract = {As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.}, }
@article {pmid39987111, year = {2025}, author = {Zeng, L and Yang, F and Xu, D and Zhou, J and Qiao, G and Wu, M and Li, C and Yu, Y and Qiu, Y and Liu, J}, title = {Actual needs of patients with amyotrophic lateral sclerosis: a qualitative study from Wuhan, China.}, journal = {BMC palliative care}, volume = {24}, number = {1}, pages = {50}, pmid = {39987111}, issn = {1472-684X}, support = {2023AFD160//Hubei Provincial Natural Science Foundation and Traditional Chinese Medicine Innovation and Development Joint/ ; 2024AFD279//Department of Science and Technology, Hubei Province, China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; China ; *Qualitative Research ; Male ; Middle Aged ; Female ; Aged ; Adult ; Needs Assessment ; Health Services Needs and Demand ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that significantly impacts individuals and families. Previous research on ALS has predominantly focused on its pathophysiology, genetic factors, and potential therapeutic interventions. While these aspects are essential for understanding and treating the disease, there has been a growing recognition of the importance of studying patients' actual needs. Understanding these needs is vital for developing patient-centered care models that can enhance the well-being of ALS patients. However, existing studies on patients' needs are often limited in scope. Many are conducted in Western countries, and the results may not be directly applicable to patients in other cultural and socioeconomic contexts. China, with its large population and diverse cultural, economic, and healthcare landscapes, presents a unique setting for studying ALS patients' needs. At the same time, traditional Chinese medicine (TCM) practices are deeply ingrained in their healthcare system and may affect the way people with ALS seek treatment and manage their condition. Therefore, these differences may lead to differences in the actual needs of ALS patients in China. In conclusion, this qualitative study on the actual needs of ALS patients in China aims to bridge the gap in the existing research. By exploring these needs, it can provide valuable insights for healthcare providers, policymakers, and researchers, ultimately contributing to the improvement of care and quality of life for ALS patients in China.<br><br>METHOD: We carried out a qualitative study using an empirical phenomenological approach. Individual in-depth interviews were performed among 22 people with ALS from the motor neuron disease rehabilitation center of a tertiary Chinese medicine hospital in China, and the interview content was analyzed qualitatively. Interview recordings were converted to text content by NVivo 11.0 software and analyzed using Colaizzi's phenomenological method.<br><br>RESULT: Three main themes were identified in this study: (1) Demand for healthcare services, (2) Emotional requirements, (3) Functional requirements. In addition, 8 sub-themes were extracted as the actual needs of ALS patients.<br><br>CONCLUSION: This study is based on the real experience of ALS patients after diagnosis, and a deep understanding of these experiences can explore the actual needs of patients from many aspects and give reasonable advice and help. Given the particularity of the disease and the uncertainty of treatment, patients will have practical needs for relevant medical support, emotional requirements, physical functions, and other aspects during the period of illness, and the corresponding support is an effective measure to reduce the burden on patients.}, }
@article {pmid39986312, year = {2025}, author = {Mizielinska, S and Hautbergue, GM and Gendron, TF and van Blitterswijk, M and Hardiman, O and Ravits, J and Isaacs, AM and Rademakers, R}, title = {Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics.}, journal = {The Lancet. Neurology}, volume = {24}, number = {3}, pages = {261-274}, doi = {10.1016/S1474-4422(25)00026-2}, pmid = {39986312}, issn = {1474-4465}, support = {R01 NS121125/NS/NINDS NIH HHS/United States ; RF1 NS123052/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *DNA Repeat Expansion/genetics ; }, abstract = {GGGGCC repeat expansions in C9orf72 are a common genetic cause of amyotrophic lateral sclerosis in people of European ancestry; however, substantial variability in the penetrance of the mutation, age at disease onset, and clinical presentation can complicate diagnosis and prognosis. The repeat expansion is bidirectionally transcribed in the sense and antisense directions into repetitive RNAs and translated into dipeptide repeat proteins, and both accumulate in the cortex, cerebellum, and the spinal cord. Furthermore, neuropathological aggregates of phosphorylated TDP-43 are observed in motor cortex and other cortical regions, and in the spinal cord of patients at autopsy. C9orf72 repeat expansions can also cause frontotemporal dementia. The GGGGCC repeat induces a complex interplay of loss-of-function and gain-of-function pathological mechanisms. Clinical trials using antisense oligonucleotides to target the GGGGCC repeat RNA have not been successful, potentially because they only target a single gain-of-function mechanism. Novel therapeutic approaches targeting the DNA repeat expansion, multiple repeat-derived RNA species, or downstream targets of TDP-43 dysfunction are, however, on the horizon, together with the development of diagnostic and prognostic biomarkers.}, }
@article {pmid39985864, year = {2025}, author = {Wilk, LS and Hoveling, RJM and van Velthoven, MFAM and Nijs, HGT and Aalders, MCG}, title = {Optimizing the detection and characterization of bruises using multispectral imaging.}, journal = {Journal of forensic and legal medicine}, volume = {111}, number = {}, pages = {102811}, doi = {10.1016/j.jflm.2025.102811}, pmid = {39985864}, issn = {1878-7487}, mesh = {Humans ; *Contusions/pathology/diagnostic imaging ; Algorithms ; Photography ; *Hematoma/diagnostic imaging/pathology ; }, abstract = {The detection and visualization of sub-dermal hematoma (bruises) plays a key role in suspected physical abuse cases, as it aids in the evaluation of both victim and suspect statements. Current methods rely on visual inspection, frequently aided by alternate light sources (ALS). Ideally, ALS increase visual contrast by exploiting differences in light absorption (due to the formation and clearance of chromophores within the bruise). However, in practice the achievable contrast is often limited by light-scattering: the short-wavelength region of the spectrum (comprising most of the chromophore-specific absorption peaks), is also strongly scattered by the dermal tissue. This, in turn, limits achievable penetration depths, effectively obscuring deep-lying bruises. ALS-based contrast enhancement is further complicated by bruise healing; diffusion and enzymatic activity alter the chromophore concentrations as well as their 3D-distribution within the tissue. To overcome these critical limitations, we employ a multi-spectral camera (8 wavelengths simultaneously) in conjunction with both observer-based scoring and a contrast-quantification algorithm to determine the optimal wavelength for the detection and characterization of bruises over time. We show that (i) bruise contrast significantly increases at 480 nm, 620 nm and 850 nm and (ii) the wavelength achieving optimal contrast gradually changes from 850 nm to 578 nm-480 nm as the bruise heals.}, }
@article {pmid39985812, year = {2025}, author = {Filippi, M and Ghirelli, A and Spinelli, EG and Agosta, F}, title = {A comprehensive update on neuroimaging endpoints in amyotrophic lateral sclerosis.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {4}, pages = {397-413}, doi = {10.1080/14737175.2025.2470324}, pmid = {39985812}, issn = {1744-8360}, mesh = {*Amyotrophic Lateral Sclerosis/diagnostic imaging ; Humans ; *Neuroimaging/methods ; *Magnetic Resonance Imaging/methods ; *Disease Progression ; *Positron-Emission Tomography/methods ; Biomarkers ; }, abstract = {INTRODUCTION: There are currently few treatments approved for amyotrophic lateral sclerosis (ALS). Additionally, there remains a significant unmet need for reliable, standardized biomarkers to assess endpoints in clinical trials. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-derived metrics could help in patient selection and stratification, shortening trial duration and reducing costs.<br><br>AREAS COVERED: This review focuses on the potential use of neuroimaging endpoints in the context of ALS therapeutic trials, providing insights on structural and functional neuroimaging, plexus and muscle alterations, glial involvement and neuroinflammation, envisioning how these surrogates of disease progression could be implemented in clinical trials. A PubMed search covering the past 15&#x2009;years was performed.<br><br>EXPERT OPINION: Neuroimaging is essential in understanding ALS pathophysiology, aiding in disease progression tracking and evaluating therapeutic interventions. High costs, limited accessibility, lack of standardization, and patient tolerability limit their use in routine ALS care. Addressing these obstacles is essential for fully harnessing neuroimaging potential in improving diagnostics and treatment in ALS.}, }
@article {pmid39985309, year = {2025}, author = {Lajoie, I and ,  and Kalra, S and Dadar, M}, title = {Regional Cerebral Atrophy Contributes to Personalized Survival Prediction in Amyotrophic Lateral Sclerosis: A Multicentre, Machine Learning, Deformation-Based Morphometry Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27196}, pmid = {39985309}, issn = {1531-8249}, support = {//Fondation Brain Canada/ ; //ALS Society of Canada/ ; }, abstract = {OBJECTIVE: Accurate personalized survival prediction in amyotrophic lateral sclerosis is essential for effective patient care planning. This study investigates whether grey and white matter changes measured by magnetic resonance imaging can improve individual survival predictions.<br><br>METHODS: We analyzed data from 178 patients with amyotrophic lateral sclerosis and 166 healthy controls in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. A voxel-wise linear mixed-effects model assessed disease-related and survival-related atrophy detected through deformation-based morphometry, controlling for age, sex, and scanner variations. Additional linear mixed-effects models explored associations between regional imaging and clinical measurements, and their associations with time to the composite outcome of death, tracheostomy, or permanent assisted ventilation. We evaluated whether incorporating imaging features alongside clinical data could improve the performance of an individual survival distribution model.<br><br>RESULTS: Deformation-based morphometry uncovered distinct voxel-wise atrophy patterns linked to disease progression and survival, with many of these regional atrophies significantly associated with clinical manifestations of the disease. By integrating regional imaging features with clinical data, we observed a substantial enhancement in the performance of survival models across key metrics. Our analysis identified specific brain regions, such as the corpus callosum, rostral middle frontal gyrus, and thalamus, where atrophy predicted an increased risk of mortality.<br><br>INTERPRETATION: This study suggests that brain atrophy patterns measured by deformation-based morphometry provide valuable insights beyond clinical assessments for prognosis. It offers a more comprehensive approach to prognosis and highlights brain regions involved in disease progression and survival, potentially leading to a better understanding of amyotrophic lateral sclerosis. ANN NEUROL 2025.}, }
@article {pmid39985291, year = {2025}, author = {Steinfurth, L and Grehl, T and Weyen, U and Kettemann, D and Steinbach, R and Rödiger, A and Grosskreutz, J and Petri, S and Boentert, M and Weydt, P and Bernsen, S and Walter, B and GüNTHER, R and Lingor, P and Koch, JC and Baum, P and Weishaupt, JH and Dorst, J and Koc, Y and Cordts, I and Vidovic, M and Norden, J and Schumann, P and Körtvélyessy, P and Spittel, S and Münch, C and Maier, A and Meyer, T}, title = {Self-assessment of amyotrophic lateral sclerosis functional rating scale on the patient's smartphone proves to be non-inferior to clinic data capture.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/21678421.2025.2468404}, pmid = {39985291}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate self-assessment of the amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) using the patient's smartphone and to analyze non-inferiority to clinic assessment.<br><br>METHODS: In an observational study, ALSFRS-R data being remotely collected on a mobile application (App-ALSFRS-R) were compared to ALSFRS-R captured during clinic visits (clinic-ALSFRS-R). ALS progression rate (ALSPR)-as calculated by the monthly decline of ALSFRS-R-and its intrasubject variability (ALSPR-ISV) between ratings were used to compare both cohorts. To investigate non-inferiority of App-ALSFRS-R data, a non-inferiority margin was determined.<br><br>RESULTS: A total of 691 ALS patients using the ALS-App and 1895 patients with clinic assessments were included. Clinical characteristics for the App-ALSFRS-R and clinic-ALSFRS-R cohorts were as follows: Mean age 60.45 (SD 10.43) and 63.69 (SD 11.30) years (p&#x2009;<&#x2009;0.001), disease duration 38.7 (SD 37.68) and 56.75 (SD 54.34) months (p&#x2009;<&#x2009;0.001) and ALSPR 0.72 and 0.59 (p&#x2009;<&#x2009;0.001), respectively. A paired sample analysis of ALSPR-ISV was applicable for 398 patients with clinic as well as app assessments and did not show a significant difference (IQR 0.12 [CI 0.11, 0.14] vs 0.12 [CI 0.11, 0.14], p&#x2009;=&#x2009;0.24; Cohen's d&#x2009;=&#x2009;0.06). CI of IQR for App-ALSFRS-R was below the predefined non-inferiority margin of 0.15 IQR, demonstrating non-inferiority.<br><br>CONCLUSIONS: Patients using a mobile application for remote digital self-assessment of the ALSFRS-R revealed younger age, earlier disease course, and faster ALS progression. The finding of non-inferiority of App-ALSFRS-R assessments underscores, that data collection using the ALS-App on the patient's smartphone can serve as additional source of ALSFRS-R in ALS research and clinical practice.}, }
@article {pmid39985110, year = {2025}, author = {Swanson, MEV and Mrkela, M and Turner, C and Curtis, MA and Faull, RLM and Walker, AK and Scotter, EL}, title = {Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {39}, pmid = {39985110}, issn = {2051-5960}, mesh = {*Microglia/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Humans ; Animals ; Mice ; Male ; Female ; Middle Aged ; Aged ; Immunophenotyping ; Mice, Transgenic ; Motor Cortex/pathology/metabolism ; Aged, 80 and over ; Microfilament Proteins/metabolism ; Antigens, CD/metabolism ; Calcium-Binding Proteins/metabolism ; }, abstract = {Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphologies changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.}, }
@article {pmid39984353, year = {2025}, author = {Comini, L and Pietro, DAD and Olivares, A and Bertella, E and Vitacca, M}, title = {Gut dysbiosis and leaky gut syndrome in moderately impaired amyotrophic lateral sclerosis patients.}, journal = {European journal of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ejim.2025.02.019}, pmid = {39984353}, issn = {1879-0828}, }
@article {pmid39982984, year = {2025}, author = {Verde, EM and Antoniani, F and Mediani, L and Secco, V and Crotti, S and Ferrara, MC and Vinet, J and Sergeeva, A and Yan, X and Hoege, C and Stuani, C and Paron, F and Kao, TT and Shrivastava, R and Polanowska, J and Bailly, A and Rosa, A and Aronica, E and Goswami, A and Shneider, N and Hyman, AA and Buratti, E and Xirodimas, D and Franzmann, TM and Alberti, S and Carra, S}, title = {SUMO2/3 conjugation of TDP-43 protects against aggregation.}, journal = {Science advances}, volume = {11}, number = {8}, pages = {eadq2475}, pmid = {39982984}, issn = {2375-2548}, mesh = {Humans ; *Small Ubiquitin-Related Modifier Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *Protein Inhibitors of Activated STAT/metabolism/genetics ; Oxidative Stress ; Protein Aggregates ; Ubiquitins/metabolism ; Sumoylation ; Stress Granules/metabolism ; Protein Binding ; Protein Aggregation, Pathological/metabolism ; Poly-ADP-Ribose Binding Proteins ; }, abstract = {Cytosolic aggregation of the RNA binding protein TDP-43 (transactive response DNA-binding protein 43) is a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that during oxidative stress, TDP-43 becomes SUMO2/3-ylated by the SUMO E3 ligase protein PIAS4 (protein inhibitor of activated STAT 4) and enriches in cytoplasmic stress granules (SGs). Upon pharmacological inhibition of TDP-43 SUMO2/3-ylation or PIAS4 depletion, TDP-43 enrichment in SGs is accompanied by irreversible aggregation. In cells that are unable to assemble SGs, SUMO2/3-ylation of TDP-43 is strongly impaired, supporting the notion that SGs are compartments that promote TDP-43 SUMO2/3-ylation during oxidative stress. Binding of TDP-43 to UG-rich RNA antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes TDP-43 SUMO2/3-ylation. We conclude that SUMO2/3 protein conjugation is a cellular mechanism to stabilize cytosolic RNA-free TDP-43 against aggregation.}, }
@article {pmid39982687, year = {2025}, author = {Loher, P and Londin, E and Ilieva, H and Pasinelli, P and Rigoutsos, I}, title = {Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39982687}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease for which accurate diagnostic and prognostic biomarkers are needed. Toward this goal, we reanalyzed two published collections of datasets generated from the plasma and serum of ALS patients and controls. We profiled these datasets for isoforms of microRNAs (miRNAs) known as isomiRs, transfer RNA-derived fragments (tRFs), and ribosomal RNA-derived fragments (rRFs), placing all remaining reads into a group labeled "not-itrs." We found that plasma and serum are rich in isomiRs (canonical, non-canonical, and non-templated), tRFs, rRFs, and members of an emerging class of small RNAs known as Y RNA-derived fragments (yRFs). In both analyzed collections, we found many isomiRs, tRFs, rRFs, and yRFs that are differentially abundant between patients and controls. We also performed a survival analysis that considered Riluzole treatment status, demographics (age at onset, age at enrollment, sex), and disease characteristics (ALSFRS, rD50, onset type) and found many of the differentially abundant small RNAs to be associated with survival time, with some of these associations being independent of Riluzole treatment. Unexpectedly, many not-itrs that did not map to the human genome mapped exactly to sequences from the SILVA database of ribosomal DNAs (rDNAs). Not-itrs from the plasma datasets mapped primarily to rDNAs from the order of Burkholderiales, and several of them were associated with patient survival. Not-itrs from the serum datasets also showed support for rDNA from Burkholderiales but a stronger support for rDNAs from the fungi group of the Nucletmycea taxon. The findings suggest that many previously unexplored small non-coding RNAs, including human isomiRs, tRFs, rRFs, and yRFs, could potentially serve as novel diagnostic and prognostic biomarkers for ALS.}, }
@article {pmid39982214, year = {2025}, author = {Peng, T and Hu, N and Huang, L and Kang, Y and Yan, Y and Zhang, H and Wan, D and Jin, X and Yang, Y}, title = {Safety of edaravone in real-world use: analysis based on FDA adverse event reporting system.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/14740338.2025.2470874}, pmid = {39982214}, issn = {1744-764X}, abstract = {BACKGROUND: Edaravone is a novel free radical scavenger utilized to treat amyotrophic lateral sclerosis (ALS). However, long-term safety data remain limited.<br><br>RESEARCH DESIGN AND METHODS: Adverse event reports related to edaravone from the second quarter of 2017 to the second quarter of 2024 were extracted from the US Food and Drug Administration (FDA) Adverse Event Reporting System database (FAERS). Disproportionality analysis was conducted utilizing the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms.<br><br>RESULTS: A total of 3,149 adverse event reports related to edaravone were analyzed. The most common adverse reactions included systemic disorders and administration site reactions, nervous system disorders, respiratory system disorders, and surgical and medical procedures. New adverse reaction signals included disseminated intravascular coagulation, gastric fistula, sputum retention, excessive salivation, fractures, elevated cystatin C. The median onset time for adverse events was 43&#x2009;days (interquartile range: 7-173&#x2009;days).<br><br>CONCLUSION: This study confirmed previously reported adverse events and identified several new ones associated with edaravone. These findings provide valuable insights for optimizing ALS patient management and highlight the need for further research into the mechanisms of these adverse reactions.}, }
@article {pmid39981400, year = {2025}, author = {Yang, EJ and Lee, SH}, title = {Herbal Medicine Extracts Improve Motor Function by Anti-Inflammatory Activity in hSOD1[G93A] Animal Model.}, journal = {Mediators of inflammation}, volume = {2025}, number = {}, pages = {1999953}, pmid = {39981400}, issn = {1466-1861}, mesh = {Animals ; Mice ; *Mice, Transgenic ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Disease Models, Animal ; *Plant Extracts/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Muscle, Skeletal/drug effects/metabolism ; Paeonia/chemistry ; Male ; Oxidative Stress/drug effects ; Herbal Medicine ; Superoxide Dismutase/metabolism ; Motor Neurons/drug effects/metabolism ; Inflammation/drug therapy/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a multicomplex neurodegenerative disorder characterized by motor neuron death, muscle atrophy, and respiratory failure. Owing to its multicomplex mechanisms and multifactorial nature in the skeletal muscle and spinal cord (SC), no effective therapy has been developed. However, herbal medicines, known for their multitarget properties, have demonstrated promising efficacy with limited side effects in treating various diseases. Specifically, Paeonia lactiflora Pallas has been demonstrated to exhibit analgesic, antidepressant, anti-inflammatory, and neuroprotective effects. However, the pharmacological mechanisms underlying the beneficial effects of P. lactiflora in hSOD1[G93A] animal models remain unexplored. Therefore, this study was conducted to investigate the multitarget effects of P. lactiflora in hSOD1[G93A] transgenic mice, an ALS model. Footprint tests, western blot assays, and immunohistochemical analysis were used to assess the effect of P. lactiflora on the tibia anterior (TA), gastrocnemius (GC), and SC. The results revealed that P. lactiflora augmented motor function and decreased motor neuron loss in hSOD1[G93A] mice. Furthermore, P. lactiflora significantly lowered the expression of proteins associated with inflammation and oxidative stress in the skeletal muscle (TA and GC) and SC. P. lactiflora also regulated autophagy function by reducing the levels of key markers, such as P62/sequestosome 1 (SQSTM1), microtubule-associated proteins 1A/1B light chain 3B, and SMAD family member 2, in the muscle and SC. Overall, P. lactiflora treatment improved motor function, prevented motor neuron death, and exhibited anti-inflammatory and antioxidative effects in the skeletal muscle and SC of ALS mouse models. These results suggest that P. lactiflora could serve as a promising multitarget therapeutic agent for systemic and multipathological diseases.}, }
@article {pmid39981199, year = {2025}, author = {Kiernan, MC}, title = {Recent developments in consensus diagnostic criteria for amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {38}, number = {}, pages = {100559}, pmid = {39981199}, issn = {2405-6502}, }
@article {pmid39980944, year = {2025}, author = {Ji, J}, title = {To the Editor: In Response to Park et al's Perspective on the Resignation of South Korean Residents: A Medical Student View.}, journal = {Journal of graduate medical education}, volume = {17}, number = {1}, pages = {113-114}, pmid = {39980944}, issn = {1949-8357}, }
@article {pmid39980027, year = {2025}, author = {Jin, Y and Conneely, KN and Ma, W and Naviaux, RK and Siddique, T and Allen, EG and Guingrich, S and Pascuzzi, RM and Jin, P}, title = {Whole-genome bisulfite sequencing of cell-free DNA unveils age-dependent and ALS-associated methylation alterations.}, journal = {Cell &amp; bioscience}, volume = {15}, number = {1}, pages = {26}, pmid = {39980027}, issn = {2045-3701}, support = {P50 HD104458/HD/NICHD NIH HHS/United States ; R35 NS111602/NS/NINDS NIH HHS/United States ; NS111602/NS/NINDS NIH HHS/United States ; HD104458//National Institute of Child Health and Human Development/ ; }, abstract = {BACKGROUND: Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns in circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such epigenetic changes also hold significant promise for the diagnosis of neurodegenerative diseases, which often progresses slowly and has a lengthy asymptomatic period. However, genome-wide cfDNA methylation changes in neurodegenerative diseases remain poorly understood.<br><br>RESULTS: We used whole-genome bisulfite sequencing (WGBS) to profile age-dependent and ALS-associated methylation signatures in cfDNA from 30 individuals, including young and middle-aged controls, as well as ALS patients with matched controls. We identified 5,223 age-related differentially methylated loci (DMLs) (FDR&#x2009;<&#x2009;0.05), with 51.6% showing hypomethylation in older individuals. Our results significantly overlapped with age-associated CpGs identified in a large blood-based epigenome-wide association study (EWAS). Comparing ALS patients to controls, we detected 1,045 differentially methylated regions (DMRs) in gene bodies, promoters, and intergenic regions. Notably, these DMRs were linked to key ALS-associated pathways, including endocytosis and cell adhesion. Integration with spinal cord transcriptomics revealed that 31% of DMR-associated genes exhibited differential expression in ALS patients compared to controls, with over 20 genes significantly correlating with disease duration. Furthermore, comparison with published single-nucleus RNA sequencing (snRNA-Seq) data of ALS demonstrated that cfDNA methylation changes reflects cell-type-specific gene dysregulation in the brain of ALS patients, particularly in excitatory neurons and astrocytes. Deconvolution of cfDNA methylation profiles suggested altered proportions of immune and liver-derived cfDNA in ALS patients.<br><br>CONCLUSIONS: cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.}, }
@article {pmid39979261, year = {2025}, author = {Liu, D and Webber, HC and Bian, F and Xu, Y and Prakash, M and Feng, X and Yang, M and Yang, H and You, IJ and Li, L and Liu, L and Liu, P and Huang, H and Chang, CY and Liu, L and Shah, SH and La Torre, A and Welsbie, DS and Sun, Y and Duan, X and Goldberg, JL and Braun, M and Lansky, Z and Hu, Y}, title = {Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1789}, pmid = {39979261}, issn = {2041-1723}, support = {R01 EY034353/EY/NEI NIH HHS/United States ; P30 EY026877/EY/NEI NIH HHS/United States ; 1F32EY029567//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; EY026877//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; EY034353//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; S10 OD025091/OD/NIH HHS/United States ; R01 EY032518/EY/NEI NIH HHS/United States ; EY032518//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; R01 EY023295/EY/NEI NIH HHS/United States ; EY023295//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; F32 EY029567/EY/NEI NIH HHS/United States ; R01 EY032159/EY/NEI NIH HHS/United States ; R01 EY024932/EY/NEI NIH HHS/United States ; EY024932//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; R01 EY025295/EY/NEI NIH HHS/United States ; S10 OD030452/OD/NIH HHS/United States ; }, mesh = {Animals ; *Cell Cycle Proteins/metabolism/genetics ; *Membrane Transport Proteins/metabolism/genetics ; *Mitochondria/metabolism ; *Axons/metabolism ; *Retinal Ganglion Cells/metabolism/pathology ; Mice ; Humans ; *Microtubules/metabolism ; Nerve Regeneration ; Optic Nerve/metabolism/pathology ; Neuroprotection ; Disease Models, Animal ; Axonal Transport ; Kinesins/metabolism/genetics ; Mice, Inbred C57BL ; Transcription Factor TFIIIA/metabolism/genetics ; Low Tension Glaucoma/metabolism/genetics/pathology ; Male ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; }, abstract = {Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a decrease of axonal mitochondria in mice. We discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Furthermore, overexpressing OPTN/TRAK1/KIF5B prevents not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes robust ON regeneration. Therefore, in addition to generating animal models for NTG and ALS, our results establish OPTN as a facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.}, }
@article {pmid39978484, year = {2025}, author = {Hülsmeier, AJ}, title = {Glycosphingolipids in neurodegeneration - Molecular mechanisms, cellular roles, and therapeutic perspectives.}, journal = {Neurobiology of disease}, volume = {207}, number = {}, pages = {106851}, doi = {10.1016/j.nbd.2025.106851}, pmid = {39978484}, issn = {1095-953X}, mesh = {Humans ; *Glycosphingolipids/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; }, abstract = {Neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal loss and pose significant global health challenges. Glycosphingolipids (GSLs), critical components of neuronal membranes, regulate signal transduction, membrane organization, neuroinflammation, and lipid raft functionality. This review explores GSL roles in neural development, differentiation, and neurogenesis, along with their dysregulation in neurodegenerative diseases. Aberrations in GSL metabolism drive key pathological features such as protein aggregation, neuroinflammation, and impaired signaling. Specific GSLs, such as GM1, GD3, and GM3, influence amyloid-beta aggregation in AD, α-synuclein stability in PD, and mutant huntingtin toxicity in HD. Therapeutic strategies targeting GSL metabolism, such as GM1 supplementation and enzyme modulation, have demonstrated potential to mitigate disease progression. Further studies using advanced lipidomics and glycomics may support biomarker identification and therapeutic advancements. This work aims to highlight the translational potential of GSL research for diagnosing and managing devastating neurodegenerative conditions.}, }
@article {pmid39977838, year = {2025}, author = {Chang, JH and Tschannen, D}, title = {An Integrative Review of Quality Improvement Competence and Engagement Among Frontline Nurses.}, journal = {Journal of nursing care quality}, volume = {40}, number = {2}, pages = {173-180}, pmid = {39977838}, issn = {1550-5065}, mesh = {Humans ; *Quality Improvement ; *Leadership ; Clinical Competence/standards ; }, abstract = {BACKGROUND: Nurses providing direct care have firsthand knowledge of gaps in practice and thus must actively engage in quality improvement (QI) to enhance patient outcomes.<br><br>PURPOSE: This integrative review evaluated QI competence and engagement among frontline nurses.<br><br>METHODS: Using Souza et al's 6-step framework, literature on QI engagement and competence was synthesized using a rigorous search strategy and quality assessment.<br><br>RESULTS: Sixteen studies revealed generally low QI engagement and competence. Factors such as education, experience, and role influenced engagement, with higher levels of education and experience linked to higher QI involvement. Nurse leaders had higher engagement, underscoring the need for strong leadership in creating a culture of improvement.<br><br>CONCLUSIONS: Successful and sustainable QI programs and supportive environments enhance QI engagement and competence among frontline nurses.}, }
@article {pmid39976286, year = {2025}, author = {Guo, K and Savelieff, MG and Jang, DG and Teener, SJ and Zhao, L and Hur, J and Goutman, SA and Feldman, EL}, title = {Longitudinal Metabolomics in Amyotrophic Lateral Sclerosis Implicates Impaired Lipid Metabolism.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27208}, pmid = {39976286}, issn = {1531-8249}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; //the Scott L. Pranger ALS Clinic Fund/ ; //the Peter R. Clark Fund for ALS Research/ ; //the Dr. Randall Whitcomb Fund for ALS Genetics/ ; K23 ES027221/ES/NIEHS NIH HHS/United States ; //the Coleman Therapeutic Discovery Fund/ ; R01ES030049/ES/NIEHS NIH HHS/United States ; UL1TR002240//National Center for Advancing Translational Sciences at the National Institutes of Health/ ; R01TS000289/CC/CDC HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; K23ES027221/ES/NIEHS NIH HHS/United States ; R01NS127188/NS/NINDS NIH HHS/United States ; R01 TS000289/TS/ATSDR CDC HHS/United States ; UL1TR000433//Michigan Institute for Clinical and Health Research/ ; //the Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; UL1 TR002240/TR/NCATS NIH HHS/United States ; //the Sinai Medical Staff Foundation/ ; //the A. Alfred Taubman Medical Research Institute/ ; //the NeuroNetwork for Emerging Therapies, University of Michigan/ ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by altered metabolome and energy homeostasis, manifesting with body mass index changes and hypermetabolism-both prognostic of disease progression and survival. The cross-sectional ALS metabolome has been characterized, but longitudinal correlations to functional decline are lacking.<br><br>METHODS: We longitudinally evaluated metabolomes from ALS plasma and terminal postmortem spinal cord and brain motor cortex tissue. We constructed 3 plasma models. A linear mixed effects model correlated all metabolite levels across all timepoints to their corresponding functional scores. An interaction model predicted a longitudinal change in function from baseline metabolites, whereas a progression model identified metabolites linked to a 20% or 50% drop in function. In postmortem samples, differential metabolites in onset versus second spinal cord segments served as a surrogate of disease progression. Mendelian randomization assessed potential causality from metabolites.<br><br>RESULTS: In plasma, all models primarily selected lipid metabolites and sub-pathways, in addition to amino acids, xenobiotics, and various less frequently selected pathways. Among lipids, fatty acids and sphingomyelins were predominant, along with plasmalogens, phosphatidylcholines, and lysophospholipids. Sex interaction findings were nominal. In the spinal cord, sphingomyelin and long-chain saturated and monounsaturated fatty acids were more abundant in the onset segment tissue, whereas phosphatidylcholines and phosphatidylethanolamines were less abundant. Mendelian randomization suggested that impaired carnitine and short chain acylcarnitine metabolism may be genetically determined in ALS, along with various antioxidant derivatives.<br><br>INTERPRETATION: Our findings suggest metabolomic changes primarily involving different lipid classes and carnitine metabolism may underscore ALS severity and progression. ANN NEUROL 2025.}, }
@article {pmid39976261, year = {2025}, author = {Menendez-Gonzalez, M}, title = {Implementing a tridimensional diagnostic framework for personalized medicine in neurodegenerative diseases.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14591}, pmid = {39976261}, issn = {1552-5279}, support = {PI21/00467//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/diagnosis/genetics ; *Biomarkers ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases (NDDs) pose a significant challenge in modern medicine due to their clinical heterogeneity, multifactorial etiologies, and frequent co-pathologies. Traditional diagnostic systems, based on clinical symptoms and post mortem findings, are limited in capturing the complex interactions among genetic, molecular, and neuroanatomical factors. This manuscript introduces a novel tridimensional diagnostic framework that integrates these factors across three key axes: etiology (genetic and environmental influences), molecular markers (primary and secondary biomarkers), and neuroanatomoclinical correlations. Through case studies, we demonstrate the framework's ability to synthesize incomplete datasets, stratify patients, and guide precision medicine. By incorporating omics technologies, neuroimaging, and AI-driven probabilistic modeling, the framework enhances diagnostic accuracy and clinical relevance. This approach may contribute to overcoming the limitations of traditional nosologies, offering a scalable and adaptable tool for both clinical practice and research and advancing the field of precision medicine in NDD management. HIGHLIGHTS: Tridimensional diagnostic system: We propose a new framework that incorporates three axes - etiology, molecular markers, and neuroanatomical-clinical correlations - to enhance diagnostic accuracy for NDDs. Personalized medicine: The tridimensional system enables the integration of genetic, molecular, and clinical data, allowing for highly personalized treatment strategies tailored to individual patients. Proteinopathies as key biomarkers: This diagnostic system emphasizes the use of primary proteinopathies (amyloid, tau, synuclein) and secondary biomarkers (eg, NfL, GFAP) to monitor disease progression and treatment efficacy. Addressing clinical heterogeneity: The framework accommodates the complexity and heterogeneity of NDDs, offering an adaptable diagnostic approach for classical conditions like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ALS. Case studies and real-world application: Practical case studies illustrate how this system can be implemented in clinical practice, enabling the combination of DMTs with symptomatic treatments.}, }
@article {pmid39976178, year = {2025}, author = {Canosa, A and Manera, U and Vasta, R and Zocco, G and Di Pede, F and Cabras, S and De Mattei, F and Palumbo, F and Iazzolino, B and Minerva, E and Sbaiz, L and Brunetti, M and Gallone, S and Grassano, M and Matteoni, E and Polverari, G and Fuda, G and Casale, F and Salamone, P and De Marco, G and Marchese, G and Moglia, C and Calvo, A and Pagani, M and Chiò, A}, title = {Brain Metabolic Features of FUS-ALS: A 2-[[18]F]FDG-PET Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27201}, pmid = {39976178}, issn = {1531-8249}, support = {//A.S.D. Polisportiva U.I.C.I Torino Onlus (Oltre la Vista, Oltre la SLA)/ ; PRIN 2017//Ministero dell'Universit&#xe0; e della Ricerca/ ; 2017SNW5MB//Ministero dell'Universit&#xe0; e della Ricerca/ ; //Fondation Thierry Latran (INSPIRED)/ ; RF-2016- 02362405//Ministero della Salute (The Italian Ministry of Health [Ricerca Sanitaria Finalizzata])/ ; 259867//European Commission's Health Seventh Framework Programme (FP7/2007-2013)/ ; GA101017598//Horizon 2020 Framework Programme (BRAINTEASER [Bringing Artificial Intelligence Home for a Better Care of Amyotrophic Lateral Sclerosis and Multiple Sclerosis])/ ; 101137074//Horizon 2020 Framework Programme/ ; }, abstract = {OBJECTIVE: We aimed at evaluating the brain metabolic features of fused in sarcoma amyotrophic lateral sclerosis (FUS-ALS) compared with sporadic ALS (sALS), using 2-[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography (2-[[18]F]FDG-PET).<br><br>METHODS: We employed the 2-sample t-test model of SPM12, implemented in MATLAB, to compare 12 FUS-ALS cases with 40 healthy controls (HC) and 48 sALS, randomly collected from the series of patients who underwent brain 2-[[18]F]FDG-PET at the ALS Center of Turin (Italy) at diagnosis from 2009 to 2019. In the comparisons between cases and HC, we included age at PET and sex as covariates. Because FUS-ALS usually shows early onset in spinal regions, in the comparison between FUS-ALS and sALS, we included singularly the following covariates in a second step, to evaluate the determinants of eventual metabolic differences: age at PET, sex, and onset (spinal/bulbar).<br><br>RESULTS: sALS patients showed significant relative hypometabolism in bilateral fronto-temporo-occipital cortex and right insula as compared with FUS-ALS. After adjusting for age, the relative hypometabolism remained in the bilateral precentral gyrus and in the right middle and inferior temporal gyrus. As compared with HC, FUS patients displayed a significant relative hypermetabolism in the pontobulbar region and right cerebellar tonsil, dentate nucleus, and uvula, while sALS showed relative hypometabolism in bilateral frontal and occipital cortices and in left temporal and parietal regions.<br><br>INTERPRETATION: Patients with FUS-ALS show relative preservation of motor cortex metabolism compared with those with sALS, possibly reflecting the prevalence of lower motor neuron impairment in their phenotype. Prospective studies are necessary to investigate the possible role of 2-[[18]F]FDG-PET as a biomarker to track disease spreading in clinical trials. ANN NEUROL 2025.}, }
@article {pmid39975337, year = {2025}, author = {Zinn, KM and McLaren, MW and Imai, MT and Jayaram, MM and Rothstein, JD and Elrick, MJ}, title = {Enterovirus D68 2A protease causes nuclear pore complex dysfunction and motor neuron toxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.23.632178}, pmid = {39975337}, issn = {2692-8205}, abstract = {The picornavirus Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death, however the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during the course of infection. We therefore sought to determine the impact of EV-D68 proteases on NPC structure and function and their role in motor neuron toxicity. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via the direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121 by 2A [pro] . Using reporter systems, we demonstrate that 2A [pro] inhibits nuclear import and export of protein cargoes and also disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. We further show that 2A [pro] is toxic to induced pluripotent stem cell derived motor neurons by demonstrating a rescue of toxicity with 2A [pro] inhibitor telaprevir at concentrations that are insufficient to inhibit viral replication. This study expands our understanding of EV-D68 neuropathogenesis and provides a rationale for targeting the NPC or 2A [pro] therapeutically in AFM.}, }
@article {pmid39975323, year = {2025}, author = {Bekier, ME and Pinarbasi, E and Mesojedec, JJ and Ghaffari, L and de Majo, M and Ullian, E and Koontz, M and Coleman, S and Li, X and Tank, EMH and Waksmacki, J and Barmada, S}, title = {Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975323}, issn = {2692-8205}, support = {UL1 TR000433/TR/NCATS NIH HHS/United States ; R44 NS124457/NS/NINDS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; }, abstract = {Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK)-a proline-directed serine/threonine kinase-promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.}, }
@article {pmid39975241, year = {2025}, author = {Ghaffari, LT and Welebob, E and Boehringer, A and Cyliax, K and Pasinelli, P and Trotti, D and Haeusler, AR}, title = {Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i[3]Neuronal Models of ALS/FTD Pathogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39975241}, issn = {2692-8205}, support = {R01 NS109150/NS/NINDS NIH HHS/United States ; R01 NS114128/NS/NINDS NIH HHS/United States ; RF1 NS114128/NS/NINDS NIH HHS/United States ; }, abstract = {The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9orf72 (C9) gene is the most common cause of ALS and FTD. Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE iPSC-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization, or a blockade of K[+] channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared to healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.}, }
@article {pmid39973992, year = {2025}, author = {Nassan, M and Ayala, IA and Sloan, J and Bonfitto, A and Stark, B and Song, S and Naymik, M and Geula, C and Gefen, T and Barbieri, E and Piras, IS and Mesulam, MM and Huentelman, MJ}, title = {The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.01.25.25320561}, pmid = {39973992}, abstract = {Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C. We then investigated ANXA11 and TARDBP in a hypothesis-driven analysis, since it was recently shown that TDP-43 and Annexin A11 co-aggregate in all TDP-C cases. 1) Whole genome sequencing was completed to identify pathogenic rare variants prioritized with Illumina's AI-based Emedgene software on 37 confirmed or probable TDP-C cases from the Northwestern-University Cohort. 2) A genome wide association study was then completed to identify common variants associated with TDP-C cases vs 290 controls. 3) Next, common and rare variants in TARDBP, and ANXA11 were investigated in TDP-C vs controls. These analyses identified novel genetic associations between FIG4 , UBQLN2 , INPP5A , and ANXA11 with TDP-C. Of these FIG4, UBQLN2 and ANXA11 have been associated previously with Amyotrophic lateral sclerosis (ALS). To further assess the observed potential genetic overlap between ALS and TDP-C, we leveraged Mendelian randomization (MR) to assess if the ALS genetic load is associated with TDP-C risk, and found evidence supporting this association. The genetic association of ANXA11 with TDP-C is particularly interesting in view of the recently discovered role of Annexin A11 in forming heterodimers with TDP-43 in all abnormal precipitates, a feature not found in TDP-A or TDP-B, which have no similar predilection for the anterior temporal lobe. In addition to the observed overlap between ALS genetics/ genetic load and TDP-C, it is worth mentioning that FIG4, INPP5A and ANXA11 have been implicated in the inositol metabolism pathway, a feature that remains to be elucidated mechanistically. Our TDP-C genetic literature review identified a surprising paucity of neuropathologically confirmed cases in published investigations. Nonetheless, the literature offers support for some of our findings and reemphasizes the absence of dominant or major pathogenic genes for TDP-C, another feature that sets this neuropathologic entity apart from TDP-A and TDP-B.}, }
@article {pmid39973136, year = {2025}, author = {Deng, FY and Zhu, GL and Ou, KL and Zhu, LH and Jia, QQ and Wang, X and Guo, MW and Li, B and Li, SH and Li, XJ and Yin, P}, title = {Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.}, journal = {Zoological research}, volume = {46}, number = {2}, pages = {263-276}, doi = {10.24272/j.issn.2095-8137.2024.286}, pmid = {39973136}, issn = {2095-8137}, mesh = {Animals ; *RNA, Messenger/metabolism/genetics ; *Brain/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; *Ribosomes/metabolism/genetics ; *Macaca fascicularis/genetics ; Gene Expression Regulation ; }, abstract = {Cytoplasmic accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. While current studies have primarily focused on gene regulation mediated by full-length nuclear TDP-43, the potential effects of cytoplasmic TDP-43 fragments remain less explored. Our previous findings demonstrated that primate-specific cleavage of TDP-43 contributes to its cytoplasmic localization, prompting further investigation into its pathological effects. In the cynomolgus monkey brain, we observed that mutant or truncated TDP-43 was transported onto the ribosome organelle. Ribosome-associated transcriptomic analysis revealed dysregulation of apoptosis- and lysosome-related genes, indicating that cytoplasmic TDP-43 induces neurotoxicity by binding to ribosomes and disrupting mRNA expression. These findings provide mechanistic insights into the gain-of-function effects of pathological TDP-43.}, }
@article {pmid39971904, year = {2025}, author = {Hossain, MA and Brahme, RR and Miller, BC and Amin, J and de Barros, M and Schneider, JL and Auclair, JR and Mattos, C and Wang, Q and Agar, NYR and Greenblatt, DJ and Manetsch, R and Agar, JN}, title = {Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1777}, pmid = {39971904}, issn = {2041-1723}, support = {R01 NS065263/NS/NINDS NIH HHS/United States ; R01NS065263//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 18-IIA-420//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; }, mesh = {Humans ; *Drug Development/methods ; *Mass Spectrometry/methods ; *Drug Discovery/methods ; *Decision Trees ; Superoxide Dismutase-1/metabolism/genetics ; Models, Theoretical ; Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors/metabolism ; }, abstract = {Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]; and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib); the most common plasma off-target, human serum albumin; three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.}, }
@article {pmid39971261, year = {2025}, author = {Álvarez-Aznar, A and Desai, M and Orlich, MM and Vázquez-Liébanas, E and Adams, RH and Brakebusch, C and Gaengel, K}, title = {Cdc42 is crucial for mural cell migration, proliferation and patterning of the retinal vasculature.}, journal = {Vascular pharmacology}, volume = {159}, number = {}, pages = {107472}, doi = {10.1016/j.vph.2025.107472}, pmid = {39971261}, issn = {1879-3649}, abstract = {AIMS: Mural cells constitute the outer lining of blood vessels and are essential for vascular development and function. Mural cell loss or malfunction has been associated with numerous diseases including diabetic retinopathy, stroke and amyotrophic lateral sclerosis. In this work, we investigate the role of CDC42 in mural cells in vivo, using the developing mouse retina as a model.<br><br>METHODS: In this study, we generated a mouse model for Cdc42 deletion in mural cells by crossing Pdgfrb-CreER[T2] mice with Cdc42flox/flox mice. This model (Cdc42[i&#x394;MC]) allowed us to investigate the role of CDC42 in pericytes and smooth muscle cells in the developing and adult retinal vasculature.<br><br>RESULTS: We find that, during postnatal development, CDC42 is required in both, pericytes and smooth muscle cells to maintain proper cell morphology, mural cell coverage and distribution. During retinal angiogenesis, Cdc42-depleted pericytes lag behind the sprouting front and exhibit decreased proliferation. Consequently, capillaries at the sprouting front remain pericyte deprived, become dilated and are prone to increased vascular leakage. In addition, arteries and arterioles deviate from their normal growth directions and trajectory. While in the adult retina, mural cell coverage normalizes and pericytes adopt a normal morphology, smooth muscle cell morphologies remain abnormal and arteriolar branching angles are markedly reduced.<br><br>CONCLUSIONS: Our findings demonstrate that CDC42 is required for mural cell migration and proliferation and suggest that mural cells are essential for normal morphogenesis and patterning of the developing retinal vasculature.}, }
@article {pmid39971247, year = {2025}, author = {Zhang, H and Sun, Y}, title = {Response to Chen et al's "Incorporating regional variability and demographic insights into melanoma public health strategies".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.02.029}, pmid = {39971247}, issn = {1097-6787}, }
@article {pmid39971210, year = {2025}, author = {Brandstötter, C and Büssing, A and Eham, M and Littger, B and Lorenzl, S and Memmel, M and Paal, P and Bublitz, SK}, title = {Assessment of the Spiritual Needs of People With Amyotrophic Lateral Sclerosis and Their Caregivers.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2025.02.012}, pmid = {39971210}, issn = {1873-6513}, abstract = {CONTEXT: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder which poses multidimensional burden to patients and caregivers.<br><br>OBJECTIVES: This study aimed to investigate spiritual needs in people with Amyotrophic Lateral Sclerosis (pALS) and their closest caregivers, and to identify factors which may contribute to these needs.<br><br>METHODS: Spiritual needs were assessed based on the Spiritual Needs Questionnaire (SpNQ) as part of a longitudinal cohort study in pALS and their closest caregivers who were included in a multiprofessional pilot project for ALS in Southern Germany with a focus on neuropalliative care.<br><br>RESULTS: About 61 pALS and 52 caregivers were assessed for their spiritual needs. We show that both pALS and their caregivers maintain stable and distinct spiritual needs over time, irrespective of age, gender, care setting, or perceived level of loneliness. While pALS emphasize generativity and inner peace needs, caregivers primarily focus on finding inner peace, which they value even more than pALS.<br><br>CONCLUSIONS: Both pALS and their caregivers have strong unmet spiritual, and particularly nonreligious needs, which should be regularly assessed by the interprofessional team. Documenting these needs is the initial step in the spiritual care process, which requires a collaborative response from the interprofessional team. All healthcare professionals involved in ALS care should be attuned to the potential for unmet spiritual needs in patients and their caregivers. Early identification of these needs can facilitate the initiation of appropriate support processes.}, }
@article {pmid39969752, year = {2025}, author = {Liao, D and Zhang, Y and Li, S and Tang, H and Bai, X}, title = {miRNAs in neurodegenerative diseases: from target screening to precision therapy.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39969752}, issn = {1590-3478}, support = {NO.2022-CXTD-05//Sichuan Province Science and Technology Support Program/ ; }, abstract = {miRNAs are critical for different disease development processes, including cell growth, signaling, apoptosis, cancer and neurodegenerative diseases. It has been shown that altered miRNA levels are associated with reactive oxygen species (ROS) formation and mitochondrial dysfunction. While mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, amyotrophic lateral sclerosis, miRNAs have the potential to be diagnostic biomarkers and therapeutic targets with a high degree of specificity, which is highly relevant in neurodegenerative pathologies.This paper gives a general summary of the current expression of miRNAs in neurodegenerative diseases, including miRNAs up-regulated or down-regulated in a variety of diseases, as well as the associated factors of influence. miRNAs are more like a double-edged sword, their multi-targeted role has brought light to many diseases for which there are currently no clear therapeutic options, but at the same time, their low specificity and possible side effects on the whole body should not be ignored, therefore However, at the same time, its low specificity and possible side effects on the whole body should not be ignored, therefore, more attention should be paid to the development of miRNA therapy in terms of its high efficiency, the use of carriers, and the clarification of side effects.}, }
@article {pmid39969750, year = {2025}, author = {de Alcântara, C and Cruzeiro, MM and França, MC and Alencar, MA and de Araújo, CM and Camargos, ST and de Souza, LC}, title = {Cognitive and behavioral follow-up of patients with amyotrophic lateral sclerosis type 8.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39969750}, issn = {1590-3478}, support = {APQ-02980-17//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; Bolsa de Produtividade//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, abstract = {BACKGROUND AND OBJECTIVE: Amyotrophic Lateral Sclerosis type 8 (ALS8) is a familial motor neuron disease caused by the VAPB p.P56S mutation. There is a lack of longitudinal studies to elucidate the cognitive and behavioral progression of this disease. We aimed to investigate the progression of cognitive performance and behavioral symptoms of ALS8 patients over time.<br><br>METHODS: The cohort was composed of 23 ALS8 patients (12 men). They underwent neuropsychological assessments in two periods of time, ranging from 24 to 48 months (mean follow-up: 33&#x2009;&#xb1;&#x2009;10).<br><br>RESULTS: There was mild motor and functional decline during the follow-up. There were no significant differences between the first and the second evaluation on tests of verbal fluency, executive functions, episodic memory, and facial emotion recognition. There was a decline in the Language subdomain from the Addenbrooke's Cognitive Examination-revised. Behavioural measures indicated decreasing stereotypic behaviours. Anxiety and depression symptoms remained stable. No patient developed dementia.<br><br>CONCLUSION: Cognitive decline parallels motor degeneration in ALS8, with a slow pattern of progression.}, }
@article {pmid39969664, year = {2025}, author = {Irdianto, SA and Dwiranti, A and Bowolaksono, A}, title = {Extrachromosomal circular DNA: a double-edged sword in cancer progression and age-related diseases.}, journal = {Human cell}, volume = {38}, number = {2}, pages = {58}, pmid = {39969664}, issn = {1749-0774}, support = {NKB-888/UN2.RST/HKP.05.00/2024//Kementerian Riset Teknologi Dan Pendidikan Tinggi Republik Indonesia/ ; }, mesh = {Humans ; *Neoplasms/genetics/pathology/therapy/etiology ; *Disease Progression ; *DNA, Circular/genetics ; *Genomic Instability/genetics ; Werner Syndrome/genetics ; Diabetes Mellitus, Type 2/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Aging/genetics ; }, abstract = {Extrachromosomal circular DNA (eccDNA) is a fascinating form of genetic material found outside the usual chromosomal DNA in eukaryotic cells, including humans. Since its discovery in the 1960s, eccDNA has been linked to critical roles in cancer progression and age-related diseases. This review thoroughly explores eccDNA, covering its types, how it forms, and its significant impact on diseases, particularly cancer. EccDNA, especially in its extrachromosomal DNA (ecDNA) form, contributes to the genetic diversity of tumour cells, helping them evolve quickly and resist treatments. Beyond cancer, eccDNA is also connected to age-related conditions like Werner syndrome, amyotrophic lateral sclerosis (ALS), and type 2 diabetes mellitus (T2DM), where it may affect genomic stability and disease development. The potential of eccDNA as a biomarker for predicting disease outcomes and as a target for new treatments is also highlighted. This review aims to deepen our understanding of eccDNA and inspire further research into its roles in human health and disease, paving the way for innovative diagnostic and therapeutic approaches.}, }
@article {pmid39969638, year = {2025}, author = {Almgren, H and Mahoney, CJ and Huynh, W and D'Souza, A and Berte, S and Lv, J and Wang, C and Kiernan, MC and Calamante, F and Tu, S}, title = {Quantifying neurodegeneration within subdivisions of core motor pathways in amyotrophic lateral sclerosis using diffusion MRI.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {215}, pmid = {39969638}, issn = {1432-1459}, support = {APP2029871//NHMRC/ ; 1156093//NHMRC Practitioner Fellowship/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Corpus Callosum/diagnostic imaging/pathology ; *Pyramidal Tracts/diagnostic imaging/pathology ; *Diffusion Magnetic Resonance Imaging ; *White Matter/diagnostic imaging/pathology ; Adult ; Disease Progression ; Efferent Pathways/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Diffusion MRI is sensitive to white matter changes in amyotrophic lateral sclerosis (ALS). The current study aimed to establish disease profiles across core motor pathways, and their relevance to clinical progression in ALS.<br><br>METHODS: Sixty-five participants (ALS&#x2009;=&#x2009;47; Control&#x2009;=&#x2009;18) were recruited for the study. White matter integrity of motor, somatosensory, and premotor subdivisions within the corticospinal tract and corpus callosum were quantified by fibre density, fibre-bundle cross-section, structural connectivity, and fractional anisotropy. Analyses focused on identifying diffusion metrics and tract profiles sensitive to ALS pathology, and their association with clinical progression.<br><br>RESULTS: Reduced fibre density of the motor subdivision of the corpus callosum (CC) and corticospinal tract (CST) demonstrated best performance in classifying ALS from controls (area-under-curve: CCmotor&#x2009;=&#x2009;0.81, CSTmotor&#x2009;=&#x2009;0.76). Significant reductions in fibre density (CCmotor: p&#x2009;<&#x2009;0.001; CSTmotor: p&#x2009;=&#x2009;0.016), and structural connectivity (CCmotor: p&#x2009;=&#x2009;0.008; CSTsomatosensory: p&#x2009;=&#x2009;0.012) indicated presence of ALS pathology. Reduced fibre density &amp; cross-section significantly correlated with severity of functional impairment (ALSFRS-R; CCmotor: r&#x2009;=&#x2009;0.52, p&#x2009;=&#x2009;0.019; CSTmotor: r&#x2009;=&#x2009;0.59, p&#x2009;=&#x2009;0.016). The largest effect sizes were generally found for motor and somatosensory subdivisions across both major white matter bundles.<br><br>CONCLUSION: Current findings suggest that ALS does not uniformly impact the corticospinal tract and corpus callosum. There is a preferential disease profile of neurodegeneration mainly impacting primary motor fibres. Microstructural white matter abnormality indicated presence of ALS pathology while macrostructural white matter abnormality was associated with severity of functional impairment. Quantification of white matter abnormality in corticospinal tract and callosal subdivisions holds translational potential as an imaging biomarker for neurodegeneration in ALS.}, }
@article {pmid39969486, year = {2025}, author = {Alder, J and Chukwuma, C and Farragher, T and Holden Smith, S and Morris, R and Ealing, J and Hamdalla, H and Bentley, A and Bokhari, S and Freeman, D and Al-Chalabi, A and Rog, D and Das, J and Chaouch, A}, title = {Impact of relative deprivation and ethnicity on the incidence rate of amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2465609}, pmid = {39969486}, issn = {2167-9223}, abstract = {Objective: This study assessed a sizable cohort of patients with amyotrophic lateral sclerosis (ALS) in a relatively deprived and ethnically diverse area in the northwest of England. We aimed to evaluate the interaction of relative deprivation and ethnicity with the incidence of ALS. Methods: Six hundred and ninety-three adults from Greater Manchester who were diagnosed with ALS between 1 January 2011 and 31 December 2021 were included in this study. Data were collected from electronic patient records. Relative deprivation was estimated using the Index of Multiple Deprivation 2019 and patients were divided into quartiles of deprivation in England. Ethnicity was sub-grouped into White, Southeast Asian, Black, and Other. Poisson's regression analysis was used to calculate the incidence rate and its interactions with deprivation and ethnicity. Results: 55.4% of patients were male, 95.4% were White, 57.4% were in the two most deprived quartiles, and 87.2% had died by the end of the observation period. The crude incidence rate was 2.21 cases per 100,000 (95% CI 2.00-2.40) per year. There was no difference in the adjusted incidence rates among the quartiles of deprivation, even when considering ethnicity as a confounding variable. The risk of ALS in the White population was 2.08 (95% CI 1.47-3.04) times greater than that in the non-White population. Conclusion: In our cohort, relative deprivation was not an independent risk factor for ALS. A stronger association between White ethnicity and ALS was noted. The reason for this association remains unclear, highlighting the need for more research in this field.}, }
@article {pmid39967643, year = {2025}, author = {Abdel-Magid, AF}, title = {Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {2}, pages = {204-206}, pmid = {39967643}, issn = {1948-5875}, abstract = {The invention in this patent application relates to 2-amino-[1,2,4]triazolo[1,5-a]pyridin derivatives represented generally herein as formula 1. These compounds have activities as receptor-interacting protein kinase 1 (RIPK1) inhibitors and may potentially provide treatment and/or prophylaxis of inflammatory and neurodegenerative diseases associated with aberrant RIPK1 activity such as ulcerative colitis, Crohn's disease, psoriasis, NASH, heart failure, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease.}, }
@article {pmid39965449, year = {2025}, author = {Awasthi, S and Tiwari, PC and Awasthi, S and Dwivedi, A and Srivastava, S}, title = {Mechanistic role of proteins and peptides in Management of Neurodegenerative Disorders.}, journal = {Neuropeptides}, volume = {110}, number = {}, pages = {102505}, doi = {10.1016/j.npep.2025.102505}, pmid = {39965449}, issn = {1532-2785}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Peptides/therapeutic use ; Proteins/metabolism/therapeutic use ; }, abstract = {Proteins and peptides have emerged as significant contributors in the management of neurodegenerative disorders due to their diverse biological functions. These biomolecules influence various cellular processes, including cellular repair, inflammation reduction, and neuronal survival, which are crucial for mitigating the effects of diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS). By interacting with specific cellular receptors, proteins and peptides like neurotrophic factors, cytokines, and enzyme inhibitors promote neurogenesis, reduce oxidative stress, and enhance synaptic plasticity. Nevertheless, till certain limitations and challenges do exist to deliver these fragile therapeutic bioactives. Moreover, targeted delivery systems, such as nanoparticles and biomolecular carriers, are being developed to improve the bioavailability and specificity of these protein-based therapeutics, ensuring efficient crossing of the blood-brain barrier. This review explores the mechanistic pathways through which these biomolecules act, emphasizing their potential to modify disease progression and improve the quality of life in patients with neurodegenerative conditions. Overall, proteins and peptides are not only seen as promising therapeutic agents but also as foundational tools in advancing personalized medicine in the field of neurodegenerative disorders.}, }
@article {pmid39965330, year = {2025}, author = {Petro, TM and Esmael, A and Pattee, GL and Al-Sarmi, F and Chiodo, F and Agarkova, IV and Dunigan, DD and Van Etten, JL}, title = {Expression of human superoxide dismutase (SOD) 1 G93A and chlorovirus ATCV-1 SOD increases the response of macrophages to inflammatory stimulants, including ATCV-1 major capsid protein glycans.}, journal = {Immunobiology}, volume = {230}, number = {2}, pages = {152881}, doi = {10.1016/j.imbio.2025.152881}, pmid = {39965330}, issn = {1878-3279}, mesh = {Animals ; Humans ; Mice ; *Macrophages/immunology ; *Superoxide Dismutase-1/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/immunology/genetics ; RAW 264.7 Cells ; *Capsid Proteins/immunology/genetics ; Polysaccharides ; Cytokines/metabolism ; Phycodnaviridae/immunology ; Female ; Interleukin-6/metabolism ; Interferon-gamma/metabolism ; Mice, Transgenic ; Male ; Inflammation Mediators/metabolism ; }, abstract = {One cause of familial Amyotrophic Lateral Sclerosis (ALS) is a mutation in Super Oxide Dismutase 1 (SOD1) whereby amino acid 93 is alanine instead of glycine (SOD1-G93A). Transgenic mice expressing human SOD1-G93A pathogenic variant develop motor neuron disease (MND), similar to ALS. Humans with ALS and SOD1-G93A mice have elevated production of inflammatory cytokines, such as IL-6, which may promote MND. We previously showed that infection with the Chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1), which encodes a SOD1, accelerates onset of MND in these mice and induces macrophages to produce high levels of IL-6. We confirm here that ALS patients compared with healthy controls have significantly elevated levels of plasma IL-6 and Interferon-gamma (IFN-γ), but not IL-17. To determine if expression of ATCV-1 SOD1 or SOD1-G93A in mouse macrophages elevates expression of inflammatory cytokines, we transfected the RAW264.7 mouse macrophage cell line with plasmids encoding ATCV-1 SOD1, wild-type human SOD1, SOD1-G93A, or an empty vector. RAW264.7 cells stably expressing wtSOD1 or G93A-SOD1 were stimulated with poly I:C and Interferon-gamma, alone, or in combination to induce inflammatory factors, such as IL-6 and Nitric Oxide (NO), anti-inflammatory factors, such as IL-10, or activation of Interferon Stimulated Response Elements (ISRE) promoters. After stimulation, production of IL-6 and NO, but not IL-10 or ISRE promoter activity was significantly higher in RAW264.7 cells expressing SOD1-G93A compared with wt SOD1. Moreover, RAW264.7 cells expressing SOD1-G93A compared with wt SOD1 produced higher levels of IL-6 and NO in response to ATCV-1 glycoproteins. Finally, transfection of plasmid encoding ATCV-1 SOD1 into RAW264.7 cells significantly increased expression of inflammatory factors in responses to poly I:C and IFN-γ, primarily in an Interferon regulatory factor 3 (IRF3) dependent fashion. These data clearly show that expression of G93A-SOD1 or ATCV-1 SOD1 in macrophages significantly elevates expression of inflammatory factors following stimulations that mimic virus infection, viral components, or T cell cytokines, thereby suggesting one mechanism by which atypical SOD1 in macrophages can contribute to ALS-MND.}, }
@article {pmid39963928, year = {2025}, author = {Lomas, C and Dubey, RC and Perez-Alvarez, G and Lopez Hernandez, Y and Atmar, A and Arias, AY and Vashist, A and Aggarwal, S and Manickam, P and Lakshmana, MK and Vashist, A}, title = {Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {6}, pages = {603-619}, pmid = {39963928}, issn = {1748-6963}, support = {R01 DA049657/DA/NIDA NIH HHS/United States ; R03 AG087475/AG/NIA NIH HHS/United States ; U01 ES033265/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/complications/drug therapy ; *Substance-Related Disorders ; *Blood-Brain Barrier/metabolism/drug effects ; Nanoparticles/chemistry ; Animals ; Neurocognitive Disorders/drug therapy/etiology ; Nanomedicine/methods ; AIDS Dementia Complex/drug therapy ; }, abstract = {Substance use disorders (SUD) and HIV-associated neurocognitive disorders (HAND) work synergistically as a significant cause of cognitive decline in adults and adolescents globally. Current therapies continue to be limited due to difficulties crossing the blood-brain barrier (BBB) leading to limited precision and effectiveness, neurotoxicity, and lack of co-treatment options for both HAND and SUD. Nanoparticle-based therapeutics have several advantages over conventional therapies including more precise targeting, the ability to cross the BBB, and high biocompatibility which decreases toxicity and optimizes sustainability. These advantages extend to other neurological disorders such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review summarizes recent advances in nanotechnology for application to HAND, SUD, and co-treatment, as well as other neurological disorders. This review also highlights the potential challenges these therapies face in clinical translation and long-term safety.}, }
@article {pmid39962920, year = {2025}, author = {}, title = {Correction to "Early Nuclear Phenotypes and Reactive Transformation in Human iPSC-Derived Astrocytes From ALS Patients With SOD1 Mutations".}, journal = {Glia}, volume = {73}, number = {5}, pages = {1107}, doi = {10.1002/glia.70003}, pmid = {39962920}, issn = {1098-1136}, }
@article {pmid39962623, year = {2025}, author = {Caratelli, S and De Paolis, F and Silvestris, DA and Baldari, S and Salvatori, I and Tullo, A and Lanzilli, G and Gurtner, A and Ferri, A and Valle, C and Padovani, S and Cesarini, V and Sconocchia, T and Cifaldi, L and Arriga, R and Spagnoli, GC and Ferrone, S and Venditti, A and Rossi, P and Pesole, G and Toietta, G and Sconocchia, G}, title = {The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity.}, journal = {Experimental hematology &amp; oncology}, volume = {14}, number = {1}, pages = {17}, pmid = {39962623}, issn = {2162-3619}, support = {TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; TITAN 2021- ARS01_00906//European Union, European Fund for Regional Development/ ; Investigator Grants 2020-24440//Italian Association for Cancer Research (AIRC) Foundation/ ; }, abstract = {BACKGROUND: Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck.<br><br>METHODS: The CD64/CD28/CD3&#x3b6; -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq.&#xa0;Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3&#x3b6; polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3&#x3b6; T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3&#x3b6; and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc&#x2009;+&#x2009;cells by bioluminescent and fluorescent imaging. IFN&#x3b3; was assessed by ELISA.<br><br>RESULTS: Compared to CD16/CD8a/CD28/CD3&#x3b6; T cells, CD32/CD8a/CD28/CD3&#x3b6; T cells, and non-transduced T cells, CD64/CD28/CD3&#x3b6; T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3&#x3b6; T-cell conjugation with CRC cells, CD64/CD28/CD3&#x3b6; cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3&#x3b6; T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3&#x3b6; T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFN&#x3b3;. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells.<br><br>CONCLUSIONS: CD64/CD28/CD3&#x3b6; T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel Fc&#x3b3;R ALs in cancer and healthy cells.}, }
@article {pmid39961705, year = {2025}, author = {Shah, NM and Kaltsakas, G and Madden-Scott, S and Apps, C and Sheridan, S and Ramsay, M and Srivastava, S and Suh, ES and D'Cruz, R and Mackie, M and Weston, N and Hart, N and Murphy, P}, title = {Mechanical insufflation-exsufflation use in neuromuscular disease: a single centre cohort study.}, journal = {BMJ open respiratory research}, volume = {12}, number = {1}, pages = {}, pmid = {39961705}, issn = {2052-4439}, mesh = {Humans ; *Insufflation/methods ; *Neuromuscular Diseases/complications ; Middle Aged ; Female ; Retrospective Studies ; Male ; Adult ; Aged ; Amyotrophic Lateral Sclerosis/therapy ; Cohort Studies ; }, abstract = {INTRODUCTION: Mechanical insufflation-exsufflation (MIE) is a commonly used therapy to augment secretion clearance in individuals with neuromuscular disease. There are no clear evidence-based guidelines on the settings that should be used in different diagnostic groups and how they should be titrated. We report on the settings used in the largest cohort of individuals using domiciliary MIE in the literature.<br><br>METHODS: A retrospective observational study reporting on all individuals initiated on MIE for long-term domiciliary use at our centre, 2013-2019.<br><br>RESULTS: This study reports on 359 adults established on domiciliary MIE. The most common diagnostic groups were congenital neuromuscular disease (26%), spinal cord injury (23%) and amyotrophic lateral sclerosis (23%). Median age at initiation was 55 years. Median (IQR) insufflation pressure was 35 (30-40) cm H2O and exsufflation pressure was 45 (40-50) cm H2O. Inspiratory time was 2.5 (2.3-2.8)&#x2009;s, expiratory time was 2.7 (2.3-2.8)&#x2009;s, and pause between expiration and inspiration was 2.0 (1.2-2.0)&#x2009;s. Median (IQR) survival following the initiation of MIE was 66 (54-78) months. Increasing age and amyotrophic lateral sclerosis were significantly associated with shorter life expectancy, while the delivery of MIE via oronasal interface compared with tracheostomy was associated with longer life expectancy.<br><br>CONCLUSION: This is the largest reported cohort of adults using domiciliary MIE. The most common groups using MIE were congenital neuromuscular disease, spinal cord injury patients and amyotrophic lateral sclerosis. The range of prescribed settings is narrow, reflecting the limited evidence base in this field and the need to better understand optimal targets for titration of different MIE settings.}, }
@article {pmid39961673, year = {2025}, author = {Aryapadi, V and Trivedi, J}, title = {Atypical presentation of amyotrophic lateral sclerosis with SOD1-H47R mutation.}, journal = {BMJ case reports}, volume = {18}, number = {2}, pages = {}, doi = {10.1136/bcr-2024-263293}, pmid = {39961673}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Middle Aged ; }, abstract = {Traditionally, amyotrophic lateral sclerosis (ALS) is recognised as a fatal neurodegenerative disease that typically emerges in the later decades of life, with a life expectancy of 2-5 years after symptom onset. We now understand that ALS exhibits a wide phenotypic clinical spectrum, significantly influenced by genetic factors. Here, we describe a patient with familial ALS carrying a heterozygous pathogenic H47R mutation of the superoxide dismutase 1 (SOD1) gene. His clinical presentation is atypical, with a slow progressive course, lower extremity weakness, and sparing of bulbar and respiratory function, consistent with the flail leg variant of ALS. The objective of this report is to increase awareness of atypical presentations of ALS and the diagnostic challenges they pose to clinicians. In addition to a description of the clinical case, we briefly discuss the new role of gene therapy in the treatment of familial ALS with SOD1 mutations.}, }
@article {pmid39961464, year = {2025}, author = {Soumya, BS and Gamit, N and Patil, M and Shreenidhi, VP and Dharmarajan, A and Warrier, S}, title = {Modeling amyotrophic lateral sclerosis with amniotic membrane-derived mesenchymal stem cells: A novel approach for disease modeling.}, journal = {Experimental cell research}, volume = {446}, number = {1}, pages = {114449}, doi = {10.1016/j.yexcr.2025.114449}, pmid = {39961464}, issn = {1090-2422}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/therapy ; *Mesenchymal Stem Cells/metabolism ; Humans ; *Amnion/cytology/metabolism ; *Cell Differentiation ; *Motor Neurons/metabolism/pathology ; Animals ; Oxidative Stress ; Superoxide Dismutase/metabolism/genetics ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism/genetics ; Oligodendrocyte Transcription Factor 2/metabolism/genetics ; Nerve Tissue Proteins/metabolism/genetics ; Cells, Cultured ; Disease Models, Animal ; Homeodomain Proteins/genetics/metabolism ; Transcription Factors/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Advancement of therapeutics for neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) has been predominantly hampered by the dearth of relevant disease models. Despite numerous animal models, significant challenges remain in correlating these with human disease complexities. In this study, the ALS model was created using amniotic membrane-derived mesenchymal stem cells (AM-MSCs) which were differentiated into motor neurons (MN) with specific MN induction media and transiently transfected with mutated human SOD1 G93A plasmid to induce ALS-like condition. Characterization included gene expression analysis, immunocytochemistry, flow cytometry, and Western blot. Functional assays assessed the extent of degeneration and model efficiency. AM-MSCs demonstrated multipotency and were positive for MSC markers. Upon differentiation, the expression of MN markers like MNX1, Olig2, and ChAT were found to be elevated. SOD1 G93A overexpression, downregulated MN markers, upregulated NURR1 gene, reduced acetylcholine (ACh), reduced glutathione, and elevated oxidative stress markers. This robust in-vitro ALS model derived from AM-MSCs offers an alternative to animal models to provide an efficient and cost-effective platform to conduct rapid drug screening.}, }
@article {pmid39961396, year = {2025}, author = {Ferraro, PM and Mollar, E and Melissari, L and Buscema, M and Bagnoli, E and Cabona, C and Gemelli, C and Vignolo, M and Maranzana, C and Marogna, M and Ferrera, L and Beronio, A and De Michelis, C and Bergamaschi, V and Bragadin, MM and Brichetto, G and Braido, F and Rao, F}, title = {Longitudinal respiratory trajectories in motor neuron disease phenotypes: Multiparametric characterization and clinical management.}, journal = {Respiratory medicine}, volume = {239}, number = {}, pages = {108003}, doi = {10.1016/j.rmed.2025.108003}, pmid = {39961396}, issn = {1532-3064}, mesh = {Humans ; *Phenotype ; *Motor Neuron Disease/physiopathology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Respiratory Function Tests/methods ; *Noninvasive Ventilation/methods ; Disease Progression ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Oximetry ; Blood Gas Analysis ; Spirometry/methods ; }, abstract = {BACKGROUND: Motor neuron diseases (MNDs) encompass amyotrophic lateral sclerosis (ALS), pure/predominant upper (pUMN) and lower motor neuron (pLMN) phenotypes. However respiratory studies have mainly focused on bulbar (B-ALS) and spinal (S-ALS) onset ALS, while little is known in other MNDs. In this study we therefore aimed at characterizing baseline and longitudinal patterns of respiratory involvement and their clinical management in MND patients stratified by their clinical phenotype.<br><br>METHODS: Serial pulmonary function tests (PFTs) (spirometry, arterial blood gas analysis, overnight pulse oximetry and peak cough expiratory flow) records of the MND patients hospitalized between 2020 and 2024 were reviewed. Using longitudinal examinations, deltas of variation in respiratory measures were generated and frequency and timings of non-invasive ventilation (NIV) adaptation were evaluated. Data were compared between phenotypes using the Kruskal-Wallis test with Bonferroni adjustment.<br><br>RESULTS: 42&#xa0;S-ALS, 105&#xa0;B-ALS, 42 pLMN and 31 pUMN patients were included. Both at baseline and longitudinally, B-ALS showed the worst respiratory parameters, followed by pLMN, S-ALS and pUMN. NIV adaptation was equally frequent between groups, but earlier in B-ALS compared to pUMN (p&#xa0;=&#xa0;0.01). At baseline, B-ALS showed worse spirometry and PCEF only, but compared to all the other phenotypes (p from <0.0001 to 0.03). Longitudinally, they conversely exhibited more severe decline in all PFTs, but only relative to pUMN (p from 0.0009 to 0.04), with deltas of variation comparable to the ones observed in S-ALS and pLMN. Among NIV users, more severe PCEF and spirometry impairment further emerged in S-ALS compared to pUMN (p from 0.01 to 0.04).<br><br>CONCLUSIONS: We evidenced convergent trajectories of respiratory decline across B-ALS, S-ALS and pLMN, highlighting the utility of multimodal assessments for tracking progressing respiratory disturbances. These findings have potential to accelerate earlier and more tailored respiratory management across diverse MND phenotypes.}, }
@article {pmid39960747, year = {2025}, author = {Turnbull, J}, title = {Platform Trials in ALS.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2025.0100}, pmid = {39960747}, issn = {1538-3598}, }
@article {pmid39960672, year = {2025}, author = {Paganoni, S and Fournier, CN and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Ajroud-Driss, S and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Shefner, JM and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and Dagostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Heiman-Patterson, T and Caress, JB and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Harvey, B and Patel, S and Mahoney, P and Duda, PW and Cudkowicz, ME and , }, title = {Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {2}, pages = {e2459058}, pmid = {39960672}, issn = {2574-3805}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Double-Blind Method ; Aged ; Treatment Outcome ; Edaravone/therapeutic use ; }, abstract = {IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.<br><br>OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.<br><br>Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.<br><br>INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n&#x2009;=&#x2009;164).<br><br>RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority,&#x2009;0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.<br><br>CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.}, }
@article {pmid39959987, year = {2025}, author = {Lee, D and Shin, Y and Roh, JS and Ahn, J and Jeoong, S and Shin, SS and Yoon, M}, title = {RETRACTED: Lee et al. Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice. Int. J. Mol. Sci. 2020, 21, 4256.}, journal = {International journal of molecular sciences}, volume = {26}, number = {4}, pages = {}, pmid = {39959987}, issn = {1422-0067}, abstract = {The journal retracts the article titled "Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice" [...].}, }
@article {pmid39958595, year = {2025}, author = {Arnold, WD and Majithia, K}, title = {Triumphs, Trials, and Future Considerations in Genetic Therapies for Hereditary Neuromuscular Diseases.}, journal = {Missouri medicine}, volume = {122}, number = {1}, pages = {46-52}, pmid = {39958595}, issn = {0026-6620}, mesh = {Humans ; *Genetic Therapy/methods/trends ; *Neuromuscular Diseases/genetics/therapy ; *Muscular Dystrophy, Duchenne/genetics/therapy ; Amyotrophic Lateral Sclerosis/genetics/therapy ; Muscular Atrophy, Spinal/genetics/therapy ; Precision Medicine/methods/trends ; }, abstract = {Neuromuscular diseases include conditions that affect the spinal motor neurons, peripheral nerves, neuromuscular junctions, and muscles, and they can result from acquired and inherited causes. The number of genetic therapies targeting the inherited causes of neuromuscular diseases has surged in the last decade. This review aims to highlight the current state of genetic therapies within the framework of precision medicine, focusing on the achievements and the gaps that remain. A major emphasis is on spinal muscular atrophy, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis, as these neuromuscular diseases have seen tremendous recent advancements. We will also discuss the future considerations necessary to accelerate the development of next-generation genetic therapies and enhance therapeutic outcomes for patients with neuromuscular diseases.}, }
@article {pmid39958549, year = {2025}, author = {Zhang, Y}, title = {Enhancing rectal cancer liver metastasis prediction: Magnetic resonance imaging-based radiomics, bias mitigation, and regulatory considerations.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {2}, pages = {102151}, pmid = {39958549}, issn = {1948-5204}, abstract = {In this article, we comment on the article by Long et al published in the recent issue of the World Journal of Gastrointestinal Oncology. Rectal cancer patients are at risk for developing metachronous liver metastasis (MLM), yet early prediction remains challenging due to variations in tumor heterogeneity and the limitations of traditional diagnostic methods. Therefore, there is an urgent need for non-invasive techniques to improve patient outcomes. Long et al's study introduces an innovative magnetic resonance imaging (MRI)-based radiomics model that integrates high-throughput imaging data with clinical variables to predict MLM. The study employed a 7:3 split to generate training and validation datasets. The MLM prediction model was constructed using the training set and subsequently validated on the validation set using area under the curve (AUC) and dollar-cost averaging metrics to assess performance, robustness, and generalizability. By employing advanced algorithms, the model provides a non-invasive solution to assess tumor heterogeneity for better metastasis prediction, enabling early intervention and personalized treatment planning. However, variations in MRI parameters, such as differences in scanning resolutions and protocols across facilities, patient heterogeneity (e.g., age, comorbidities), and external factors like carcinoembryonic antigen levels introduce biases. Additionally, confounding factors such as diagnostic staging methods and patient comorbidities require further validation and adjustment to ensure accuracy and generalizability. With evolving Food and Drug Administration regulations on machine learning models in healthcare, compliance and careful consideration of these regulatory requirements are essential to ensuring safe and effective implementation of this approach in clinical practice. In the future, clinicians may be able to utilize data-driven, patient-centric artificial intelligence (AI)-enhanced imaging tools integrated with clinical data, which would help improve early detection of MLM and optimize personalized treatment strategies. Combining radiomics, genomics, histological data, and demographic information can significantly enhance the accuracy and precision of predictive models.}, }
@article {pmid39958442, year = {2025}, author = {Ozbey, D and Saribas, S and Kocazeybek, B}, title = {Gut microbiota in Crohn's disease pathogenesis.}, journal = {World journal of gastroenterology}, volume = {31}, number = {6}, pages = {101266}, pmid = {39958442}, issn = {2219-2840}, mesh = {Humans ; *Crohn Disease/microbiology/immunology/therapy ; *Gastrointestinal Microbiome ; *Fecal Microbiota Transplantation ; Treatment Outcome ; Intestinal Mucosa/microbiology/immunology/pathology ; Feces/microbiology ; Colon/microbiology/pathology/immunology ; Dysbiosis ; Ileum/microbiology/pathology/immunology ; Animals ; Colitis, Ulcerative/microbiology/therapy/immunology ; }, abstract = {Inflammatory bowel diseases (IBDs) are classified into two distinct types based on the area and severity of inflammation: Crohn's disease (CD) and ulcerative colitis. In CD, gut bacteria can infiltrate mesenteric fat, causing expansion known as creeping fat, which may limit bacterial spread and inflammation but can promote fibrosis. The gut bacteria composition varies depending on whether the colon or ileum is affected. Fecal microbiota transplantation (FMT) transfers feces from a healthy donor to restore gut microbiota balance, often used in IBD patients to reduce inflammation and promote mucosal repair. The use of FMT for CD remains uncertain, with insufficient evidence to fully endorse it as a definitive treatment. While some studies suggest it may improve symptoms, questions about the duration of these improvements and the need for repeated treatments persist. There is a pressing need for methods that provide long-term benefits, as highlighted by Wu et al's research.}, }
@article {pmid39957655, year = {2025}, author = {Mombaur, B and Dias, K}, title = {Patient Navigation in Amyotrophic Lateral Sclerosis (ALS): A Potential Approach to Timely Diagnosis.}, journal = {Journal of health care for the poor and underserved}, volume = {36}, number = {1}, pages = {361-374}, doi = {10.1353/hpu.2025.a951602}, pmid = {39957655}, issn = {1548-6869}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Patient Navigation/organization &amp; administration ; Healthcare Disparities ; Delayed Diagnosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) poses challenges for timely diagnosis due to its protean early manifestations and lack of definitive tests. This article explores how patient navigation interventions can expedite diagnosis, particularly for underserved patients who face disproportionately longer delays. Patient navigation has proven effective in reducing disparities in various diseases by providing guidance and support to patients and caregivers. It enhances awareness, facilitates communication with health care providers, and streamlines diagnosis. Drawing from literature on patient navigation in other diseases, this article proposes tailored adaptations for ALS diagnosis and addresses potential implementation barriers and strategies to overcome them. Integrating patient navigation into the ALS diagnostic pathway holds promise for improving efficiency, optimizing outcomes, and reducing health care disparities among underserved populations.}, }
@article {pmid39957101, year = {2025}, author = {Kikuchi, K and Yamazaki, Y and Kanekura, K and Hayamizu, Y}, title = {Graphene Biosensor Differentiating Sensitive Interactions between Ribonucleic Acid and Dipeptide Repeats in Liquid-Liquid Phase Separation.}, journal = {ACS applied materials &amp; interfaces}, volume = {17}, number = {8}, pages = {12765-12771}, pmid = {39957101}, issn = {1944-8252}, mesh = {*Dipeptides/chemistry ; *Graphite/chemistry ; *Biosensing Techniques/methods ; Humans ; RNA/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Transistors, Electronic ; Liquid-Liquid Extraction/methods ; Phase Separation ; }, abstract = {Liquid-Liquid Phase Separation (LLPS) plays a crucial role in cell biology and is closely associated with neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Recent studies connect mutations in the C9ORF72 gene to the production of arginine-rich dipeptide repeat proteins (R-DPRs), such as poly(PR) and poly(GR). These R-DPRs disrupt LLPS in membrane-less organelles (MLOs) and contribute to disease pathology. While traditional analysis techniques like nuclear magnetic resonance (NMR), fluorescence recovery after photobleaching (FRAP), and Förster resonance energy transfer (FRET) provide insights into LLPS's role in these diseases, their ability is limited in detecting weak intermolecular interactions within LLPS droplets. This study employs graphene field-effect transistors (GFETs) for their superior sensitivity in detecting these molecular interactions. We immobilized RNA (poly-A) on GFETs and measured the electrical conductivity of GFETs to characterize shifts in the voltage of the charge neutral point in GFETs, allowing for the detection of dipeptide repeat peptides, such as (PR)12, (GR)12, and R12. Our results show that interactions between peptides and RNA require a specific peptide concentration threshold and vary between peptide types. Notably, the minimal conductivity shift suggests that peptides containing proline residues exhibit a nonuniform spatial distribution during interactions with RNA on graphene surfaces. This finding indicates that peptide rigidity induced by prolines plays a vital role in these molecular interactions and their multivalent contacts with RNA, which agrees with findings reported in other recent works. The capability of GFETs to detect these interactions at nanomolar concentrations marks a significant advancement in sensitivity over existing methods. This research sheds light on the mechanisms of LLPS involving R-DPRs and opens avenues for further understanding of related neurodegenerative diseases.}, }
@article {pmid39956874, year = {2025}, author = {Demaegd, KC and Kernan, A and Cooper-Knock, J and van Vugt, JJFA and Harvey, C and Moll, T and O'Brien, D and Gornall, S and Drury, L and Farhan, SMK and Dion, PA and Rouleau, GA and Western, A and Parsons, PJ and Mclean, B and Benatar, M and van den Berg, LH and Van Damme, P and Willem Dankbaar, J and Hendrikse, J and Koole, W and de Bie, C and Hobson, E and Veldink, JH and van de Warrenburg, B and Pasterkamp, RJ and van Rheenen, W and Kirby, J and Shaw, PJ and van Es, MA}, title = {An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2.}, journal = {European journal of human genetics : EJHG}, volume = {}, number = {}, pages = {}, pmid = {39956874}, issn = {1476-5438}, support = {216596/Z/19/Z//Wellcome Trust (Wellcome)/ ; 899-792//Motor Neurone Disease Association (MNDA)/ ; 974-797//Motor Neurone Disease Association (MNDA)/ ; 972-797//Motor Neurone Disease Association (MNDA)/ ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, abstract = {Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31-33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≥34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2-positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term 'ATXN2-related neurodegeneration'. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.}, }
@article {pmid39956201, year = {2025}, author = {Potestio, L and Martora, F and Megna, M}, title = {Response to Sood et al's "Real-world experience of bimekizumab for plaque psoriasis in adult patients with prior exposure to interleukin-17 inhibitors: A 16-week multicenter retrospective review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.10.129}, pmid = {39956201}, issn = {1097-6787}, }
@article {pmid39956001, year = {2025}, author = {Romero-Gavilán, F and Cerqueira, A and García-Arnáez, I and Scalschi, L and Vicedo, B and Azkargorta, M and Elortza, F and Izquierdo, R and Gurruchaga, M and Goñi, I and Suay, J}, title = {Proteomic evaluation of borosilicate hybrid sol-gel coatings with osteogenic, immunomodulatory and antibacterial properties.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {250}, number = {}, pages = {114561}, doi = {10.1016/j.colsurfb.2025.114561}, pmid = {39956001}, issn = {1873-4367}, mesh = {Humans ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Staphylococcus aureus/drug effects ; *Osteogenesis/drug effects ; *Proteomics ; *Coated Materials, Biocompatible/chemistry/pharmacology ; *Escherichia coli/drug effects ; Silicates/chemistry/pharmacology ; Surface Properties ; Microbial Sensitivity Tests ; Osteoblasts/drug effects/metabolism/cytology ; Immunologic Factors/pharmacology/chemistry ; Gels/chemistry/pharmacology ; }, abstract = {Silica hybrid sol-gel coatings represent an interesting approach to bioactivate dental implants. Boron is known for its osteogenic, angiogenic and antibacterial functions in biomedical applications. This study describes the synthesis of a novel borosilicate hybrid sol-gel coating using a mixture of methyltrimethoxysilane, tetraethyl orthosilicate and trimethyl borate (TMB). Coatings with different amounts of boron were obtained, and their physiochemical properties were examined; in vitro tests with human osteoblasts and macrophages (THP-1) were carried out. The effects of these materials on bacteria viability were evaluated using Escherichia coli and Staphylococcus aureus. The human serum proteins adsorbed onto the coatings were analysed employing proteomic techniques. To synthesise the new materials, the appropriate sol-gel reactions were developed; boron was integrated into the silica network, and well-adhering coatings were obtained. These borosilicate coatings were non-cytotoxic, displayed osteogenic potential, and upregulated adsorption of proteins related to bone regeneration (IGF2, ALS and APOE). Boron upregulated the expression of TNF-α, INFg and TGF-β and increased the TNF-α and TGF-β cytokine production in THP-1. Moreover, the addition of boron caused downregulation of NOX2 expression. Proteomic analysis revealed that boron-doping reduced the adsorption of immunoglobulins and complement system proteins. It also caused an increase in the levels of apolipoproteins, antioxidant proteins and serum amyloid A proteins, which was in agreement with in vitro results. The coatings with 10 and 20 % TMB displayed antibacterial effect against S. aureus. The results of this study will enhance our comprehension of interactions between boron-containing biomaterials and biological systems.}, }
@article {pmid39955058, year = {2025}, author = {Paul, S and Dansithong, W and Figueroa, KP and Gandelman, M and Hivare, P and Scoles, DR and Pulst, SM}, title = {Staufen2 dysregulation in neurodegenerative disease.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {3}, pages = {108316}, pmid = {39955058}, issn = {1083-351X}, mesh = {Humans ; Animals ; MicroRNAs/genetics/metabolism ; *RNA-Binding Proteins/genetics/metabolism ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; HEK293 Cells ; TOR Serine-Threonine Kinases/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Spinocerebellar Ataxias/metabolism/genetics/pathology ; 3' Untranslated Regions ; *Neurodegenerative Diseases/metabolism/genetics ; *Cytoskeletal Proteins/genetics/metabolism ; Disease Models, Animal ; Stress Granules/metabolism/genetics ; }, abstract = {Staufen2 (STAU2) is an RNA-binding protein that controls mRNA trafficking and expression. Previously, we showed that its paralog, Staufen1 (STAU1), was overabundant in cellular and mouse models of neurodegenerative diseases and amyotrophic lateral sclerosis (ALS) patient spinal cord. Here, we investigated features of STAU2 that might parallel STAU1. STAU2 protein, but not mRNA, was overabundant in spinocerebellar ataxia type 2 (SCA2), ALS/frontotemporal dementia patient fibroblasts, ALS patient spinal cord tissues, and in central nervous system tissues from SCA2 and ALS animal models. Exogenous expression of STAU2 in human embryonic kidney 293 cells activated mechanistic target of rapamycin (mTOR) and stress granule formation. Targeting STAU2 by RNAi normalized mTOR in SCA2 and C9ORF72 cellular models. The microRNA miR-217, previously identified as downregulated in SCA2 mice, targets the STAU2 3'-UTR. We now demonstrate that exogenous expression of miR-217 significantly reduced STAU2 and mTOR levels in cellular models of neurodegenerative disease. These results suggest a functional link between STAU2 and mTOR signaling and identify a major role for miR-217 that could be exploited in therapeutic development.}, }
@article {pmid39954969, year = {2025}, author = {Utami, KH and Morimoto, S and Mitsukura, Y and Okano, H}, title = {The roles of intrinsically disordered proteins in neurodegeneration.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1869}, number = {4}, pages = {130772}, doi = {10.1016/j.bbagen.2025.130772}, pmid = {39954969}, issn = {1872-8006}, mesh = {Humans ; *Intrinsically Disordered Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Proteostasis ; Proteasome Endopeptidase Complex/metabolism ; Animals ; Autophagy ; Protein Folding ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.}, }
@article {pmid39954940, year = {2025}, author = {Satao, KS and Doshi, GM}, title = {Intercellular communication via exosomes: A new paradigm in the pathophysiology of neurodegenerative disorders.}, journal = {Life sciences}, volume = {365}, number = {}, pages = {123468}, doi = {10.1016/j.lfs.2025.123468}, pmid = {39954940}, issn = {1879-0631}, mesh = {*Exosomes/metabolism/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are one of the leading causes of death and disability and pose a great economic burden on healthcare systems. Generally, these neurodegenerative disorders have a progressive deterioration in neural function and structure, and deposition of misfolded proteins commonly occurs, such as amyloid-β in AD and α-synuclein in PD. However, there exists a special class of exosomes, which acts like a transmitter and enhances communication between cells. The present review discusses the significant role of exosomes in neurodegenerative diseases, with a focus on Amyotrophic lateral Sclerosis (ALS), AD, PD, and Huntington's disease (HD). In this review, the biogenesis of exosomes is discussed from multivesicular bodies and onwards to their release into the extracellular environment. The present review focuses on recent data concerning the possible use of modified exosomes as ND therapy. Indeed, future work is needed to explain the processes driving exosome biogenesis and cargo selection, while opening new routes by the use of exosome-based therapeutics in neurodegenerative disease diagnosis and treatment.}, }
@article {pmid39954710, year = {2025}, author = {Nadeem, ZA and Ahmed, S}, title = {Amyotrophic lateral sclerosis and lovastatin: a promising treatment perspective.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2463943}, pmid = {39954710}, issn = {2167-9223}, }
@article {pmid39954573, year = {2025}, author = {Kiernan, MC and Timmins, HC}, title = {Utility of the Gold Coast criteria for amyotrophic lateral sclerosis: Experience with fast progressors.}, journal = {Journal of the neurological sciences}, volume = {470}, number = {}, pages = {123417}, doi = {10.1016/j.jns.2025.123417}, pmid = {39954573}, issn = {1878-5883}, }
@article {pmid39954119, year = {2025}, author = {Jacobsen, AB and Fanella, G and de Carvalho, M and Koltzenburg, M and Oliveira Santos, M and Cengiz, B and Blicher, J and Obál, I and Heintzelmann, MB and Nix, W and Camdessanché, JP and Fuglsang-Frederiksen, A and Tankisi, H}, title = {Variability of the Penn upper motor neuron score in amyotrophic lateral sclerosis: need for a revised score.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {208}, pmid = {39954119}, issn = {1432-1459}, support = {R346-2020-1946//Lundbeck Foundation/ ; R392-2022-699//Lundbeck Foundation/ ; J.nr.23-2B-12533//Aage og Johanne Louis-Hansens Fond/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Male ; Female ; Aged ; Middle Aged ; Reproducibility of Results ; Aged, 80 and over ; *Severity of Illness Index ; Observer Variation ; Motor Neurons/pathology/physiology ; }, abstract = {There is a need for a consensus on a clinical scale for evaluating upper motor neuron (UMN) burden in amyotrophic lateral sclerosis (ALS) to improve consistency in clinical diagnosis, research and monitoring of disease progression. The Penn upper motor neuron score (PUMNS) is the most commonly published scale, however, the reliability of the scale has only been evaluated in a single study involving two raters. The objective of this study was to evaluate the inter-rater reliability of the PUMNS in ALS patients among multiple raters, and to discuss an updated UMN score including the signs with the highest inter-rater reliability. This study included seven ALS patients (mean age: 71 ± 11.5, six males, one female). Each patient was evaluated with the PUMNS by eight raters from different centers blinded to previous observations. The intra-class correlation coefficient (ICC) was calculated to assess the inter-rater reliability of the total PUMNS. The inter-rater reliability of the binary subscores was assessed with Gwet's AC1 coefficient. The inter-rater agreement for the total PUMNS yielded an ICC of 0.81 (95% CI 0.56;0.96). Items with the highest inter-rater reliability included Hoffman's sign, Babinski's sign, clonus and deep tendon reflexes, while the facial reflex (Gwet's AC1 -0.038 (95% CI -0.25,0.18)) and crossed adduction (0.18 (95% CI (-0.32,0.67)) had the lowest inter-rater reliability. In conclusion, PUMNS demonstrated good inter-rater reliability overall, while some of the subscores had poor inter-rater reliability. Based on this, we call for an updated UMN score to enhance diagnostic accuracy and research consistency in ALS.}, }
@article {pmid39954028, year = {2025}, author = {Al Ojaimi, Y and Vallet, N and Dangoumau, A and Lanznaster, D and Bruno, C and Lefevre, A and Osman, S and Dupuy, C and Emond, P and Vourc'h, P and Corcia, P and Krupova, Z and Veyrat-Durebex, C and Blasco, H}, title = {Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {1}, pages = {21}, pmid = {39954028}, issn = {1559-1166}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/blood ; Male ; Middle Aged ; Female ; Aged ; Biomarkers/blood ; Extracellular Vesicles/metabolism ; Proteome/metabolism ; Metabolome ; Adult ; Proteomics/methods ; Case-Control Studies ; Lipid Metabolism ; Exosomes/metabolism ; }, abstract = {The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.}, }
@article {pmid39953725, year = {2025}, author = {Nishida, K and Sakashita, K and Futamura, N}, title = {Decision-making trends in therapeutic interventions for multiple system atrophy: a 24-year retrospective study.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70000}, pmid = {39953725}, issn = {2330-1619}, support = {JPMH23FC1010//the Ministry of Health, Labour and Welfare, Japan/ ; }, abstract = {BACKGROUND: Managing multiple system atrophy (MSA) is challenging. While invasive interventions for amyotrophic lateral sclerosis are well-studied, those for MSA remain less explored.<br><br>OBJECTIVES: To explore factors influencing treatment choices and trends in advanced-stage MSA.<br><br>METHODS: A retrospective cohort study analyzed 128 MSA patients at Hyogo Chuo National Hospital, Japan, from 2000 to 2024, focusing on treatment period and age at onset.<br><br>RESULTS: Tracheostomy invasive ventilation (TIV) decreased after 2014 (26.9% vs. 9.2%; P&#x2009;=&#x2009;0.023). TIV-treated patients remained similarly young before and after 2014 (age at onset 52.7 vs. 54.5&#x2009;years; P&#x2009;=&#x2009;0.659) and tracheostomy was chosen by younger patients after 2014 (58.3 vs. 51.5&#x2009;years; P&#x2009;<&#x2009;0.001). Conversely, enteral nutrition increased in older patients (57.4 vs. 62.9&#x2009;years; P&#x2009;=&#x2009;0.011).<br><br>CONCLUSIONS: In Japanese MSA, preferences for invasive treatments shifted, with younger patients favoring TIV and tracheostomy, while older patients preferred less invasive options, emphasizing personalized care.}, }
@article {pmid39952435, year = {2025}, author = {Truel, JS and Novice, M and Shapiro, J and Lo Sicco, KI}, title = {Response to Folliat et al's "Characteristics of pruritus in lichen planopilaris and frontal fibrosing alopecia: A cohort study in a French hospital".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.11.084}, pmid = {39952435}, issn = {1097-6787}, }
@article {pmid39952329, year = {2025}, author = {Ji, Y and Jiang, Q and Chen, B and Chen, X and Li, A and Shen, D and Shen, Y and Liu, H and Qian, X and Yao, X and Sun, H}, title = {Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.}, journal = {Biochemical pharmacology}, volume = {234}, number = {}, pages = {116799}, doi = {10.1016/j.bcp.2025.116799}, pmid = {39952329}, issn = {1873-2968}, mesh = {Humans ; *Unfolded Protein Response/physiology ; *Endoplasmic Reticulum Stress/physiology ; *Muscular Atrophy/metabolism/pathology ; Animals ; *Muscle, Skeletal/metabolism/pathology ; }, abstract = {Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.}, }
@article {pmid39950184, year = {2025}, author = {Høj, A and Holm-Yildiz, S and Krag, T and Dejanovic, D and van Overeem Hansen, T and Dunø, M and Ørngreen, MC and Vissing, J and Løkken, N}, title = {2-[[18]F] FDG PET/CT in Rapid Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report.}, journal = {JIMD reports}, volume = {66}, number = {2}, pages = {e12469}, pmid = {39950184}, issn = {2192-8304}, abstract = {Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn metabolic myopathy affecting fat and protein metabolism. Patients with late-onset MADD typically present with exercise intolerance and muscle weakness. We present a patient with an acute, very late-onset symptom debut at 52 years of age. Over 5 months, the patient deteriorated from asymptomatic to almost complete loss of ambulation. He had a substantial weight loss, head-drop, progressive proximal limb and chewing weakness. Due to the rapid progression, amyotrophic lateral sclerosis, myositis, myasthenia gravis and a paraneoplastic syndrome in relation to underlying malignancy were considered first. A 2-[[18]F] FDG PET/CT scan was performed to exclude a paraneoplastic syndrome. The scan revealed diffuse and symmetric, pathologically high 2-[[18]F] FDG-uptake in the patient's neck, shoulder, and paravertebral muscles, which was later suggested as a sign of a metabolic myopathy. Muscle biopsy (Oil Red O staining) and acylcarnitine profile (elevated C5-C18 acylcarnitines) findings suggested MADD, which was confirmed by genetic analysis showing biallelic variants in the ETFDH gene (c.1763A>G, p.(His588Arg); c.897G>A, p.(Leu299=)). After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level. A posttreatment muscle biopsy showed less disrupted ultrastructure of the myofibers. We learned from this case of rapid and late-onset MADD that 2-[[18]F] FDG PET/CT, with diffuse and symmetric 2-[[18]F] FDG-uptake in skeletal muscle, can be valuable in clarifying this rare diagnosis.}, }
@article {pmid39949668, year = {2025}, author = {Xu, J and Yu, Y and Wang, Y and Zhang, S and Liu, E and Wang, W and Zhu, C and Li, J}, title = {Postoperative Axial Length Prediction Model in Children With Congenital Cataract and Intraocular Lens Implantation.}, journal = {Journal of ophthalmology}, volume = {2025}, number = {}, pages = {9948890}, pmid = {39949668}, issn = {2090-004X}, abstract = {Purpose: To develop a prediction model for postoperative axial length (AL) in Asian children with congenital cataracts undergoing primary/secondary intraocular lens (IOL) implantation. Design: Retrospective observational study. Methods: Data were collected from children who underwent cataract surgery for congenital cataracts at the Eye Hospital of Wenzhou Medical University between 2006 and 2020. All participants completed preoperative and at least 1-year of postoperative follow-up. SPSS 26.0 software was used to analyze the variable factors affecting AL growth and the interactions among these factors. A generalized estimating equation (GEE) was employed to assess the correlation between the AL and related univariates over time. The univariate model was applied to build a multivariate model to predict the postoperative AL. Two validation sets were used to verify the accuracy of the formula. Results: The study involved 86 children, accounting for 148 eyes. The median age at the time of surgery was 3.00 years, with a median age of 9.50 years at the final follow-up visit. The median duration of follow-up was 5.00 years. The preoperative and final follow-up mean ALs were 21.79 ± 1.77 and 23.36 ± 1.90 mm, respectively. Taking the predicted AL (Y) as the dependent variable and the age at surgery (X 1), age at review (X 2), and preoperative AL (X 3) as the independent variables, the prediction model was established as Y = 0.20 - 0.473 × X 1 + 0.446 × X 2 + 0.993 × X 3 - 0.014 × (X 2 - X 1)∗X 2. Conclusions: This model predicts AL growth in children following congenital cataract surgery and IOL implantation, helping ophthalmologists select appropriate IOL power.}, }
@article {pmid39948244, year = {2025}, author = {Picard, F and Nonaka, T and Belotti, E and Osseni, A and Errazuriz-Cerda, E and Jost-Mousseau, C and Bernard, E and Conjard-Duplany, A and Bohl, D and Hasegawa, M and Raoul, C and Galli, T and Schaeffer, L and Leblanc, P}, title = {Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {76}, pmid = {39948244}, issn = {1420-9071}, support = {MyoNeurALP strategic grants//AFM-T&#xe9;l&#xe9;thon/ ; MyoNeurALP strategic grants//AFM-T&#xe9;l&#xe9;thon/ ; SPREADALS//Agence Nationale de la Recherche/ ; SPREADALS//Agence Nationale de la Recherche/ ; SPREADALS//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *Protein Folding ; *Endopeptidases/metabolism/genetics ; HEK293 Cells ; Autophagy ; }, abstract = {Proteinopathies, such as amyotrophic lateral sclerosis (ALS), are marked by the accumulation of misfolded proteins that disrupt cellular processes. Eukaryotic cells have developed protein quality control systems to eliminate these aberrant proteins, but these systems often fail to differentiate between normal and misfolded proteins. In ALS, pathological inclusions primarily composed of misfolded TDP-43 are a hallmark of the disease. Recently, a novel unconventional secretion process called misfolding-associated protein secretion (MAPS) has been discovered to selectively export misfolded proteins. USP19, an Endoplasmic Reticulum-associated ubiquitin peptidase, plays a crucial role in this process. In this study, we investigated the impact of ER-anchored USP19 on the secretion of misfolded TDP-43. Here we found that USP19 overexpression significantly promotes the secretion of soluble and aggregated misfolded TDP-43, requiring both ER anchoring and ubiquitin peptidase activity. Characterization of the cellular and molecular mechanisms involved in this process highlighted the importance of early autophagosomal and late endosomal/amphisomal compartments, while lysosomes did not play a key role. By using dominant-negative mutants and small interfering RNAs, we identified that USP19-mediated secretion of misfolded TDP-43 is modulated by key factors involved in cellular trafficking and secretion pathways, such as ATG7, the ESCRT-O HGS/HRS, the Rab GTPases RAB11A, RAB8A, and RAB27A, and the v-SNARE VAMP7. We also confirmed the crucial role of the DNAJC5/CSPα cochaperone. Overall, this study provides new insights into how cells manage the secretion of misfolded TDP-43 proteins and potentially opens new avenues for therapeutic interventions in ALS and related disorders.}, }
@article {pmid39947885, year = {2025}, author = {Iacoangeli, A and Dilliott, AA and Al Khleifat, A and Andersen, PM and Başak, NA and Cooper-Knock, J and Corcia, P and Couratier, P and deCarvalho, M and Drory, VE and Glass, JD and Gotkine, M and Lerner, YM and Hardiman, O and Landers, JE and McLaughlin, RL and Pardina, JSM and Morrison, K and Pinto, S and Povedano, M and Shaw, CE and Shaw, PJ and Silani, V and Ticozzi, N and van Damme, P and van den Berg, LH and Vourc'h, P and Weber, M and Veldink, JH and ,  and Dobson, R and Rouleau, GA and Al-Chalabi, A and Farhan, SMK}, title = {Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335364}, pmid = {39947885}, issn = {1468-330X}, abstract = {BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.<br><br>METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.<br><br>RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.<br><br>CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.}, }
@article {pmid39947630, year = {2025}, author = {Moreno-Martinez, L and Gaja-Capdevila, N and Mosqueira-Martín, L and Herrando-Grabulosa, M and Rodriguez-Gomez, L and Gonzalez-Imaz, K and Calvo, AC and Sagartzazu-Aizpurua, M and Moreno-García, L and Fuentes, JM and Acevedo-Arozena, A and Aizpurua, JM and Miranda, JI and López de Munain, A and Vallejo-Illarramendi, A and Navarro, X and Osta, R and Gil-Bea, FJ}, title = {Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1[G93A] amyotrophic lateral sclerosis (ALS) mice.}, journal = {British journal of pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bph.17448}, pmid = {39947630}, issn = {1476-5381}, support = {PID2022-140354OB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; PID2020-119780RB-100//Agencia Estatal de Investigaci&#xf3;n/ ; IKERBASQUE/PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; PIF19/184//Euskal Herriko Unibertsitatea/ ; PI2020/08-1//CIBER-CALS/ ; CB06/05/1105//Instituto de Salud Carlos III of Spain/ ; CB06/05/0041//Instituto de Salud Carlos III of Spain/ ; BIO19/ROCHE/017/BD//Roche Stop Fuga de Cerebros/ ; IT1732-22//Basque Government/ ; }, abstract = {BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated Ca[2+] influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca[2+], as a therapeutic target.<br><br>EXPERIMENTAL APPROACH: A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)[G93A] mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.<br><br>KEY RESULTS: Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1[G93A] mice produced preservation of motor nerve conduction, with the 61-mg&#xb7;kg[-1] dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10&#x2009;days compared to vehicle.<br><br>CONCLUSIONS AND IMPLICATIONS: FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.}, }
@article {pmid39947279, year = {2025}, author = {Gelbenegger, G and Cheskes, S and Jilma, B and Zeitlinger, M and Lin, S and Drennan, IR and Jorda, A}, title = {Amiodarone dose in patients with shockable out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {}, number = {}, pages = {110534}, doi = {10.1016/j.resuscitation.2025.110534}, pmid = {39947279}, issn = {1873-1570}, abstract = {BACKGROUND: Amiodarone is used in shockable out-of-hospital cardiac arrest (OHCA), but the ideal dose is unknown.<br><br>METHODS: This was an analysis from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (2011-2015). Patients with shockable OHCA who received 5 or more defibrillation attempts and treatment with 300 or 450&#xa0;mg of amiodarone were included. Outcomes were ROSC at ED arrival, survival at hospital discharge, and favorable neurologic function at discharge. Group-differences were adjusted for using inverse probability weighting and a multiple logistic regression model.<br><br>RESULTS: The present study included 910 patients; 426 received amiodarone 300&#xa0;mg and 484 received amiodarone 450&#xa0;mg. The amiodarone 300&#xa0;mg group had a higher estimated probability of ROSC at ED arrival as compared with the amiodarone 450&#xa0;mg group (30.8% [95% CI, 26.6-35.1] vs 24.2% [95% CI, 20.5-27.9], respectively; adjusted probability difference, 6.6% (0.9-12.3), p&#xa0;=&#xa0;0.0234). The group differences in survival at hospital discharge (21.3% [95% CI, 17.2-25.4] vs 18.0% [95% CI, 14.6-21.5]; adjusted probability difference, 3.3% [-2.3-8.8]) and favorable neurologic outcome at discharge (16.5% [95% CI, 12.9-20.2] vs 12.7% [95% CI, 9.5-16.0]; adjusted probability difference, 3.8% [95% CI, -1.2-8.7]) did not reach statistical significance.<br><br>CONCLUSION: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300&#xa0;mg was associated with a similar survival compared with a total dose of amiodarone 450&#xa0;mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA.}, }
@article {pmid39947099, year = {2025}, author = {Tan, HHG and Nitert, AD and van Veenhuijzen, K and Dukic, S and van Zandvoort, MJE and Hendrikse, J and van Es, MA and Veldink, JH and Westeneng, HJ and van den Berg, LH}, title = {Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103749}, pmid = {39947099}, issn = {2213-1582}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/complications ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; *Cognitive Dysfunction/diagnostic imaging/etiology/physiopathology/pathology ; Gray Matter/diagnostic imaging/pathology ; Adult ; Neuroimaging/methods ; White Matter/diagnostic imaging/pathology ; Brain/diagnostic imaging/pathology ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with frequent extra-motor involvement. In the present study, we investigated whether specific cognitive and behavioral deficits in ALS correlate with distinct extra-motor neurodegeneration patterns on brain MRI.<br><br>METHODS: We performed multimodal brain MRI and Edinburgh cognitive and behavioral ALS screen (ECAS) in 293 patients and 237 controls. Follow-up data were acquired from 171 patients with a median duration of 7.9&#xa0;months. Domain-level cognitive scores from the ECAS were compared with grey and white matter MRI parameters. Interaction analyses between patients and controls were performed to explore whether correlates were specific to ALS, rather than related to normal aging. Follow-up data were used to assess changes of domain-associated brain structures over time.<br><br>RESULTS: Language impairment was significantly associated with (left predominant) frontal, temporal, parietal and subcortical grey matter neurodegeneration. Letter fluency with widespread cortical and subcortical grey matter involvement. Memory dysfunction with hippocampal and medial-temporal atrophy. Executive impairment was exclusively correlated with widespread white matter impairment. Visuospatial scores did not correlate with MRI parameters. Interaction analyses between patients and controls showed that most ECAS-MRI correlations were stronger in ALS than in controls (75.7% significant in grey matter, 52.7% in white matter). Longitudinal analyses showed that all grey matter structures associated with cognitive domains worsened over time while, for this study population, ECAS domain scores did not decline significantly.<br><br>CONCLUSIONS: MRI can capture the heterogeneity of cognitive and behavioral involvement in ALS and provides a useful longitudinal biomarker for progression of extra-motor neurodegeneration.}, }
@article {pmid39946662, year = {2025}, author = {Cordts, I and Fuetterer, C and Wachinger, A and von Heynitz, R and Kessler, T and Freigang, M and Quinten, AL and Bjelica, B and Brakemeier, S and Hobbiebrunken, E and Hagenacker, T and Petri, S and Koch, JC and Hahn, A and Lingor, P and Deschauer, M and Günther, R and Weiler, M and Haller, B and Feneberg, E}, title = {Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen.}, journal = {Neurology}, volume = {104}, number = {5}, pages = {e213371}, pmid = {39946662}, issn = {1526-632X}, mesh = {Humans ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Male ; Female ; Adult ; *Oligonucleotides/therapeutic use ; Retrospective Studies ; Middle Aged ; *Muscular Atrophy, Spinal/drug therapy/blood/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.<br><br>METHODS: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.<br><br>RESULTS: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (&#x394; HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; &#x394; RULM, 0.9 [IQR 0.4-1.3], p < 0.001; &#x394; ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (&#x394; HFMSE &#x2264; 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.<br><br>DISCUSSION: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.}, }
@article {pmid39946043, year = {2025}, author = {Patnana, DP and Kanikaram, SP and Kumar, P and Cheerala, VSK and Sivaramakrishnan, V and Tripathi, P and Chandra, BP}, title = {Simultaneous determination of polycyclic aromatic hydrocarbons, their derivatives, and phthalic acid esters bound to ambient PM2.5 during pre-summer season in Bengaluru, India, and potential effect on protein aggregation diseases.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, pmid = {39946043}, issn = {1614-7499}, abstract = {Air pollution pertaining to particulate matter (PM) is a major issue in most of the metropolitan cities across the world. Inhalation exposure to organic species like polycyclic aromatic hydrocarbons (PAHs), derivatives of PAHs (oxygenated and nitrated PAHs), and phthalic acid esters (PAEs) bound to PM is of major concern owing to its carcinogenic, mutagenic, and endocrine disrupting nature. In this study for the first time, we report a total of 22 aromatic organic species which include PAHs, derivatives of PAHs, and PAEs using an optimized high-performance liquid chromatography coupled to the tandem mass spectrometer (HPLC-MS/MS) method. Further, this optimized method was used to carry out the measurements of the 22 targeted organic constituents bound to the ambient fine particulate matter (PM2.5) collected in Bengaluru, a metropolitan city in India as a part of a pilot study during the pre-summer season. Among the reported compounds, benzo[b]fluoranthene (3.82 ng m[-3]), 9-nitroanthracene (10.47 ng m[-3]), and diethyl phthalate (5.38 ng m[-3]) are the most abundant PAHs, the derivatives of PAHs, and PAEs, respectively. Determined diagnostic ratios of PAHs have shown that the sampling site is majorly influenced by traffic emissions. Benzo[a]pyrene, a Group 1 carcinogen has occasionally exceeded the limits set by National Ambient Air Quality Standards (NAAQs), India during the sampling period. Further, a preliminary study was performed using a yeast model of amyotrophic lateral sclerosis (ALS) expressing transactive response DNA binding protein 43 (TDP43) and we demonstrated that commonly reported organics such as PAHs and PAEs bound to PM2.5 have induced significantly elevated aggregation in wild type TDP43. Preliminary results of this study indicate that there is a need for further detailed health risk assessment due to inhalation exposure of organic constituents bound to the ambient PM in Bengaluru.}, }
@article {pmid39945358, year = {2025}, author = {Badger, SE and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Moutin, C and Mohd Imran, K and Day, JC and Cooper-Knock, J and Mead, RJ and Alix, JJP}, title = {A bacterial artificial chromosome mouse model of amyotrophic lateral sclerosis manifests 'space cadet syndrome' on two FVB backgrounds.}, journal = {Disease models &amp; mechanisms}, volume = {18}, number = {2}, pages = {}, pmid = {39945358}, issn = {1754-8411}, support = {Alix/Apr19/871-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; //University of Sheffield/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Disease Models, Animal ; *C9orf72 Protein/genetics ; *Mice, Transgenic ; *Chromosomes, Artificial, Bacterial/genetics ; *Phenotype ; Frontotemporal Dementia/genetics/pathology ; Mice ; Humans ; Syndrome ; }, abstract = {C9orf72-related amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) has proven difficult to model in mice. Liu et al. (2016) reported a bacterial artificial chromosome (BAC) transgenic mouse displaying behavioural, motor and pathological abnormalities. This was followed by multiple laboratories independently refuting and confirming phenotypes. A proposed explanation centred on the use of different FVB background lines (from The Jackson Laboratory and Janvier Labs). We studied C9orf72 BAC mice on both backgrounds and found significantly elevated levels of dipeptide repeat proteins, but no evidence of a transgene-associated phenotype. We observed seizures and a gradual decline in functional performance in transgenic and non-transgenic mice, irrespective of genetic background. The phenotype was in keeping with the so-called 'space cadet syndrome'. Our findings indicate that the differences previously reported are not due to C9orf72 status and highlight the importance of using genetic backgrounds that do not confound interpretation of neurodegenerative phenotypes.}, }
@article {pmid39944773, year = {2025}, author = {Cheng, R and Dimitriou, D and Yao, G and Li, X and Lv, X and Yang, Y and Ying, H and Wang, Z and Tsai, TY}, title = {Outperformance of Combined Artificial Anterolateral Ligament and ACL Reconstruction Compared With Isolated Artificial ACL Reconstruction in Knees With Anterolateral Structure and ACL Deficiency: A Biomechanical Analysis.}, journal = {Orthopaedic journal of sports medicine}, volume = {13}, number = {2}, pages = {23259671241309270}, pmid = {39944773}, issn = {2325-9671}, abstract = {BACKGROUND: Despite the promising clinical outcomes of artificial polyethylene terephthalate (PET) ligaments in isolated anterior cruciate ligament reconstruction (ACLR), their biomechanical performance after combined anterolateral ligament reconstruction (ALLR)/ACLR in anterolateral structure (ALS)/anterior cruciate ligament (ACL)-deficient knees has not been investigated.<br><br>PURPOSE/HYPOTHESIS: The purpose of this study was to compare biomechanical performance in cadaveric knees between combined artificial ALLR/ACLR and isolated artificial ACLR using PET ligaments. It was hypothesized that combined artificial ALLR/ACLR would restore native knee stability and outperform isolated artificial ACLR in ALS/ACL-deficient knees.<br><br>STUDY DESIGN: Controlled laboratory study.<br><br>METHODS: Eight fresh-frozen cadaveric knees were tested using a robotic manipulator. Each knee was tested in 4 states: (1) ALS/ACL intact, (2) ALS/ACL deficient, (3) ACLR, and (4) ALLR/ACLR. The anterior tibial translation (ATT) and tibial internal rotation (IR) in each knee condition were measured under 3 loads: (1) 89 N of anterior tibial loading, (2) 5 N&#xb7;m of IR torque, and (3) simulated pivot shift (combined 5 N&#xb7;m of IR torque and 7 N&#xb7;m of valgus load).<br><br>RESULTS: During 89 N of anterior tibial loading, there were no significant differences in ATT between the isolated ACLR and ALLR/ACLR knees. During 5 N&#xb7;m of IR torque, the mean tibial IR at 45&#xb0; of flexion was significantly higher in the ACLR knees (32.49&#xb0;&#xb1; 7.96&#xb0;) than in the ALLR/ACLR knees (21.78&#xb0;&#xb1; 3.03&#xb0;) (P < .05). During the simulated pivot shift, the mean ATT and tibial IR at 30&#xb0; and 45&#xb0; of flexion were significantly higher in the ACLR knees (ATT: 5.09 &#xb1; 2.74 mm at 30&#xb0;, 5.43 &#xb1; 2.79 mm at 45&#xb0;; IR: 30.08&#xb0;&#xb1; 7.31&#xb0; at 30&#xb0;, 32.55&#xb0;&#xb1; 6.48&#xb0; at 45&#xb0;) than in the ALLR/ACLR knees (ATT: 1.93 &#xb1; 2.71 mm at 30&#xb0;, 1.17 &#xb1; 2.26 mm at 45&#xb0;; IR: 22.12&#xb0;&#xb1; 4.05&#xb0; at 30&#xb0;, 22.18&#xb0;&#xb1; 3.37&#xb0; at 45&#xb0;) (P < .05).<br><br>CONCLUSION: Combined artificial ALLR/ACLR restored native knee stability across multiple flexion angles and outperformed isolated artificial ACLR in ALS/ACL-deficient knees, particularly with respect to ATT and tibial IR during the pivot-shift test.<br><br>CLINICAL RELEVANCE: The indications of the artificial PET ligament may be expanded to include combined ALLR/ACLR to restore knee stability better than isolated artificial ACLR in ALS/ACL-deficient knees.}, }
@article {pmid39944166, year = {2025}, author = {Islam, S and Noorani, A and Sun, Y and Michikawa, M and Zou, K}, title = {Multi-functional role of apolipoprotein E in neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1535280}, pmid = {39944166}, issn = {1663-4365}, abstract = {Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer's disease (SAD). Specifically, the ApoEε4 allele is a significant risk factor for SAD, while ApoEε2 allele provides protection compared to the more common ApoEε3 allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid β-protein (Aβ) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE's diverse roles, emphasizing its involvement in Aβ clearance through ApoE receptors. It also covers ApoE's influence in other neurodegenerative diseases like Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington's disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.}, }
@article {pmid39944085, year = {2025}, author = {Sakurai, H and Suzuki, M and Asakura, A}, title = {Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1556403}, pmid = {39944085}, issn = {2296-634X}, }
@article {pmid39942798, year = {2025}, author = {Długosz, A and Błaszak, B and Czarnecki, D and Szulc, J}, title = {Mechanism of Action and Therapeutic Potential of Xanthohumol in Prevention of Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, pmid = {39942798}, issn = {1420-3049}, mesh = {*Propiophenones/pharmacology/therapeutic use ; *Flavonoids/pharmacology/chemistry/therapeutic use ; Humans ; *Neurodegenerative Diseases/prevention &amp; control/drug therapy/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use ; Alzheimer Disease/prevention &amp; control/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism/prevention &amp; control ; Humulus/chemistry ; }, abstract = {Xanthohumol (XN), a bioactive plant flavonoid, is an antioxidant, and as such, it exhibits numerous beneficial properties, including anti-inflammatory, antimicrobial, and antioxidative effects. The main dietary source of XN is beer, where it is introduced through hops. Although the concentration of XN in beer is low, the large quantities of hop-related post-production waste present an opportunity to extract XN residues for technological or pharmaceutical purposes. The presented study focuses on the role of XN in the prevention of neurodegenerative diseases, analyzing its effect at a molecular level and including its signal transduction and metabolism. The paper brings up XN's mechanism of action, potential effects, and experimental and clinical studies on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Additionally, challenges and future research directions on XN, including its bioavailability, safety, and tolerance, have been discussed.}, }
@article {pmid39942481, year = {2025}, author = {Kavanaugh, MS and Zawadzki, MJ and Johnson, KT and Boville, MR}, title = {Moments of Care: Perceptions of Young Carers and Day-to-Day Well-Being.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {39942481}, issn = {2227-9032}, abstract = {Background/Objectives: Over 5 million youth under the age of 19 provide daily, hands-on care to an ill or injured family member across the United States. Yet how these young carers perceive the care they deliver in the moment, and how these perceptions relate to well-being, is unexplored, particularly in complex neurological conditions. This paper presents initial data on young carers for a family member with amyotrophic lateral sclerosis (ALS). Methods: Ecological momentary assessment (EMA) was used to measure perceptions of care in the moments of care and the cognitive and emotional states of the young carers during those moments. Young carers (n = 15) aged 10-19 were followed for seven days, completing assessments three times per day, which provided 260 total measurements. Young carers reported frequently engaging in caregiving (~39% of assessments). Results: The results indicated that it was not simply performing a caregiving task that related to outcomes, but rather how caregiving moments were perceived that mattered. Caregiving moments perceived as more fulfilling resulted in young carers feeling less discontent and more focused, whereas caregiving moments perceived as lacking resources predicted more discontent and distress. Exploratory analyses highlighted the potential for burden for young carers. They reported high levels of worry when they were not around the care recipient, with this worry predicting feeling more discontent and distressed. Conclusions: Young carers are deeply involved in care and perceive care differently across moments, both positive and negative. These initial data can be used to develop targeting support programs in the moment of care, potentially lessening the negative impacts of care.}, }
@article {pmid39941101, year = {2025}, author = {Orywal, K and Socha, K and Iwaniuk, P and Kaczyński, P and Farhan, JA and Zoń, W and Łozowicka, B and Perkowski, M and Mroczko, B}, title = {Vitamins in the Prevention and Support Therapy of Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941101}, issn = {1422-0067}, support = {NdS/551580/2022/2022//Polish Ministry of Education and Science/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/prevention &amp; control/metabolism ; *Vitamins/therapeutic use ; Dietary Supplements ; Animals ; Alzheimer Disease/prevention &amp; control/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world's population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins' potential benefits for neuroprotection and the management of neurodegenerative diseases.}, }
@article {pmid39941012, year = {2025}, author = {Sonkodi, B}, title = {PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39941012}, issn = {1422-0067}, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; Protons ; Central Nervous System Sensitization ; Pain/metabolism/physiopathology ; Neurodegenerative Diseases/metabolism ; Motor Neurons/metabolism ; Pain Threshold ; }, abstract = {The current opinion manuscript posits that not only Piezo2 voltage block, but also proton affinity and availability in relation to Piezo2, a mechanically gated ion channel, may count in the mediation of pain and its sensitivity. Moreover, this paper argues that autonomously acquired Piezo2 channelopathy on somatosensory terminals is likely the initiating peripheral impaired input source that drives the central sensitization of spinal nociceptive neurons on the chronic path as being the autonomous pain generator. In parallel, impaired proprioception and the resultant progressive deficit in neuromuscular junctions of motoneurons might be initiated on the chronic path by the impairment of the proton-based ultrafast proprioceptive feedback to motoneurons due to disconnection through vesicular glutamate transporter 1. The irreversible form of this autonomously acquired Piezo2 ion channel microdamage, in association with genetic predisposition and/or environmental risk factors, is suggested to lead to progressive motoneuron death in addition to loss of pain sensation in amyotrophic lateral sclerosis. Furthermore, the impairment of the proton-based ultrafast long-range oscillatory synchronization to the hippocampus through vesicular glutamate transporter 2 may gain further importance in pain modulation and formation on the chronic path. Overall, this novel, unaccounted Piezo2-initiated protonic extrafast signaling, including both the protonic ultrafast proprioceptive and the rapid nociceptive ones, within the nervous system seems to be essential in order to maintain life. Hence, its microdamage promotes neurodegeneration and accelerates aging, while the complete loss of it is incompatible with life sustainment, as is proposed in amyotrophic lateral sclerosis.}, }
@article {pmid39940966, year = {2025}, author = {Jamerlan, AM and Shim, KH and Sharma, N and An, SSA}, title = {Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940966}, issn = {1422-0067}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; 2021R1A6A1A03038996//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Protein Multimerization ; alpha-Synuclein/metabolism/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Neurodegenerative Diseases/metabolism/diagnosis ; Protein Aggregates ; DNA-Binding Proteins/metabolism/chemistry ; tau Proteins/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; }, abstract = {Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.}, }
@article {pmid39940644, year = {2025}, author = {Lee, AJB and Bi, S and Ridgeway, E and Al-Hussaini, I and Deshpande, S and Krueger, A and Khatri, A and Tsui, D and Deng, J and Mitchell, CS}, title = {Restoring Homeostasis: Treating Amyotrophic Lateral Sclerosis by Resolving Dynamic Regulatory Instability.}, journal = {International journal of molecular sciences}, volume = {26}, number = {3}, pages = {}, pmid = {39940644}, issn = {1422-0067}, support = {U19 AG065169/AG/NIA NIH HHS/United States ; 1944247//National Science Foundation/ ; 253558//Chan Zuckerberg Initiative/ ; R35 GM152245/GM/NIGMS NIH HHS/United States ; R35GM152245/NH/NIH HHS/United States ; K01 NS069616/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy/pathology ; Animals ; *Homeostasis ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; Humans ; Disease Progression ; Superoxide Dismutase-1/genetics/metabolism ; Computer Simulation ; Oxidative Stress ; }, abstract = {Amyotrophic lateral sclerosis (ALS) has an interactive, multifactorial etiology that makes treatment success elusive. This study evaluates how regulatory dynamics impact disease progression and treatment. Computational models of wild-type (WT) and transgenic SOD1-G93A mouse physiology dynamics were built using the first-principles-based first-order feedback framework of dynamic meta-analysis with parameter optimization. Two in silico models were developed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate ALS pathology dynamics and their response to in silico treatments. The model simulates functional molecular mechanisms for apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using curated data from published SOD1-G93A mouse experiments. Temporal disease progression measures (rotarod, grip strength, body weight) were used for validation. Results illustrate that untreated SOD1-G93A ALS dynamics cannot maintain homeostasis due to a mathematical oscillating instability as determined by eigenvalue analysis. The onset and magnitude of homeostatic instability corresponded to disease onset and progression. Oscillations were associated with high feedback gain due to hypervigilant regulation. Multiple combination treatments stabilized the SOD1-G93A ALS mouse dynamics to near-normal WT homeostasis. However, treatment timing and effect size were critical to stabilization corresponding to therapeutic success. The dynamics-based approach redefines therapeutic strategies by emphasizing the restoration of homeostasis through precisely timed and stabilizing combination therapies, presenting a promising framework for application to other multifactorial neurodegenerative diseases.}, }
@article {pmid39939579, year = {2025}, author = {Zhou, T and Solis, NV and Marshall, M and Yao, Q and Pearlman, E and Filler, SG and Liu, H}, title = {Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {1562}, pmid = {39939579}, issn = {2041-1723}, support = {R01 EY036478/EY/NEI NIH HHS/United States ; R01 GM117111/GM/NIGMS NIH HHS/United States ; R01EY036478//U.S. Department of Health &amp; Human Services | NIH | National Eye Institute (NEI)/ ; R01GM117111//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Inflammasomes/metabolism ; Humans ; *Caspase 8/metabolism ; *Fas-Associated Death Domain Protein/metabolism/genetics ; Animals ; *Fungal Proteins/metabolism/genetics ; *Signal Transduction ; *Candida albicans/metabolism ; Mice ; *Interleukin-1beta/metabolism ; Jurkat Cells ; Protein Domains ; Apoptosis ; Macrophages/metabolism/microbiology ; CARD Signaling Adaptor Proteins/metabolism/genetics ; }, abstract = {High-damaging Candida albicans strains tend to form hyphae and exacerbate intestinal inflammation in ulcerative colitis patients through IL-1β-dependent mechanisms. Fungal agglutinin-like sequence (Als) proteins worsen DSS-induced colitis in mouse models. FADD and caspase-8 are important regulators of gut homeostasis and inflammation. However, whether they link directly to fungal proteins is not fully understood. Here, we report that Als proteins induce IL-1β release in immune cells. We show that hyphal Als3 is internalized in macrophages and interacts with caspase-8 and the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC). Caspase-8 is essential for Als3-mediated ASC oligomerization and IL-1β processing. In non-immune cells, Als3 is associated with cell death core components FADD and caspase-8. N-terminal Als3 (N-Als3) expressed in Jurkat cells partially inhibits apoptosis. Mechanistically, N-Als3 promotes oligomerization of FADD and caspase-8 through their death effector domains (DEDs). N-Als3 variants with a mutation in the peptide-binding cavity or amyloid-forming region are impaired in DED oligomerization. Together, these results demonstrate that DEDs are intracellular sensors of Als3. This study identifies additional potential targets to control hypha-induced inflammation.}, }
@article {pmid39938954, year = {2025}, author = {Flügel, V and Hering, T and Dadaczynski, K}, title = {Development and validation of a questionnaire on parental health literacy in the context of promoting healthy lifestyles during childhood: a study protocol.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e088037}, pmid = {39938954}, issn = {2044-6055}, mesh = {Humans ; *Health Literacy ; Surveys and Questionnaires ; *Parents ; Child ; *Health Promotion/methods ; *Healthy Lifestyle ; Child, Preschool ; Reproducibility of Results ; Research Design ; Female ; Male ; Factor Analysis, Statistical ; }, abstract = {INTRODUCTION: Becoming a parent presents profound changes and numerous challenges, notably the necessity for reliable information regarding their child's health. Given the overabundance of information available today, it is important for parents to acquire the skills necessary to find, understand, evaluate and apply health information. Research demonstrates that this ability, known as parental health literacy (PHL), is crucial for developing and maintaining a healthy lifestyle during childhood. However, there is currently no reliable instrument for measuring PHL in the field of prevention and health promotion. This paper presents the development and validation of a new questionnaire designed to assess parents' ability to process health-related information to support the healthy development of their children aged 3-6 years.<br><br>METHODS AND ANALYSIS: The development of the item pool is based on S&#xf8;rensen et al's conceptualisation of general health literacy (finding, understanding, evaluating and applying health information). Empirical findings suggest that communication with healthcare providers and the social network represents another important skill area for parents and is therefore included as an additional subscale. The questionnaire will be developed in four stages, including a literature search and analysis, expert consultations via Delphi study, cognitive interviews with parents and a validation study. The validation study uses exploratory (EFA) and confirmatory factor analysis (CFA) for construct validity, first identifying test dimensions through EFA, then confirming these dimensions with CFA to ensure the factor structure aligns with theoretical expectations. This methodology, alongside reliability and correlational analyses, seeks to assess the questionnaire's validity and reliability, expecting strong correlations with existing related constructs.<br><br>ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of Fulda University of Applied Sciences. All participants receive a consent form together with the study information, in which they give their written consent to the storage, processing and linking of all data collected. The results of the study will be presented at national and international conferences and published in specialist journals.<br><br>TRIAL REGISTRATION NUMBER: DRKS00033482.}, }
@article {pmid39938752, year = {2025}, author = {Zhu, Y and Tian, M and Lu, S and Qin, Y and Zhao, T and Shi, H and Li, Z and Qin, D}, title = {The antioxidant role of aromatic plant extracts in managing neurodegenerative diseases: A comprehensive review.}, journal = {Brain research bulletin}, volume = {222}, number = {}, pages = {111253}, doi = {10.1016/j.brainresbull.2025.111253}, pmid = {39938752}, issn = {1873-2747}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Antioxidants/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; Animals ; Flavonoids/therapeutic use/pharmacology ; Polyphenols/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.}, }
@article {pmid39937422, year = {2025}, author = {Grassano, M and Chiò, A}, title = {microRNA in ALS: finally ready for prime time?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1463-1464}, pmid = {39937422}, issn = {1590-3478}, }
@article {pmid39936986, year = {2025}, author = {Ramírez, OA and Hellwig, A and Zhang, Z and Bading, H}, title = {Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.}, journal = {Cells}, volume = {14}, number = {3}, pages = {}, pmid = {39936986}, issn = {2073-4409}, mesh = {*Receptors, N-Methyl-D-Aspartate/metabolism ; *Dendrites/drug effects/metabolism ; Animals ; *TRPM Cation Channels/metabolism ; *Mitochondria/metabolism/drug effects ; *Signal Transduction/drug effects ; Endoplasmic Reticulum/metabolism/drug effects ; Humans ; Calcium/metabolism ; Organelles/metabolism/drug effects ; Neurons/drug effects/metabolism/pathology ; Rats ; N-Methylaspartate/pharmacology/toxicity ; Calcium Signaling/drug effects ; }, abstract = {Focal swellings of dendrites ("dendritic blebbing") together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called "overactivation" of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein-protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER-mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity ("two-hit hypothesis"). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases.}, }
@article {pmid39936815, year = {2025}, author = {Mendes, RA and Lima, ILB and Dourado Júnior, MET and Gonçalves, MJ}, title = {Is there a decline in speech and swallowing in Amyotrophic Lateral Sclerosis over ten years?.}, journal = {CoDAS}, volume = {37}, number = {2}, pages = {e20240159}, pmid = {39936815}, issn = {2317-1782}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Female ; Retrospective Studies ; *Deglutition Disorders/physiopathology/etiology ; Middle Aged ; Longitudinal Studies ; *Disease Progression ; Aged ; Speech Disorders/etiology/physiopathology ; Adult ; Dysarthria/etiology/physiopathology ; Deglutition/physiology ; Time Factors ; Cohort Studies ; }, abstract = {PURPOSE: To analyze the evolution of speech and swallowing decline in patients with amyotrophic lateral sclerosis (ALS) over a ten-year period.<br><br>METHODS: A retrospective and longitudinal cohort study. Data were collected using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) from 101 medical records of ALS patients treated at the multidisciplinary neuromuscular diseases clinic of a University Hospital over a ten-year period. The data were statistically analyzed, adopting a significance level of p<0.05.<br><br>RESULTS: The analysis of the studied functions indicated that speech, swallowing, and salivation are altered over ten years in ALS. There are differences in patterns between the variables sex and disease type concerning symptoms related to dysarthria and dysphagia in these individuals, which may indicate the rate of progression over a given time interval.<br><br>CONCLUSION: There is a decline in speech and swallowing over ten years in ALS. The bulbar type leads to a faster decline in the studied functions than the spinal type.}, }
@article {pmid39936380, year = {2025}, author = {Lero, CM and Yang, A and Everett, E and Pitzer, KA and McCoy Gross, K and Washington, KT}, title = {Associations Between End-Stage ALS Care and Specialty Palliative Care: A Hypothesis-Generating Study.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {4}, pages = {632-638}, pmid = {39936380}, issn = {1097-4598}, support = {T32 MH019960/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/mortality ; Male ; Female ; *Palliative Care ; Middle Aged ; Aged ; Terminal Care ; Hospice Care ; Aged, 80 and over ; }, abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) care is typically delivered via a multidisciplinary approach that may include specialty palliative care (SPC). Opportunities for SPC to enhance ALS care have been identified; however, investigation of these proposed benefits is scant. In this exploratory study, investigators examined associations between receipt of SPC and variables particularly relevant to end-stage ALS.<br><br>METHODS: Researchers reviewed electronic health records for all patients with ALS who received standard ALS care from one Midwestern US academic medical center and died between January 1, 2020, and June 30, 2022 (N&#x2009;=&#x2009;156). Receipt of SPC, duration of illness, hospice enrollment and length of service, report of a healthcare proxy, documentation of a healthcare proxy, participation in goals of care conversations, and location of death were examined.<br><br>RESULTS: Patients who received SPC (59%), had lower mean forced vital capacity (FVC) (p&#x2009;<&#x2009;0.05), and more often used respiratory support (p&#x2009;<&#x2009;0.001), participated in goals of care conversations (p&#x2009;<&#x2009;0.001), reported a healthcare proxy (p&#x2009;<&#x2009;0.01), and enrolled in hospice (p&#x2009;<&#x2009;0.001) than patients who received standard care alone. No differences between groups were found in duration of illness (mean&#x2009;=&#x2009;51.7&#x2009;months), use of assistive feeding, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores (mean&#x2009;=&#x2009;32.1), documentation of a healthcare proxy, length of hospice stay (mean&#x2009;=&#x2009;47.3&#x2009;days), or location of death.<br><br>DISCUSSION: Clinical characteristics and end-of-life outcome differences between groups support further investigation of the proposed benefits of SPC regarding hospice enrollment, report of healthcare proxies, and documented goals of care conversations.}, }
@article {pmid39936266, year = {2025}, author = {Denton, TT and Carter, GT and Goddard, M and Weiss, J and Weeks, DL and Weydt, P and Russo, EB and Weiss, MD}, title = {Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.}, journal = {Muscle &amp; nerve}, volume = {}, number = {}, pages = {}, doi = {10.1002/mus.28359}, pmid = {39936266}, issn = {1097-4598}, abstract = {A unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1[G93A] mouse model of ALS. The use of CEs in SOD1[G93A] murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS.}, }
@article {pmid39936211, year = {2025}, author = {Naveed, A and Usmani, WA and Vandara, MP and Karmani, VK}, title = {Tofersen for Amyotrophic Lateral Sclerosis: A Step Forward or Another False Hope?.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {35}, number = {2}, pages = {259-260}, doi = {10.29271/jcpsp.2025.02.259}, pmid = {39936211}, issn = {1681-7168}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Treatment Outcome ; }, abstract = {Null.}, }
@article {pmid39936179, year = {2025}, author = {Morrison, AH and Jimenez, JV and Hsu, JY and Elman, L and Choi, PJ and Ackrivo, J}, title = {Identifying Daytime Hypercapnia Using Transcutaneous Carbon Dioxide Monitoring in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {4}, pages = {611-619}, pmid = {39936179}, issn = {1097-4598}, support = {K23 HL151879/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/physiopathology ; *Hypercapnia/blood/diagnosis ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; *Blood Gas Monitoring, Transcutaneous/methods ; *Carbon Dioxide/blood ; Respiratory Function Tests ; Vital Capacity/physiology ; Adult ; }, abstract = {INTRODUCTION/AIMS: Respiratory failure from hypoventilation is the most common cause of death in amyotrophic lateral sclerosis (ALS). However, ALS care rarely assesses hypercapnia, a physiologic measure of hypoventilation. We investigated the prevalence and clinical significance of daytime hypercapnia measured by transcutaneous carbon dioxide (tcCO2) monitoring in patients with ALS.<br><br>METHODS: This retrospective study included patients seen at two ALS clinics in the United States between 2012 and 2024 who had tcCO2 measured concurrently with pulmonary function tests (PFTs), which included forced vital capacity (FVC) and, at one site, maximum inspiratory pressure (MIP). We assessed the prevalence of hypercapnia (tcCO2&#x2009;>&#x2009;45&#x2009;mmHg), the sensitivity and specificity of patient symptoms and PFTs for hypercapnia, and the relationship between hypercapnia and survival.<br><br>RESULTS: Daytime hypercapnia was present in 33/328 (10%) patients at baseline. Hypercapnia was associated with an increased rate of death (aHR 2.1, 95% CI 1.4-3.3). Orthopnea or dyspnea was 70% sensitive for hypercapnia (95% CI 51%-84%). Absolute value of MIP (|MIP|)&#x2009;<&#x2009;60&#x2009;cmH2O was 95% sensitive (95% CI 74%-100%) and 22% specific (95% CI 16%-30%), FVC&#x2009;<&#x2009;50% predicted was 33% sensitive (95% CI 18%-52%) and 82% specific (95% CI 78%-87%), and FVC&#x2009;<&#x2009;80% predicted was 85% sensitive (95% CI 68%-95%) and 31% specific (95% CI 26%-36%) for hypercapnia.<br><br>DISCUSSION: TcCO2 monitoring identified strengths and weaknesses of PFTs in identifying hypercapnia in ALS. We found high sensitivity of |MIP|&#x2009;<&#x2009;60&#x2009;cmH2O and FVC&#x2009;<&#x2009;80% predicted and high specificity of FVC&#x2009;<&#x2009;50% predicted. Prospective studies should investigate the optimal clinical role for tcCO2.}, }
@article {pmid39935503, year = {2025}, author = {Tsuruta, M and Shil, S and Taniguchi, S and Kawauchi, K and Miyoshi, D}, title = {The role of cytosine methylation in regulating the topology and liquid-liquid phase separation of DNA G-quadruplexes.}, journal = {Chemical science}, volume = {16}, number = {10}, pages = {4213-4225}, pmid = {39935503}, issn = {2041-6520}, abstract = {Aberrant expansion of GGGGCC DNA repeats that form G-quadruplexes (G4) is the main cause of amyotrophic lateral sclerosis (ALS). Expanded GGGGCC repeats induce liquid-liquid phase separation (LLPS) through their interaction with cellular proteins. Furthermore, GGGGCC expansion induces cytosine methylation (mC). Previous studies have shown that even slight chemical modifications of RNAs and proteins can drastically affect their LLPS ability, yet the relationship between LLPS and epigenetic DNA modifications like mC remains unexplored. As a model system, we investigated the effects of mC on LLPS induced by GGGGCC repeat DNAs and show for the first time that mC suppresses LLPS by altering the topology of G4 from being parallel to antiparallel.}, }
@article {pmid39933444, year = {2025}, author = {Rob, M and Yousef, M and Lakshmanan, AP and Mahboob, A and Terranegra, A and Chaari, A}, title = {Microbial signatures and therapeutic strategies in neurodegenerative diseases.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {184}, number = {}, pages = {117905}, doi = {10.1016/j.biopha.2025.117905}, pmid = {39933444}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/microbiology ; *Gastrointestinal Microbiome ; Dysbiosis/microbiology ; Probiotics/therapeutic use ; Animals ; Metabolome ; Fecal Microbiota Transplantation ; Machine Learning ; Biomarkers/metabolism ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.}, }
@article {pmid39933412, year = {2025}, author = {Noli, B and Borghero, G and Mascia, MM and Hkir, M and Puligheddu, M and Cocco, C}, title = {NERP-1 modifications in amyotrophic lateral sclerosis.}, journal = {Tissue &amp; cell}, volume = {93}, number = {}, pages = {102780}, doi = {10.1016/j.tice.2025.102780}, pmid = {39933412}, issn = {1532-3072}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/blood/pathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; Motor Neurons/metabolism/pathology ; Nerve Growth Factors/metabolism/blood ; Oxidative Stress ; Cell Line ; Adult ; Protein Precursors/metabolism ; Nerve Growth Factor ; }, abstract = {VGF peptides, such as NERPs (neuroendocrine regulatory peptides 1 and 2), are derived from amino acids 282-306 and 313-350, respectively, of the human proVGF, which is produced in spinal cord motor neurons. Although certain VGF-derived peptides are changed in ALS, less is known about NERPs. Possible modulations of NERPs and additional VGF peptides (NAPP and TPGH) were investigated using specific antibodies through competitive ELISA in the plasma of ALS patients (at both the initial and advanced phases; n = 46 each vs. 46 controls). As additional controls, naïve PD patients were also enrolled (n = 19 vs. 18 controls) while the potential VGF peptide role in oxidative stress was investigated using a motoneuron-like cell line (NSC34) stressed with sodium arsenate (SA). Western blot (WB) and sephadex chromatography (SC) were used to identify the molecular weight (MW) forms recognized by the VGF antibodies. Exclusively NERP-1 immunoreactivity was changed (elevated) in all plasma samples of ALS patients (compared to controls). Therefore, the NERP-1 antibody was the sole antibody used in ELISA with PD samples and NSC-34 cells. No alterations were seen in PD samples (vs. controls) while NERP-1 immunoreactivity decreased within SA-treated cells but increased in their culture medium. The viability test performed by adding NERP-1 to the stressed cells showed no protective effect. Using WB and SC, we revealed NERP-1 antibody reactivity against various MW forms, including those compatible with the NERP-1 peptide and/or proVGF. NERP-1 is suggested as a possible ALS blood biomarker.}, }
@article {pmid39933343, year = {2025}, author = {Hatamli, K and Eritja, R and Giménez, E and Benavente, F and Gargallo, R}, title = {Resolution of complex mixtures of duplex and antiparallel triplex DNA structures by capillary electrophoresis and multivariate analysis.}, journal = {Talanta}, volume = {288}, number = {}, pages = {127616}, doi = {10.1016/j.talanta.2025.127616}, pmid = {39933343}, issn = {1873-3573}, mesh = {*Electrophoresis, Capillary/methods ; *DNA/chemistry/analysis ; Multivariate Analysis ; Nucleic Acid Conformation ; Spectrophotometry, Ultraviolet ; }, abstract = {Triplex DNA structures, which are formed by the addition of an extra strand to a target B-DNA duplex, have attracted increasing interest due to their analytical and therapeutic applications. These structures are classified into parallel and antiparallel, depending on the orientation of the Triplex-Forming Oligonucleotide (TFO) relative to the B-DNA duplex. Whereas the formation of parallel triplexes is easily detected by monitoring spectral changes in the UV region, the formation of antiparallel triplexes produces small or even no spectral variations, which makes their detection difficult and uncertain. In this study, we propose the use of capillary electrophoresis with ultraviolet absorption spectrophotometric (CE-UV) detection combined with the multivariate curve resolution-alternating least squares (MCR-ALS) chemometric method to analyse mixtures of DNA sequences capable of forming mixtures of B-DNA duplex and triplex antiparallel structures. Rapid and reproducible CE-UV analysis in hydroxypropylcellulose (HPC)-coated capillaries are done in a pH 7.4 buffer containing Mg(II) for the stabilization of the intermolecular species. Spectra measured from 220 to 300 nm along the CE-UV analysis of individual DNA strands and of their mixtures at different ratios are merged into an augmented data matrix. This is later analyzed with MCR-ALS to deconvolute characteristic pure spectra and electropherograms for each one of the CE-UV analysis considered. This procedure has allowed the resolution and detection of DNA species present in mixtures of DNA strands capable of forming duplexes, as well as antiparallel triplex structures.}, }
@article {pmid39933303, year = {2025}, author = {Zeng, JY and Huang, HW and Zhuang, SP and Wu, Y and Chen, S and Zou, ZY and Chen, HJ}, title = {Soma and neurite density imaging detects brain microstructural impairments in amyotrophic lateral sclerosis.}, journal = {European journal of radiology}, volume = {184}, number = {}, pages = {111981}, doi = {10.1016/j.ejrad.2025.111981}, pmid = {39933303}, issn = {1872-7727}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; *Neurites/pathology ; Adult ; Aged ; Brain/diagnostic imaging/pathology ; Diffusion Tensor Imaging/methods ; Diffusion Magnetic Resonance Imaging/methods ; }, abstract = {OBJECTIVE: To investigate whole-brain microstructural changes in amyotrophic lateral sclerosis (ALS) using soma and neurite density imaging (SANDI), a novel multicompartment model of diffusion-weighted imaging that estimates apparent soma and neurite density.<br><br>METHODS: This study consists of 41 healthy controls and 43 patients with ALS, whose diffusion-weighted data were acquired. The SANDI-derived (including signal fractions of soma (fsoma), neurite (fneurite), and extra-cellular space (fextra)) and diffusion tensor imaging (DTI)-derived metrics were obtained. Voxel-based analyses were performed to evaluate intergroup differences and the correlation of SANDI and DTI metrics with clinical parameters.<br><br>RESULTS: In ALS patients, fneurite reduction involved both gray matter (primarily the bilateral precentral gyri, supplementary motor area, medial frontal gyrus, anterior cingulate cortex, inferior frontal gyrus, orbital gyrus, paracentral lobule, postcentral gyrus, middle cingulate cortex, hippocampus and parahippocampal gyrus, and insula, and left anterior parts of the temporal lobe) and white matter (primarily the bilateral corticospinal tract, body of corpus callosum, and brainstem) (P <0.05 after false discovery rate correction). The fextra increment showed a similar spatial distribution in ALS patients. Interestingly, the decreased fsoma in ALS primarily located in gray matter; while, the increased fsoma primarily involved white matter. The spatial distribution of fneurite/fextra/fsoma changes was larger than that detected by conventional DTI metrics, and the fneurite/fextra/fsoma were correlated with disease severity.<br><br>CONCLUSIONS: SANDI may serve as a clinically relevant model, superior to conventional DTI, for characterizing microstructural impairments such as neurite degeneration and soma alteration in ALS.}, }
@article {pmid39933302, year = {2025}, author = {Li, H and Qiao, Z and Xiao, X and Cao, X and Li, Z and Liu, M and Jiao, Q and Chen, X and Du, X and Jiang, H}, title = {G protein-coupled receptors: A golden key to the treasure-trove of neurodegenerative diseases.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {46}, number = {}, pages = {155-168}, doi = {10.1016/j.clnu.2025.01.032}, pmid = {39933302}, issn = {1532-1983}, mesh = {Humans ; *Receptors, G-Protein-Coupled/metabolism ; *Neurodegenerative Diseases/drug therapy ; *Signal Transduction/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Parkinson Disease/drug therapy/metabolism ; }, abstract = {G protein-coupled receptors (GPCRs) are a class of transmembrane proteins that distribute in various organs extensively. They can regulate physiological functions such as perception, neurotransmission and endocrinology through the synergies of signaling pathways. At present, Food and Drug Administration (FDA) have approved more than 500 drugs targeting GPCRs to treat a variety of conditions, including neurological diseases, gastrointestinal diseases and tumors. Conformational diversity and dynamic changes make GPCRs a star target for the treatment of neurodegenerative diseases. Moreover, GPCRs can also open biased signaling pathways for G protein and β-arrestin, which has unique functional selectivity and the possibility of overcoming side effects. Some studies believe that biased drugs will be the mainstream direction of drug innovation in the future. To disclose the essential role and research process of GPCRs in neurodegenerative diseases, we firstly reviewed several pivotal GPCRs and their mediated signaling pathways in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Then we focused on the biased signaling pathway of GPCRs in these diseases. Finally, we updated the GPCR drugs under research for the treatment of neurodegenerative diseases in the clinical trials or approval. This review could provide valuable targets for precision therapy to cope with the dysfunction of neurodegenerative diseases in the future.}, }
@article {pmid39932579, year = {2025}, author = {Ando, M and Higuchi, Y and Yuan, JH and Yoshimura, A and Yano, C and Hobara, T and Kojima, F and Hiramatsu, Y and Nozuma, S and Nakamura, T and Sakiyama, Y and Hashiguchi, A and Okamoto, Y and Matsushige, T and Mitsui, J and Tsuji, S and Takashima, H}, title = {SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights.}, journal = {Journal of neurology}, volume = {272}, number = {3}, pages = {191}, pmid = {39932579}, issn = {1432-1459}, support = {2016100002B//Ministry of Health, Labour and Welfare/ ; 201442014A//Agency for Medical Research and Development/ ; 201442071A//Agency for Medical Research and Development/ ; 18H02742//JSPS KAKENHI/ ; 20K16604//JSPS KAKENHI/ ; 21K15702//JSPS KAKENHI/ ; 21H02842//JSPS KAKENHI/ ; 22K15713//JSPS KAKENHI/ ; 22K07495//JSPS KAKENHI/ ; 22K07519//JSPS KAKENHI/ ; 23K06931//JSPS KAKENHI/ ; }, mesh = {Humans ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Japan ; Adult ; Cohort Studies ; Aged ; *Peripheral Nervous System Diseases/genetics/diagnosis/physiopathology ; East Asian People ; }, abstract = {BACKGROUND: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort.<br><br>METHODS: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings.<br><br>RESULTS: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1's role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy.<br><br>CONCLUSION: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.}, }
@article {pmid39932195, year = {2025}, author = {Ruggieri, V and Scaricamazza, S and Bracaglia, A and D'Ercole, C and Parisi, C and D'Angelo, P and Proietti, D and Cappelletti, C and Macone, A and Lozanoska-Ochser, B and Bouchè, M and Latella, L and Valle, C and Ferri, A and Giordani, L and Madaro, L}, title = {Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115123}, doi = {10.1016/j.celrep.2024.115123}, pmid = {39932195}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; Mice ; *Polyamines/metabolism ; *Mice, Transgenic ; Disease Models, Animal ; Humans ; Homeostasis ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1[G93A] mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1[G93A] mice, opening new perspectives for the treatment of ALS.}, }
@article {pmid39931973, year = {2025}, author = {Xu, C and Diemant, T and Zhang, S and Liu, X and Passerini, S}, title = {Enhanced Cathode-Electrolyte Interphase for Prolonged Cycling Stability of Aluminum-Selenium Batteries Using Locally Concentrated Ionic Liquid Electrolytes.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {}, number = {}, pages = {e202500041}, doi = {10.1002/anie.202500041}, pmid = {39931973}, issn = {1521-3773}, support = {//China Sponsorship Council/ ; //China Scholarship Council/ ; //Helmholtz Association/ ; Start-up Research Fund of Southeast University4003002418//Start-up Research Fund of Southeast University/ ; }, abstract = {Al-Se batteries (ASeBs) with high theoretical specific capacity and discharge voltage are promising energy storage devices. However, the detrimental shuttle effect occurring in conventional ionic liquid electrolytes (ILEs) challenges their development. Herein, a thicker cathode/electrolyte interphase (CEI) is constructed via employing locally concentrated IL electrolytes (LCILEs) to overcome these issues. It is demonstrated that LCILEs facilitate the incorporation of Emim[+] into the electrode/electrolyte interphases, and, meanwhile, more Al-Cl species deposits are observed in the CEI. The formed CEI effectively prevents the dissolution of poly-selenides, inhibiting their related parasitic reactions. These result in ASeBs, employing the LCILE, to deliver a specific discharge capacity of 218 mAh g[-1] at 0.5 A g[-1] after 100 cycles at 20 °C, while the cell using the neat ILE only maintains 38 mAh g[-1] under the same conditions. Moreover, an Al-S cell operated in LCILEs reaches 578 mAh g[-1] at 0.1 A g[-1] after 150 cycles, which is also significantly better than 317 mAh g[-1] in the neat ILE. This study provides an LCILE-based strategy to reinforce the CEI in order to suppress the shuttle effect, realizing Al-chalcogen batteries with better performance.}, }
@article {pmid39930680, year = {2025}, author = {Guzanova, EV and Sorokina, TA and Zorkova, AV}, title = {[Nutritional care for patients with neurodegenerative diseases in the outpatient practice of a neurologist].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {1}, pages = {76-83}, doi = {10.17116/jnevro202512501176}, pmid = {39930680}, issn = {1997-7298}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/complications ; *Malnutrition/therapy ; *Ambulatory Care ; Neurologists ; Nutritional Support/methods ; Dehydration/therapy/etiology ; Amyotrophic Lateral Sclerosis/therapy/complications ; Aged ; Outpatients ; }, abstract = {Nutrition is a basic factor of health and well-being of people, affecting the quality and duration of life. Meanwhile, patients with neurodegenerative diseases of the central nervous system are particularly at risk of malnutrition and dehydration with serious health consequences. The article presents an analysis of the main causes of malnutrition in patients with neurodegenerative diseases, and considers a clinical case of including additional nutritional support in the comprehensive management of a patient with amyotrophic lateral sclerosis. The importance of screening elderly patients for the risks of malnutrition and dehydration during an outpatient medical appointment and including appropriate additional diagnostic and therapeutic (additional enteral nutrition and fluid regimen) measures in the work of an outpatient neurologist is emphasized.}, }
@article {pmid39929612, year = {2025}, author = {Chen, BL and Lu, JZ and Zhou, XM and Wen, XD and Jiang, YJ and Luo, N}, title = {[Mechanism of Daotan Xixin Decoction in treating APP/PS1 mice based on high-throughput sequencing technology and bioinformatics analysis].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {2}, pages = {301-313}, doi = {10.19540/j.cnki.cjcmm.20241011.401}, pmid = {39929612}, issn = {1001-5302}, mesh = {Animals ; Mice ; *Drugs, Chinese Herbal/pharmacology/administration &amp; dosage ; Male ; *Computational Biology ; *Mice, Inbred C57BL ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Hippocampus/drug effects/metabolism ; Mice, Transgenic ; High-Throughput Nucleotide Sequencing ; Amyloid beta-Peptides/metabolism/genetics ; Memory/drug effects ; Amyloid beta-Protein Precursor/genetics/metabolism ; Signal Transduction/drug effects ; }, abstract = {This study aims to investigate the therapeutic effect and mechanism of Daotan Xixin Decoction on APP/PS1 mice. Twelve APP/PS1 male mice were randomized into four groups: APP/PS1 and low-, medium-, and high-dose Daotan Xixin Decoction. Three C57BL/6 wild-type mice were used as the control group. The learning and memory abilities of mice in each group were examined by the Morris water maze test. The pathological changes of hippocampal nerve cells were observed by hematoxylin-eosin staining and Nissl staining. Immunohistochemistry was employed to detect the expression of β-amyloid(Aβ)_(1-42) in the hippocampal tissue. The high-dose Daotan Xixin Decoction group with significant therapeutic effects and the model group were selected for high-throughput sequencing. The differentially expressed gene(DEG) analysis, Gene Ontology(GO) analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and Gene Set Variation Analysis(GSVA) were performed on the sequencing results. RT-qPCR and Western blot were conducted to determine the mRNA and protein levels, respectively, of some DEGs. Compared with the APP/PS1 group, Daotan Xixin Decoction at different doses significantly improved the learning and memory abilities of APP/PS1 mice, ameliorated the neuropathological damage in the CA1 region of the hippocampus, increased the number of neurons, and decreased the deposition of Aβ_(1-42) in the brain. A total of 1 240 DEGs were screened out, including 634 genes with up-regulated expression and 606 genes with down-regulated expression. The GO analysis predicted the biological processes including RNA splicing and protein folding, the cellular components including spliceosome complexes and nuclear spots, and the molecular functions including unfolded protein binding and heat shock protein binding. The KEGG pathway enrichment analysis revealed the involvement of neurodegenerative disease pathways, amyotrophic lateral sclerosis, and splicing complexes. Further GSVA pathway enrichment analysis showed that the down-regulated pathways involved nuclear factor-κB(NF-κB)-mediated tumor necrosis factor-α(TNF-α) signaling pathway, UV response, and unfolded protein response, while the up-regulated pathways involved the Wnt/β-catenin signaling pathway. The results of RT-qPCR and Western blot showed that compared with the APP/PS1 group, Daotan Xixin Decoction at different doses down-regulated the mRNA and protein levels of signal transducer and activator of transcription 3(STAT3), NF-κB, and interleukin-6(IL-6) in the hippocampus. In conclusion, Daotan Xixin Decoction can improve the learning and memory abilities of APP/PS1 mice by regulating the STAT3/NF-κB/IL-6 signaling pathway.}, }
@article {pmid39929585, year = {2025}, author = {Huang, M and Stremlau, M and Zavras, J and Zivko, C and Thomas, AG and Pietri, P and Machairaki, V and Slusher, BS}, title = {Neutral sphingomyelinase 2: A promising drug target for CNS disease.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {102}, number = {}, pages = {65-101}, doi = {10.1016/bs.apha.2024.10.015}, pmid = {39929585}, issn = {1557-8925}, mesh = {Humans ; *Sphingomyelin Phosphodiesterase/metabolism/antagonists &amp; inhibitors ; Animals ; *Central Nervous System Diseases/drug therapy/metabolism/enzymology ; Enzyme Inhibitors/pharmacology/therapeutic use ; Molecular Targeted Therapy ; }, abstract = {Neutral sphingomyelinase 2 (nSMase2), encoded by the SMPD3 gene, is a pivotal enzyme in sphingolipid metabolism, hydrolyzing sphingomyelin to produce ceramide, a bioactive lipid involved in apoptosis, inflammation, membrane structure, and extracellular vesicle (EV) biogenesis. nSMase2 is abundantly expressed in the central nervous system (CNS), particularly in neurons, and its dysregulation is implicated in pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and neuroviral diseases. In this review, we discuss the critical role of nSMase2 in the CNS and its involvement in neurological as well as non-neurological diseases. We explore the enzyme's functions in sphingolipid metabolism, its regulatory mechanisms, and the implications of its dysregulation in disease pathogenesis. The chapter highlights the therapeutic potential of pharmacologically targeting nSMase2 with small molecule inhibitors and emphasizes the need for further research to optimize inhibitor specificity and efficacy for clinical applications. By understanding the multifaceted roles of nSMase2, we aim to provide insights into novel therapeutic strategies for treating complex diseases associated with its dysregulation.}, }
@article {pmid39929580, year = {2025}, author = {Matheoudakis, K and O'Connor, JJ}, title = {Modulatory and protective effects of prolyl hydroxylase domain inhibitors in the central nervous system.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {102}, number = {}, pages = {211-235}, doi = {10.1016/bs.apha.2024.10.006}, pmid = {39929580}, issn = {1557-8925}, mesh = {Humans ; Animals ; *Prolyl-Hydroxylase Inhibitors/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Central Nervous System/metabolism/drug effects ; }, abstract = {Oxygen is essential for all mammalian species, with complex organs such as the brain requiring a large and steady supply to function. During times of low or inadequate oxygen supply (hypoxia), adaptation is required in order to continue to function. Hypoxia inducible factors (HIF) are transcription factors which are activated during hypoxia and upregulate protective genes. Normally, when oxygen levels are sufficient (normoxia) HIFs are degraded by oxygen sensing prolyl hydroxylase domain proteins (PHD), but during hypoxia PHDs no longer exert influence on HIFs allowing their activation. Given that PHDs regulate the activity of HIFs, their pharmacological inhibition through PHD inhibitors (PHDIs) is believed to be the basis of their neuroprotective benefits. This review discusses some of the potential therapeutic benefits of PHDIs in a number of neurological disorders which see hypoxia as a major pathophysiological mechanism. These include stroke, Parkinson's disease, and amyotrophic lateral sclerosis. We also explore the potential neuroprotective benefits and limitations of PHDIs in a variety of disorders in the central nervous system (CNS). Additionally, the activation of HIFs by PHDIs can have modulatory effects on CNS functions such as neurotransmission and synaptic plasticity, mechanisms critical to cognitive processes such as learning and memory.}, }
@article {pmid39929112, year = {2025}, author = {Zhao, H and Liu, L and Zeng, Y and Nie, X and Wang, J and Bai, L and Pan, L}, title = {Identification of metabolic enzyme genes linked to mesosulfuron-methyl resistance in Bromus japonicus.}, journal = {Plant physiology and biochemistry : PPB}, volume = {221}, number = {}, pages = {109609}, doi = {10.1016/j.plaphy.2025.109609}, pmid = {39929112}, issn = {1873-2690}, mesh = {*Sulfonylurea Compounds/pharmacology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; Acetolactate Synthase/genetics/metabolism ; Plant Proteins/genetics/metabolism ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Genes, Plant ; }, abstract = {Bromus japonicus is a very troublesome weed in major winter wheat fields in China and substantially reduces wheat yield. Resistance to acetolactate synthase (ALS)-inhibiting herbicides in B. japonicus has become increasingly prevalent in recent years. While the mechanism of target site resistance (TSR) to ALS-inhibiting herbicides in B. japonicus has been well elucidated, the understanding of non-target site resistance (NTSR) remains limited. In this study, we identified a B. japonicus population (BJ-NTSR-1) which has developed resistance to mesosulfuron-methyl. Compared to the mesosulfuron-methyl-susceptible population (BJ-S), the resistance level of BJ-NTSR-1 was found to be 22.56 times higher. Based on the results of ALS gene sequencing and relative expression analyses, TSR was not detected in the BJ-NTSR-1 population. Additionally, pretreatment with cytochrome P450 (CYP450) and glutathione S-transferase (GST) inhibitors did not reverse the resistance to mesosulfuron-methyl in BJ-NTSR-1 population. RNA-seq and RT-qPCR analyses revealed that, three uridine 5'-diphospho-glucosyl transferase (UGT) genes (UGT76F1, UGT88F5, and UGT85A1), four ATP-binding cassette (ABC) transporter genes (ABCB19s, ABCG1, and ABCB21), and three CYP450 genes (CYP71C1, CYP71C2, and CYP72A15) are significantly upregulated in the BJ-NTSR-1 population. Among these genes, the overexpression of ABCG1 enhanced yeast resistance to mesosulfuron-methyl. These genes are likely involved in mediating NTSR to mesosulfuron-methyl in the BJ-NTSR-1 population. This study presents the first global report that CYP450, UGT, and ABC transporter genes may collectively mediate NTSR to ALS-inhibiting herbicides in Brome species.}, }
@article {pmid39928509, year = {2025}, author = {Scafide, KN and Arundel, L and Assas, G and King, EL}, title = {Pressure injury detection using alternate light: a proof-of-concept study.}, journal = {Journal of wound care}, volume = {34}, number = {Sup2}, pages = {S17-S23}, doi = {10.12968/jowc.2023.0304}, pmid = {39928509}, issn = {0969-0700}, mesh = {Humans ; *Pressure Ulcer/diagnostic imaging ; Female ; Male ; Middle Aged ; *Proof of Concept Study ; Adult ; Aged ; Skin Pigmentation ; Light ; Ultrasonography ; Aged, 80 and over ; Contusions ; }, abstract = {OBJECTIVE: Identification of early-stage pressure injuries (PIs) during visual skin assessment may be subjective and unreliable. An alternate light source (ALS) has been shown to increase the probability of detecting evidence of bruises on individuals with darker skin tones. Bruises and early-stage PIs are often difficult to identify, especially in those with darker skin tones, where melanin concentration is high. Given the effect skin pigmentation has on detecting both types of cutaneous injuries, this proof-of-concept study aimed to describe the characteristics of Stage 1 PIs and deep tissue PIs as viewed under an ALS.<br><br>METHOD: Eligible participants were first examined by a certified wound ostomy continence nurse using environmentally available white light. A blinded second examiner then evaluated the size of the potential tissue impairment using violet (406nm) and blue (448nm) ALS viewed through yellow and orange goggles, respectively. Portable ultrasound was used to confirm tissue involvement. Data were summarised using descriptive statistics.<br><br>RESULTS: The study included 10 participants (40% of whom were from minority racial/ethnic groups) with a mean Braden Scale score of 11.1. The majority of PIs (80%) involved deep tissue and were located on lower extremities (60%). The median PI size was larger by 17.5cm[2] and 13.7cm[2], respectively, using ALS compared with white light when viewed under violet and blue wavelengths. Ultrasound data were limited to non-extremity regions (n=3 participants) with hypoechoic areas noted as being 10-13mm in thickness and up to 16.7mm deep.<br><br>CONCLUSION: Evidence of tissue damage that extended beyond that visualised under white light was noted with ALS. Usefulness of ultrasound was limited over bony prominences where there was too little subcutaneous tissue. Further research is warranted to investigate the potential application of ALS for the early detection of PIs.}, }
@article {pmid39928236, year = {2025}, author = {Kaspute, G and Ramanavicius, A and Prentice, U}, title = {Natural drug delivery systems for the treatment of neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {217}, pmid = {39928236}, issn = {1573-4978}, support = {S-MIP-24-111//Research Council of Lithuania (LMTLT)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Drug Delivery Systems/methods ; *Biological Products/administration &amp; dosage ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Liposomes ; Anti-Inflammatory Agents/administration &amp; dosage ; Nanoparticles/chemistry ; }, abstract = {Today, herbal drugs are prominent in the pharmaceutical industry due to their well-known therapeutic and side effects. Plant-based compounds often face limitations such as poor solubility, low bioavailability, and instability in physiological environments, restricting their therapeutic efficacy and delivery. Nanotechnology-based solutions, including nanoparticle formulations and advanced delivery systems like liposomes and transfersomes, address these issues by enhancing solubility, stability, bioavailability, and targeted delivery, thereby optimizing the therapeutic potential of phytoactive compounds. Neuroinflammation can be a cause of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, or amyotrophic lateral sclerosis. Consequently, there is a need for the optimal delivery of a pharmacological anti-inflammatory agents to the CNS. Thus, the non-invasive administration of a stable compound at a therapeutic concentration is needed to assure molecule crossing through the blood-brain barrier. Natural resources have more structural diversity and novelty than synthetic compounds, e.g. plant-derived drug products have higher molecular weights, incorporate more oxygen atoms, and are more complex. As a result, plant-derived products have unique features which can be used to effectively modulate neuroinflammation. Therefore, this review aims to identify herbal molecules capable of targeting neuroinflammation and present novel strategies for their efficient delivery.}, }
@article {pmid39927436, year = {2025}, author = {}, title = {Novel Biomarkers of FTD-ALS.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {31}, number = {1}, pages = {6}, doi = {10.1177/10738584241308752}, pmid = {39927436}, issn = {1089-4098}, }
@article {pmid39926223, year = {2025}, author = {Moore, S and Donlon, NE}, title = {Improving gastrointestinal scoring systems for predicting short-term mortality in critically ill patients.}, journal = {World journal of gastroenterology}, volume = {31}, number = {5}, pages = {102622}, pmid = {39926223}, issn = {2219-2840}, mesh = {Humans ; *Critical Illness/mortality ; *Intensive Care Units/statistics &amp; numerical data ; *Gastrointestinal Diseases/mortality/diagnosis ; Retrospective Studies ; *Severity of Illness Index ; Prognosis ; Hospital Mortality ; Predictive Value of Tests ; }, abstract = {Shen et al's retrospective study aims to compare the utility of two separate scoring systems for predicting mortality attributable to gastrointestinal (GI) injury in critically ill patients [the GI Dysfunction Score (GIDS) and the Acute Gastrointestinal Injury (AGI) grade]. The authors note that this study is the first proposal that suggests an equivalence between the ability of both scores to predict mortality at 28 days from intensive care unit (ICU) admission. Shen et al retrospectively analysed an ICU cohort of patients utilising two physicians administering both the AGI grade and GIDS score, using electronic healthcare records and ICU flowsheets. Where these physicians disagreed about the scores, the final decision as to the scores was made by an associate chief physician, or chief physician. We note that the primary reason for the development of GIDS was to create a clear score for GI dysfunction, with minimal subjectivity or inter-operator variability. The subjectivity inherent to the older AGI grading system is what ultimately led to the development of GIDS in 2021. By ensuring consensus between physicians administering the AGI, Shen et al have controlled for one of this grading systems biggest issues. We have concerns, however, that this does not represent the real-world challenges associated with applying the AGI compared to the newer GIDS, and wonder if this arbitration process had not been instituted, would the two scoring systems remain equivalent in terms of predicted mortality?}, }
@article {pmid39924298, year = {2025}, author = {Malouin-Lachance, A and Capolupo, J and Laplante, C and Hudon, A}, title = {Does the Digital Therapeutic Alliance Exist? Integrative Review.}, journal = {JMIR mental health}, volume = {12}, number = {}, pages = {e69294}, pmid = {39924298}, issn = {2368-7959}, mesh = {Humans ; *Therapeutic Alliance ; *Artificial Intelligence ; *Mental Disorders/therapy ; Telemedicine ; Psychotherapy/methods ; }, abstract = {BACKGROUND: Mental health disorders significantly impact global populations, prompting the rise of digital mental health interventions, such as artificial intelligence (AI)-powered chatbots, to address gaps in access to care. This review explores the potential for a "digital therapeutic alliance (DTA)," emphasizing empathy, engagement, and alignment with traditional therapeutic principles to enhance user outcomes.<br><br>OBJECTIVE: The primary objective of this review was to identify key concepts underlying the DTA in AI-driven psychotherapeutic interventions for mental health. The secondary objective was to propose an initial definition of the DTA based on these identified concepts.<br><br>METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) for scoping reviews and Tavares de Souza's integrative review methodology were followed, encompassing systematic literature searches in Medline, Web of Science, PsycNet, and Google Scholar. Data from eligible studies were extracted and analyzed using Horvath et al's conceptual framework on a therapeutic alliance, focusing on goal alignment, task agreement, and the therapeutic bond, with quality assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool.<br><br>RESULTS: A total of 28 studies were identified from an initial pool of 1294 articles after excluding duplicates and ineligible studies. These studies informed the development of a conceptual framework for a DTA, encompassing key elements such as goal alignment, task agreement, therapeutic bond, user engagement, and the facilitators and barriers affecting therapeutic outcomes. The interventions primarily focused on AI-powered chatbots, digital psychotherapy, and other digital tools.<br><br>CONCLUSIONS: The findings of this integrative review provide a foundational framework for the concept of a DTA and report its potential to replicate key therapeutic mechanisms such as empathy, trust, and collaboration in AI-driven psychotherapeutic tools. While the DTA shows promise in enhancing accessibility and engagement in mental health care, further research and innovation are needed to address challenges such as personalization, ethical concerns, and long-term impact.}, }
@article {pmid39923073, year = {2025}, author = {Wang, Z and Yin, Z and Sun, G and Zhang, D and Zhang, J}, title = {Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk.}, journal = {Lipids in health and disease}, volume = {24}, number = {1}, pages = {41}, pmid = {39923073}, issn = {1476-511X}, mesh = {Humans ; *Lipid Metabolism/genetics ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Liver/metabolism/pathology ; *Cholesterol, LDL/blood ; *Neurodegenerative Diseases/genetics ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Brain/metabolism/pathology ; *Alzheimer Disease/genetics/metabolism ; Parkinson Disease/genetics/metabolism ; Multiple Sclerosis/genetics/metabolism ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Female ; Risk Factors ; Male ; Apolipoprotein B-100/genetics ; }, abstract = {BACKGROUND: The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.<br><br>METHODS: Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10[-8]) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.<br><br>RESULTS: MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR&#x2009;=&#x2009;1.10, 95% CI: 1.03-1.18, P&#x2009;=&#x2009;4.23&#x2009;&#xd7;&#x2009;10&#x207b;[3]) and low-density lipoprotein cholesterol (LDLC, OR&#x2009;=&#x2009;1.10, 95% CI: 1.03-1.17, P&#x2009;=&#x2009;3.28&#x2009;&#xd7;&#x2009;10&#x207b;[3]) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.<br><br>CONCLUSIONS: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver&#x2012;brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.}, }
@article {pmid39922547, year = {2025}, author = {Rossi, S and Milani, M and Della Valle, I and Apolloni, S}, title = {Transcriptomic profiling of symptomatic and end-stage SOD1-G93A transgenic mice reveals extracellular matrix components as key players in ALS pathogenesis.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {4}, pages = {167707}, doi = {10.1016/j.bbadis.2025.167707}, pmid = {39922547}, issn = {1879-260X}, }
@article {pmid39922366, year = {2025}, author = {Kopalli, SR and Behl, T and Kyada, A and Rekha, MM and Kundlas, M and Rani, P and Nathiya, D and Satyam Naidu, K and Gulati, M and Bhise, M and Gupta, P and Wal, P and Fareed, M and Ramniwas, S and Koppula, S and Gasmi, A}, title = {Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression.}, journal = {Neuroscience}, volume = {569}, number = {}, pages = {161-183}, doi = {10.1016/j.neuroscience.2025.02.007}, pmid = {39922366}, issn = {1873-7544}, mesh = {*Neuronal Plasticity/drug effects/physiology ; Humans ; *Flavonoids/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology ; Neuroprotection/drug effects/physiology ; Disease Progression ; Signal Transduction/drug effects ; }, abstract = {Flavonoids are a broad family of polyphenolic chemicals that are present in a wide variety of fruits, vegetables, and medicinal plants. Because of their neuroprotective qualities, flavonoids have attracted a lot of interest. The potential of flavonoids to control synaptic plasticity-a crucial process underlying memory, learning, and cognitive function-is becoming more and more clear. Dysregulation of synaptic plasticity is a feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (0.4 %), Parkinson's (1-2 %), Alzheimer's (5-7 %), and Huntington's ((0.2 %)). This review discusses the molecular mechanisms via which flavonoids influence synaptic plasticity as well as their therapeutic potential in neurodegenerative diseases. Flavonoids modulate key signaling pathways such as MAPK/ERK and PI3K/Akt/mTOR to support neuroprotection, synaptic plasticity, and neuronal health, while also influencing neurotrophic factors (BDNF, NGF) and their receptors (TrkB, TrkA). They regulate neurotransmitter receptors like GABA, AMPA, and NMDA to balance excitatory and inhibitory transmission, and exert antioxidant effects via the Nrf2-ARE pathway and anti-inflammatory actions by inhibiting NF-κB signaling, highlighting their potential for treating neurodegenerative diseases. These varied reactions support the preservation of synapse function and neuronal integrity in the face of neurodegenerative insults. Flavonoids can reduce the symptoms of neurodegeneration, prevent synaptic loss, and enhance cognitive function, according to experimental studies. However, there are still obstacles to using these findings in clinical settings, such as limited bioavailability and the need for consistent dose. The focus of future research should be on improving flavonoid delivery systems and combining them with conventional medications.}, }
@article {pmid39921200, year = {2025}, author = {Shiozumi, T and Matsuyama, T and Nishioka, N and Kiguchi, T and Kitamura, T and Ohta, B and Iwami, T}, title = {Evaluation of interventions in prehospital and in-hospital settings and outcomes for out-of-hospital cardiac arrest patients meeting the termination of resuscitation rule in Japan: A nationwide database study (The JAAM-OHCA Registry).}, journal = {Resuscitation}, volume = {208}, number = {}, pages = {110530}, doi = {10.1016/j.resuscitation.2025.110530}, pmid = {39921200}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Japan/epidemiology ; Male ; Female ; *Registries ; *Emergency Medical Services/methods ; Retrospective Studies ; Aged ; *Cardiopulmonary Resuscitation/methods ; Middle Aged ; Resuscitation Orders ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Databases, Factual ; }, abstract = {BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a global health burden with low survival rates. The termination of resuscitation (TOR) rule, widely adopted internationally, aims to preserve dignity, optimize resources, and protect healthcare providers. However, prehospital TOR is not implemented in Japan, presenting legal and practical challenges. This study analyzes temporal trends in prehospital and in-hospital interventions for OHCA patients with poor predicted outcomes.<br><br>METHODS: This retrospective study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest (JAAM-OHCA) registry (June 2014-December 2021). Adult OHCA patients with medical causes were included if they fulfilled all the advanced life support (ALS) TOR rule criteria: unwitnessed arrest, no return of spontaneous circulation, no bystander-initiated cardiopulmonary resuscitation, and no automated external defibrillator use or defibrillation. Prehospital and in-hospital interventions were evaluated.<br><br>RESULTS: Among 11,334 patients meeting the inclusion criteria, 2,447 received all three ALS interventions (advanced airway management, intravenous access, and epinephrine administration). Over time, in-hospital interventions, including endotracheal intubation (56%) and epinephrine administration (82%), decreased, while advanced therapies, including coronary angiography, extracorporeal membrane oxygenation, and targeted temperature management, remained rare (<1%). The median time to TOR after hospital arrival shortened to 18&#xa0;min. In contrast, prehospital epinephrine administration increased, while advanced airway management and intravenous access decreased.<br><br>CONCLUSIONS: OHCA patients who met TOR rule showed a decrease in in-hospital interventions. Further efforts are warranted to avoid futile medical treatments and promote patient-centered care.}, }
@article {pmid39920775, year = {2025}, author = {Yousefian-Jazi, A and Kim, S and Chu, J and Choi, SH and Nguyen, PTT and Park, U and Kim, MG and Hwang, H and Lee, K and Kim, Y and Hyeon, SJ and Rhim, H and Ryu, HL and Lim, G and Stein, TD and Lim, K and Ryu, H and Lee, J}, title = {Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {16}, pmid = {39920775}, issn = {1750-1326}, support = {R01NS109537//NIH R01/ ; 2E30954//KIST Grant/ ; HU23C0217//Korea Dementia Research Project Grant/ ; 2022R1A2C3013138//National Research Foundation/ ; R01 NS109537/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *MEF2 Transcription Factors/metabolism/genetics ; Mice ; *Mitochondria/metabolism ; Humans ; *Motor Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Disease Models, Animal ; Mutation/genetics ; Enhancer Elements, Genetic/genetics ; HEK293 Cells ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear.<br><br>METHODS: Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element. To examine the alteration of MEF2C transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of MEF2C-knockdown (MEF2C-KD) in mice, we developed AAV expressing shRNA for MEF2C based on AAV-U6 promoter vector. Neuropathological alterations of MEF2C-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis.<br><br>RESULTS: Here, we show that enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits.<br><br>CONCLUSIONS: Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.}, }
@article {pmid39920055, year = {2025}, author = {Ramsden, V and McInnes, E and Wilson, P and Babl, FE and Kuhn, L and Cowie, J and Campbell, P and Middleton, S and Wilson, C and Straiton, N and Tavender, E}, title = {Sustainability of healthcare system improvements, programmes and interventions in acute care settings: protocol for a mixed methods systematic review.}, journal = {BMJ open}, volume = {15}, number = {2}, pages = {e094174}, pmid = {39920055}, issn = {2044-6055}, mesh = {Humans ; *Systematic Reviews as Topic ; *Delivery of Health Care/organization &amp; administration ; Research Design ; Quality Improvement/organization &amp; administration ; }, abstract = {INTRODUCTION: Sustaining evidence-based care is challenging in all clinical settings. Acute care settings have a unique set of contextual factors that may impact sustainability (eg, fast-paced, regular staff turnover). Much of the previous research explores sustainability across undifferentiated healthcare settings making it difficult to determine factors that influence sustainability in acute care settings. The aim of this review is to identify facilitators and barriers that influence the delivery of sustained healthcare interventions (eg, integration of clinical guidelines) within adult and paediatric hospital-based acute care settings.<br><br>METHODS AND ANALYSIS: A mixed methods systematic review updating Cowie et al's (which included studies from 2008 to 2017) previously published systematic review will be conducted. The following databases will be searched: Medline, Embase, Cochrane Database of Systematic Reviews, CINAHL and Allied and Complementary Medicine (AMED), from November 2017 to the present for studies published in English. Relevant reference lists of included studies will be manually searched. Empirical quantitative and qualitative studies that report the sustainability of an intervention or programme in acute care settings using a theoretical framework(s), model(s) or theory(ies) to explore facilitators and barriers, will be included. Studies will be exported into Covidence (Melbourne) and pairs of reviewers will independently screen abstracts and full-text studies. The discussion will be used to resolve any disagreements and a third coauthor enlisted should a consensus not be reached. Two independent coauthors will extract key study characteristics and assess each study's quality. Data will be extracted using Covidence (Melbourne). Evidence tables will be used to present descriptive data. Facilitators and barriers will be mapped to the Consolidated Framework for Sustainability Constructs in Healthcare and a narrative approach will be used to present key findings.<br><br>ETHICS AND DISSEMINATION: No primary data will be collected so formal ethical approval is not required. Findings will be disseminated through peer-reviewed publications, presented at international conferences and on social media.<br><br>PROSPERO REGISTRATION NUMBER: PROSPERO CRD42024547535.}, }
@article {pmid39918735, year = {2025}, author = {Wentzel, A and Smith, W and Jansen van Vuren, E and Kruger, R and Breet, Y and Wonkam-Tingang, E and Hanchard, NA and Chung, ST}, title = {Allostatic load and cardiometabolic health in a young adult South African population: the African-PREDICT study.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {328}, number = {3}, pages = {H581-H593}, doi = {10.1152/ajpheart.00845.2024}, pmid = {39918735}, issn = {1522-1539}, support = {//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; //South African Medical Research Council (SAMRC)/ ; //South African National Research Foundation (SA-NRF)/ ; //Newton Fund (NF)/ ; //Pfizer (South Africa)/ ; //Boeringer-Ingelheim (South Africa)/ ; //Norvatis (South Africa)/ ; //MediClinic Hospital Group (South Africa)/ ; //Roche Holding | Roche Diagnostics (Roche Diagnostics Corporation)/ ; }, mesh = {Humans ; Adult ; Male ; Female ; *Allostasis ; South Africa/epidemiology ; Young Adult ; Prospective Studies ; Blood Pressure ; Cardiometabolic Risk Factors ; Cardiovascular Diseases/physiopathology/epidemiology ; Biomarkers/blood ; Prediabetic State/physiopathology/epidemiology/blood ; Black People ; Masked Hypertension/physiopathology/epidemiology/diagnosis ; Dehydroepiandrosterone/blood ; Risk Assessment ; Hydrocortisone/blood/metabolism ; C-Reactive Protein/metabolism ; Age Factors ; Risk Factors ; }, abstract = {Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile by using a tiered approach stratified by age [emerging adults (EA) aged 20-24 yr vs. young adults (YA) aged 25-30 yr] and ALS (high vs. low). In 1,054 healthy participants of the African Prospective Study on Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT), we determined: 1) ALS in EA versus YA; 2) the relationship between ALS and cardiovascular (CV) health, and 3) the odds of high ALS > 4 to identify masked hypertension (HT) and prediabetes as cardiometabolic outcomes. A nine-component, four-domain ALS was compiled: neuroendocrine [dehydroepiandrosterone (DHEA), cortisol], inflammatory [interleukin-6 (IL-6), C-reactive protein (CRP)], cardiovascular [systolic blood pressure (SBP) and diastolic blood pressure (DBP)], and metabolic [total cholesterol, high density lipoprotein cholesterol (HDL-cholesterol), body mass index (BMI)]. Retinal vessel caliber, pulse wave velocity (PWV), and cardiac structure and function were assessed. Median ALS was 3 (range: 1-9). A high-ALS > 4 was more common in YA versus EA (47 vs. 35%, P = 0.032). Higher ALS associated with narrower retinal arteries (P < 0.01), greater PWV (P ≤ 0.01), lower diastolic function (P < 0.01), and left ventricular (LV) function (P < 0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular functions (all P ≤ 0.01), in EA and YA independent of traditional CVD risk factors. The composite ALS identified early-stress dysregulation in cardiometabolic health and higher odds for masked hypertension and prediabetes in young adults. Cumulative stress may be a modifiable, independent cardiometabolic risk factor in younger populations that needs further investigation.NEW &amp; NOTEWORTHY This is the first study to assess the effect of stress, as a composite allostatic load score, on micro-, macrovascular, and central cardiac features in healthy emerging and young adults, independent of traditional cardiovascular risk markers. It exemplifies independent stress-induced changes throughout the cardiovascular tree, which may increase the risk of cardiometabolic complications, masked hypertension, and prediabetes. Sustained stress may be a key etiological factor in cardiometabolic disease development in a young population.}, }
@article {pmid39917359, year = {2025}, author = {Ahmadi Marzaleh, M and Bastani, P and Raeyat Mohtashami, A and Farhadi, P and Ghanbari, S and Ravangard, R}, title = {Predicting Factors Affecting the Behavior of Healthcare Employees in the Use of Personal Protective Equipment During Epidemics Based on Godin et al's Model: A Study in Iran.}, journal = {Health services insights}, volume = {18}, number = {}, pages = {11786329251316668}, pmid = {39917359}, issn = {1178-6329}, abstract = {BACKGROUND: Protecting healthcare employees and preventing infection transmission are paramount concerns during epidemics. Predicting healthcare employees' behavior regarding the use of personal protective equipment (PPE) and identifying the related effective factors can guide educational and administrative strategies and enable timely interventions during outbreaks. This study aimed to predict factors affecting the healthcare employees' behavior in the use of PPE at Shiraz University of Medical Sciences in Iran, based on Godin et al's model.<br><br>METHODS: This was a cross-sectional and descriptive-analytical study. After reviewing the related articles and interviewing the experts and based on the model of Godin et al. (2008), a questionnaire was developed, validated, and tested for reliability using face and content validity as well as Cronbach's alpha. Collected data were analyzed using SPSS v.21 and modeled by Structural Equation Modeling (SEM) via SPSS v.21 and Smart PLS v.3 software.<br><br>RESULTS: The questionnaire was valid (CVI&#x2009;=&#x2009;86.42, CVR&#x2009;=&#x2009;81.71) and reliable (&#x3b1;&#x2009;=&#x2009;.85). The model exhibited appropriate measurement, structural, and overall fit. Beliefs about consequences, social influences, habits/past behavior, role and identity, characteristics of employees, moral norms, and beliefs about capabilities indirectly and significantly influenced behavior (P&#x2009;<&#x2009;.001). Additionally, beliefs about capabilities (P&#x2009;<&#x2009;.001), habits/past behavior (P&#x2009;=&#x2009;.001), and intention (P&#x2009;=&#x2009;.001) directly and significantly influenced PPE use behavior during epidemics.<br><br>CONCLUSION: The results emphasized the necessity of targeted interventions based on the studied model constructs within healthcare organizations. By promoting positive beliefs about PPE effectiveness and encouraging appropriate intentions and behaviors, healthcare organizations can significantly improve employee's adherence to PPE use during pandemics.}, }
@article {pmid39916983, year = {2024}, author = {González Bolívar, S and Ayoubi, R and Alende, C and Fothouhi, M and Shlaifer, I and McPherson, PS and Laflamme, C and ,  and , }, title = {A guide to selecting high-performing antibodies for VAPB (UniProt ID: O95292) for use in western blot, immunoprecipitation, and immunofluorescence.}, journal = {F1000Research}, volume = {13}, number = {}, pages = {1559}, pmid = {39916983}, issn = {2046-1402}, mesh = {Humans ; *Fluorescent Antibody Technique/methods ; *Immunoprecipitation/methods ; *Blotting, Western ; *Antibodies/immunology ; HEK293 Cells ; Vesicular Transport Proteins ; }, abstract = {VAPB is an adaptor protein known for its role as an anchor for other proteins at the endoplasmic reticulum. A mutant form of VAPB has been linked to amyotrophic lateral sclerosis and the underlying mechanisms resulting from this defect are studied by researchers in this area to uncover its implication in the disease. Here we have characterized six VAPB commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.}, }
@article {pmid39916853, year = {2025}, author = {Rosina, M and Scaricamazza, S and Riggio, F and Fenili, G and Giannessi, F and Matteocci, A and Nesci, V and Salvatori, I and Angelini, DF and Aquilano, K and Chiurchiù, V and Lettieri Barbato, D and Mercuri, NB and Valle, C and Ferri, A}, title = {Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.}, journal = {Heliyon}, volume = {11}, number = {3}, pages = {e41801}, pmid = {39916853}, issn = {2405-8440}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. The contribution of peripheral organs remains incompletely understood. We focused our attention on brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) given their role in regulating systemic energy balance. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed consistent changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting alterations such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content. In parallel, such EVs negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS mouse model and could impact on skeletal muscle homeostasis through the secretion of dysfunctional EVs.}, }
@article {pmid39916336, year = {2025}, author = {Calvi, F and Fortuna, A and Bello, L and Anglani, M and Cecchin, D and Sabbatini, D and Andrigo, C and Ferullo, M and Ruggero, S and Falda, M and Pegoraro, E and Sorarù, G}, title = {MEPs and MRI Motor Band Sign as Potential Complementary Markers of Upper Motor Neuron Involvement in Amyotrophic Lateral Sclerosis.}, journal = {European journal of neurology}, volume = {32}, number = {2}, pages = {e70055}, pmid = {39916336}, issn = {1468-1331}, support = {//EuroBiobank/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging ; Aged ; *Motor Neurons/pathology ; Retrospective Studies ; *Evoked Potentials, Motor/physiology ; Adult ; Positron-Emission Tomography ; Biomarkers ; Neural Conduction/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of both upper and lower motor neurons (UMNs and LMNs). Recognizing the involvement of UMNs is challenging because of the absence of reliable biomarkers beyond clinical evaluation.<br><br>AIM: To identify a reliable marker of UMN damage in a cohort of patients with ALS referring to the Motor Neuron Disease Clinic of the University Hospital of Padova.<br><br>METHODS: We retrospectively evaluated the clinical records of 79 patients with ALS and compared the results of various investigations, including the motor-evoked potentials (MEPs), positron emission tomography-magnetic resonance imaging (MRI) and light neurofilaments (NfLs), with the degree of UMN clinical involvement, as assessed by the Penn Upper Motor Neuron Score (PUMNS).<br><br>RESULTS: MEPs, considering the central motor conduction time (CMCT) values in both the upper and lower limbs, showed a significant correlation with the relative PUMNS subscores (p&#x2009;=&#x2009;0.01, &#x3c1;&#x2009;=&#x2009;0.4; and p&#x2009;=&#x2009;0.005, &#x3c1;&#x2009;=&#x2009;0.45, respectively). Additionally, there was a positive correlation between NfLs and PUMNS values (p&#x2009;=&#x2009;0.04, &#x3c1;&#x2009;=&#x2009;0.33). The presence of the motor band sign on MRI was associated with higher PUMNS values. Receiver operating characteristic analysis revealed that PUMNS accurately predicted abnormalities in CMCT values (specificity 86%, sensitivity 62%) and the presence of the motor band sign (specificity 58%, sensitivity 80%).<br><br>INTERPRETATION: In our cohort of patients with ALS, CMCT values proved to be the most reliable test for assessing UMN involvement, albeit the presence of the motor band sign on MRI showed higher sensitivity.}, }
@article {pmid39915090, year = {2025}, author = {Noh, MY and Kwon, MS and Oh, KW and Nahm, M and Park, J and Jin, HK and Bae, JS and Son, B and Kim, SH}, title = {miRNA-214 to predict progression and survival in ALS.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-335177}, pmid = {39915090}, issn = {1468-330X}, abstract = {BACKGROUND: Reliable biomarkers are essential for predicting the progression speed and prognosis of patients with amyotrophic lateral sclerosis (ALS). We previously identified NCK-associated protein 1 (NCKAP1) as a critical factor in the defective phagocytosis observed in induced microglia-like cells (iMGs) from patients with rapidly progressive sporadic ALS. This study explored the roles of microRNA (miRNA)-214, which targets the NCKAP1 gene, in the progression of ALS.<br><br>METHODS: The discovery cohort (n=29) was used to identify miR-214 targeting NCKAP1 genes. The validation cohort (n=132) was used to determine the clinical usability of miR-214 for predicting disease progression speed and survival time.<br><br>RESULTS: In the discovery cohort, miR-214 levels were increased in plasma and iMGs from rapidly progressive ALS participants. This finding was validated in another cohort of 132 ALS participants and 30 age-matched healthy volunteers. Plasma miR-214 levels correlated with disease progression, severity and survival, distinguishing between rapidly progressive and slowly progressive ALS. In addition, miR-214 levels also correlated with plasma neurofilament light chain (NfL) and cerebrospinal fluid inflammatory cytokines, showing specific associations with increased NfL and monocyte chemoattractant protein 1 (MCP-1). Survival prediction accuracy improved when miR-214 levels were considered with NfL or MCP-1 levels.<br><br>CONCLUSIONS: Plasma miRNA-214 could serve as a novel biomarker for predicting the progression and prognosis of ALS.}, }
@article {pmid39914774, year = {2025}, author = {Zamani, A and Walker, AK and Wright, DK}, title = {Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106832}, doi = {10.1016/j.nbd.2025.106832}, pmid = {39914774}, issn = {1095-953X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Glymphatic System/metabolism/pathology ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; Mice, Transgenic ; Aquaporin 4/metabolism/genetics ; Magnetic Resonance Imaging ; Brain/metabolism/pathology/diagnostic imaging ; Male ; Humans ; Longitudinal Studies ; }, abstract = {Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target.}, }
@article {pmid39914266, year = {2025}, author = {Wei, D and Freydenzon, A and Guinebretiere, O and Zaidi, K and Yang, F and Ye, W and Hammar, N and Modig, K and Wray, NR and Feychting, M and Hamieh, N and Ventelou, B and Lekens, B and Gantzer, L and Durrleman, S and McRae, A and Couvy-Duchesne, B and Fang, F and Nedelec, T and , }, title = {Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {113}, number = {}, pages = {105585}, pmid = {39914266}, issn = {2352-3964}, mesh = {Humans ; *Biomarkers/blood ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/blood ; *Alzheimer Disease/diagnosis/epidemiology/blood/etiology ; Australia/epidemiology ; Europe/epidemiology ; Male ; *Parkinson Disease/diagnosis/epidemiology/blood/drug therapy ; Female ; Aged ; Aged, 80 and over ; Case-Control Studies ; Neurodegenerative Diseases/epidemiology/diagnosis/etiology/blood ; Risk Factors ; Middle Aged ; }, abstract = {BACKGROUND: Many studies have investigated early predictors for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, evidence is sparse regarding specific and common predictors for these diseases. We aimed to identify medication use, health conditions, and blood biomarkers that might be associated with the risk of AD, PD, and ALS ten years later.<br><br>METHODS: We conducted population-based nested case-control studies of AD, PD, and ALS using electronic medical records in Europe (France, the UK, and Sweden) and Australia. We retrieved data on medication use, diagnosed health conditions, and measured blood biomarkers from electronic medical records or biomedical cohorts. Conditional logistic regression models and meta-analysis were applied to assess the associations between these factors and the risk of receiving a diagnosis of AD, PD, or ALS.<br><br>FINDINGS: We included a total of 149,642 AD cases (mean age: 79.1-81.2 years), 252,696 PD cases (73.2-75.9 years), and 27,533 ALS cases (64.4-69.6 years). The prescription of psychoanaleptics and nasal preparations was consistently associated with an increased risk of AD, PD, and ALS 5-10 years later. Constipation and use of related medications were associated with an increased risk of AD and PD, while diabetes and use of antidiabetics were associated with a reduced risk of ALS. A higher level of triglycerides was associated with a lower risk of AD, whereas a higher level of Apolipoprotein B was associated with a lower risk of PD, 5-10 years later.<br><br>INTERPRETATION: Psychoanaleptics and nasal preparations may serve as common predictors for diagnosis of AD, PD, and ALS 5-10 years later. Conversely, the increased prevalence of constipation is specific to AD and PD, while the decreased prevalence of diabetes and use of antidiabetics is specific to ALS.<br><br>FUNDING: EU Joint Programme-Neurodegenerative Disease Research.}, }
@article {pmid39914221, year = {2025}, author = {Gusain, S and Mishra, CB and Yadav, K and Sharma, M and Saluja, D and Tiwari, M}, title = {Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {120}, number = {}, pages = {118091}, doi = {10.1016/j.bmc.2025.118091}, pmid = {39914221}, issn = {1464-3391}, mesh = {*Carbazoles/chemistry/pharmacology/chemical synthesis ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Humans ; *Superoxide Dismutase-1/metabolism/genetics/chemistry/antagonists &amp; inhibitors ; *Protein Aggregates/drug effects ; Mutation ; Animals ; Apoptosis/drug effects ; Mice ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.}, }
@article {pmid39913612, year = {2025}, author = {Thomas, EV and Han, C and Kim, WJ and Asress, S and Li, Y and Taylor, JA and Gearing, M and Fournier, CN and McEachin, ZT and Seyfried, NT and Glass, JD}, title = {ALS plasma biomarkers reveal neurofilament and pTau correlate with disease onset and progression.}, journal = {Annals of clinical and translational neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/acn3.70001}, pmid = {39913612}, issn = {2328-9503}, support = {5P01NS084974/CL/CLC NIH HHS/United States ; //American Academy of Neurology/ ; }, abstract = {OBJECTIVE: We performed a pilot screen to assess the utility of the NULISA™ (Nucleic-acid-Linked Immuno-Sandwich Assay) platform in the identification of amyotrophic lateral sclerosis (ALS) biomarkers.<br><br>METHODS: Plasma from 86 individuals (48 ALS, 18 asymptomatic C9orf72 repeat expansion carriers (AsymC9), and 20 healthy controls) was analyzed via a multiplexed NULISA&#x2122; assay that includes 120 neurodegeneration-associated proteins. Statistical analysis of NULISA&#x2122; results was performed to identify proteins differentially expressed in plasma and their correlation with disease-associated parameters.<br><br>RESULTS: ALS plasma showed elevation of the established biomarkers, neurofilament light chain (NEFL) and neurofilament heavy chain (NEFH). Compared to controls and AsymC9, microtubule-associated protein tau (MAPT), phosphorylated tau 181 (pTau181), phosphorylated tau 217 (pTau217), phosphorylated tau 231 (pTau231), and phosphorylated TDP-43 (pTDP-43) were elevated in ALS.&#x2009;NEFL levels positively correlated with pTau181, pTau217, pTau231, and pTDP-43.&#x2009;MAPT and pTDP-43 were also correlated with pTau181, pTau217 and pTau231. Elevated pTau was negatively correlated with survival and ALSFRS-R. Spinal onset ALS was associated with higher pTau181, pTau217, and pTau231.<br><br>INTERPRETATION: We confirm previous reports showing elevated pTau181 in ALS plasma and show elevation of other phosphorylated tau forms, pTau217 and pTau231, typically observed in Alzheimer's disease. We provide preliminary data showing the detection and elevation of pTDP-43-409/410 in a subset of ALS samples compared to healthy controls. Neurofilament and tau levels are highly correlated suggesting their elevation may reflect a common pathology and disease state. Total and phosphorylated tau are correlated with multiple disease measures, such as ALS duration, ALSFRS-R, and site of onset.}, }
@article {pmid39910731, year = {2025}, author = {Singh, S and Khan, S and Khan, S and Ansari, O and Malhotra, N and Shukla, SK and Narang, J}, title = {Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {4}, pages = {563-587}, doi = {10.1021/acschemneuro.4c00664}, pmid = {39910731}, issn = {1948-7193}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Biosensing Techniques/methods ; Electromyography/methods ; Biomarkers ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients' speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.}, }
@article {pmid39910638, year = {2025}, author = {Möhwald, LM and Maier, A and Grehl, T and Weyen, U and Weydt, P and Günther, R and Lingor, P and Göricke, B and Petri, S and Grosskreutz, J and Boentert, M and Cordts, I and Weishaupt, JH and Dorst, J and Münch, C and Meyer, T and Baum, P}, title = {Shared prognostic information in amyotrophic lateral sclerosis - systematic assessment of the patients' perception of neurofilament light chain and the ALS functional rating scale.}, journal = {Neurological research and practice}, volume = {7}, number = {1}, pages = {6}, pmid = {39910638}, issn = {2524-3489}, support = {Open Access Publishing Fund of Leipzig University ("Read &amp; Publish" contract with Springer Nature)//Open Access Publishing Fund of Leipzig University ("Read &amp; Publish" contract with Springer Nature)/ ; }, abstract = {BACKGROUND: In amyotrophic lateral sclerosis (ALS), neurofilament light chain (NfL) was introduced as a prognostic biomarker. More recently, NfL values can be shared on the patient's ALS app. Also, the ALS functional rating scale (ALSFRS-R) is an established patient-reported assessment of disease progression. The scale can be obtained during clinic visits or remotely. However, few systematic data are available on the patients' perception of prognostic information about NfL and ALSFRS-R and the remote sharing of these data.<br><br>METHODS: In a multicenter study, 149 ALS patients were assessed for their perception of shared information about NfL and ALSFRS-R using an investigator-designed survey and established questionnaires. The recommendation of NfL and ALSFRS-R to fellow patients was assessed using the Net Promoter Score (NPS). Burden by shared information was investigated in two distinct settings: (1) clinic information when receiving results on NfL and/or ALSFRS-R during clinic visits and (2) remote information about NfL values and self-rating of the ALSFRS-R via the ALS app. General anxiety was measured by the Fear of Progression Questionnaire - Short Form (FoP-Q-SF).<br><br>RESULTS: Information about NfL and ALSFRS-R, respectively (n&#x2009;=&#x2009;149), were regarded as relevant for patients themselves (75.2% and 77.2%) and for research (98% and 96%). The NPS showed a high recommendation rate for NfL (+&#x2009;21) and ALSFRS-R (+&#x2009;26). Only a minority of patients perceived shared information about NfL as burdensome, with a lower burden in the clinic setting (n&#x2009;=&#x2009;1, 4.2%) than in the remote setting (n&#x2009;=&#x2009;8, 12%; p&#x2009;=&#x2009;0.015). Remote digital assessment of the ALSFRS-R was well received, with a reported burden in 9.8% (n&#x2009;=&#x2009;9) of the participants. The FoP-Q-SF revealed fear of progression in 40% of the respondents (n&#x2009;=&#x2009;60).<br><br>CONCLUSIONS: This study underscored the relevance of information about NfL and ALSFRS-R from the patient's perspective. Furthermore, patients proved to appreciate the relevance of this data for ALS research. Sharing information about NfL or ALSFRS-R was rarely perceived as burdensome even in a remote setting using the ALS app. These findings pave the way for further development of the patient-centered approach to sharing prognostic information in ALS.}, }
@article {pmid39910617, year = {2025}, author = {Mai, YD and Zhang, Q and Fung, CL and Leung, SO and Chong, CH}, title = {CD22 modulation alleviates amyloid β-induced neuroinflammation.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {32}, pmid = {39910617}, issn = {1742-2094}, mesh = {Animals ; Mice ; Humans ; *Sialic Acid Binding Ig-like Lectin 2/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; *Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism ; Microglia/metabolism/drug effects ; Mice, Inbred C57BL ; Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use ; Male ; }, abstract = {Neuroinflammation is a crucial driver of multiple neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Yet, therapeutic targets for neurodegenerative diseases based on neuroinflammation still warrant investigation. CD22 has been implicated in neuroinflammatory diseases, namely AD. Specifically, plasma soluble CD22 (sCD22) level is upregulated in patients with AD. Direct experimental evidence for the role of CD22 in neuroinflammation is needed, as is a better understanding of its impact on microglia activation and therapeutic potential. Here we reported that sCD22 promotes neuroinflammation both in vivo and in vitro. sCD22 activated microglia via both p38 and ERK1/2 signaling pathway for the secretion of TNFα, IL-6 and CCL3. Moreover, sCD22 activated microglia via sialic acid binding domain and 2,6 linked sialic acid glycan on sCD22. The pivotal therapeutic potential of targeting CD22 was demonstrated in Amyloid β (Aβ) induced-neuroinflammation in hCD22 transgenic mice. Suciraslimab improved working memory and resolved neuroinflammation in vivo. Further, membrane CD22 inhibited Amyloid β (Aβ) induced-NFκB signaling pathway and mechanistic study delineated that suciraslimab suppressed Aβ-induced IL-1β secretion in human microglia and PBMC. Suciraslimab also suppressed IL-12 and IL-23 secretion in human PBMC. Moreover, suciraslimab reduced the surface expression of α4 integrin on B cells. Intriguingly, we discovered that CD22 interact with Aβ and suciraslimab enhanced internalization of CD22-Aβ complex in microglia. Our data highlights the importance of sCD22 in driving neuroinflammation and the dual mechanism of targeting CD22 to resolve Aβ-induced inflammation and promote Aβ phagocytosis.}, }
@article {pmid39910275, year = {2025}, author = {Peters, TL and Qiu, W and Yang, H and Huang, W and Hu, Y and Zou, Z and Ye, W}, title = {Associations of cachexia and frailty with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4437}, pmid = {39910275}, issn = {2045-2322}, support = {2024XH028//Postdoctoral Fund project of Fujian Medical University Union Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications ; *Cachexia/etiology ; Female ; Male ; *Frailty/complications ; Middle Aged ; Aged ; Prospective Studies ; Risk Factors ; Hand Strength ; United Kingdom/epidemiology ; Body Mass Index ; }, abstract = {In the present study, we investigated the associations of cachexia (loss of muscle, weight and fat) and frailty (loss of weight and muscle) status with the risk of developing amyotrophic lateral sclerosis, because these specific terms are rarely used in this research area. In this prospective study, we extracted cachexia and frailty status from the UK Biobank cohort to study the associations of these conditions (as determined via international classification of disease-10 codes) with amyotrophic lateral sclerosis. There was a greater risk of developing amyotrophic lateral sclerosis among individuals with cachexia and frailty status after adjusting for age, sex, income (pounds), body mass index, UK Biobank centers and smoking status. Among individuals with frailty status: a grip strength of < 21 kg, a slow walking speed, and exhaustion (more than half the days or nearly every day) increase the risk of developing amyotrophic lateral sclerosis. We believe that studying cachexia and frailty status can be used to help define and treat amyotrophic lateral sclerosis.}, }
@article {pmid39908935, year = {2025}, author = {Lu, T and Li, J and Xiao, E and Zhong, H and Deng, J and Ma, L and Ning, Z and Xiao, T}, title = {Assemblage of root-associated microbiome contributes to disparate performance of two rice genotypes under aluminum stress.}, journal = {Plant physiology and biochemistry : PPB}, volume = {220}, number = {}, pages = {109539}, doi = {10.1016/j.plaphy.2025.109539}, pmid = {39908935}, issn = {1873-2690}, mesh = {*Oryza/microbiology/genetics/drug effects ; *Aluminum/toxicity ; *Microbiota/drug effects/genetics ; *Genotype ; *Plant Roots/microbiology/drug effects/genetics ; *Stress, Physiological/genetics ; Rhizosphere ; Soil Microbiology ; }, abstract = {Aluminum (Al) toxicity severely inhibits rice growth under acidic soils, posing a significant threat to food security. The assemblies of root-associated microbiomes throughout the lifecycle of rice are hypothesized to furnish a resilient reservoir of ecological functions for rice growth performance under Al stresses. However, the mechanisms that drive the assembly of root-associated microbiomes of rice are largely unknown. In this study, we chose two rice genotypes (including aluminum-tolerant (Al-T) and aluminum-sensitive (Al-S)) as model plants to investigate the microbial assemblage of root-associated microbiome and their potential roles on the plant growth performance under Al stress. The microbial community diversity (Shannon) and evenness (Chao1) in the endosphere of the Al-T genotype gradually decreased, converging towards levels observed in the Al-S genotype. In addition, the rhizosphere and endosphere microbiomes of Al-T genotype are primarily influenced by deterministic processes, while those of Al-S genotype are more influenced by stochastic processes. Compared to Al-S genotype, Al-T genotype exhibited higher complexity and stability in its rhizosphere and endosphere microbiomes, while the rhizoplane microbiome showed the opposite trend. In the rhizosphere microbiome of the Al-T genotype, we identified Gallionellales, Rhodobacterales, and Rhizobiales as keystone taxa. Their abundance was closely associated with microbial functions, including indole-3-acetic acid (IAA) synthesis, phosphorus solubilization, glutathione (GSH) metabolism, and 1-aminocyclopropane-1-carboxylate (ACC) metabolism. In the Al-S genotype, the keystone taxa included Actinomycetales and Burkholderiales. This study offers new insights into plant adaptation to abiotic stress and underscores the significance of the assemblage of root-associated microbiome in this process.}, }
@article {pmid39908735, year = {2025}, author = {Ghannam, IAY and Hassan, RM and Abdel-Maksoud, MS}, title = {Peroxisome proliferator-activated receptors (PPARs) agonists as promising neurotherapeutics.}, journal = {Bioorganic chemistry}, volume = {156}, number = {}, pages = {108226}, doi = {10.1016/j.bioorg.2025.108226}, pmid = {39908735}, issn = {1090-2120}, mesh = {Humans ; *Peroxisome Proliferator-Activated Receptors/agonists/metabolism ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis/therapeutic use ; Molecular Structure ; }, abstract = {Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPARα agonists (fibrates), PPARγ agonists (thiazolidindiones), and PPARβ/δ agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.}, }
@article {pmid39908264, year = {2025}, author = {Hobert, MA and Helle, N and Siebert, C and Eisenhauer, A and Gledhill, M and Maetzler, W}, title = {Exploiting the Fractionation of Stable Isotopes in Biochemical Processes for Medical Diagnosis: A Narrative Review.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2024.1577}, pmid = {39908264}, issn = {2152-5250}, abstract = {Analysis of isotope distributions plays a crucial role in medical diagnostics. While radioactive and radiogenic isotopes - those that undergo or result from radioactive decay - are widely used, stable isotopes are less commonly applied despite their significant diagnostic potential. For example, calcium isotope ratio analysis is already commercially utilized for calcium loss and the early diagnosis of osteoporosis. Additionally, analyses of iron, copper, and zinc isotope ratios have been explored in various conditions, including hemochromatosis, Wilson's disease, cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. Altered isotope ratios in these diseases are thought to reflect pathophysiologically relevant processes, making them promising biomarkers. This review provides a comprehensive overview of the current and potential applications of stable isotope analysis in medicine.}, }
@article {pmid39907297, year = {2024}, author = {Čižek Sajko, M and Suklan, J and Osmanović, D and Peterlin, B}, title = {Translational Research on Polygenic Risk Scores in Common Neurodegenerative Diseases - A Scoping Review Protocol.}, journal = {Acta medica academica}, volume = {53}, number = {3}, pages = {303-308}, pmid = {39907297}, issn = {1840-2879}, mesh = {Humans ; Alzheimer Disease/genetics/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; *Multifactorial Inheritance ; Multiple Sclerosis/genetics ; *Neurodegenerative Diseases/genetics ; Parkinson Disease/genetics/diagnosis ; Research Design ; Risk Assessment ; Risk Factors ; *Translational Research, Biomedical ; Scoping Review as Topic ; }, abstract = {OBJECTIVE: The purpose of this protocol is to clearly describe the process for the scoping review we plan to conduct on the topic of polygenic risk scores (PRS) in common neurodegenerative diseases. We will present the review's objective, the strategy for evidence search, the data extraction and analysis procedure, and how the results will be presented.<br><br>METHODS: The inclusion criteria for the planned scoping review will focus on evidence sources that involve PRS applied to neurogenerative diseases such as Multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Amyotrophic lateral sclerosis in any phase of translational research, from early development to clinical implementation. This includes its use in risk prediction, early diagnosis, prognosis, and treatment decision-making. The research questions were created based on the population, context, and concept framework. We will consider both peer-reviewed papers and grey literature published in English or German for inclusion. Two independent reviewers will search for information.<br><br>CONCLUISON: The findings from the scoping review will be presented descriptively and summarized according to the research questions to illustrate the current status of translational research on PRS in common neurodegenerative diseases.}, }
@article {pmid39907139, year = {2025}, author = {Matera, AG}, title = {Chaperone dysfunction in motor neuron disease: new insights from studies of the SMN complex.}, journal = {Genetics}, volume = {229}, number = {3}, pages = {}, pmid = {39907139}, issn = {1943-2631}, support = {R35 GM136435/GM/NIGMS NIH HHS/United States ; //USA National Institutes of Health/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Muscular Atrophy, Spinal/genetics/metabolism ; Motor Neuron Disease/genetics/metabolism/pathology/etiology ; Animals ; SMN Complex Proteins/metabolism/genetics ; Molecular Chaperones/metabolism/genetics ; Motor Neurons/metabolism/pathology ; }, abstract = {Spinal muscular atrophy and amyotrophic lateral sclerosis are devastating neurodegenerative diseases characterized by motor neuron loss. Although these 2 disorders have distinct genetic origins, recent studies suggest that they share common etiological mechanisms rooted in proteostatic dysfunction. At the heart of this emerging understanding is the survival motor neuron (SMN) complex.}, }
@article {pmid39906330, year = {2024}, author = {Hruška, J and Bachmann, P and Odei, SA}, title = {Enhancing ALS disease management: exploring integrated user value through online communities evidence.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1393261}, pmid = {39906330}, issn = {1664-2295}, abstract = {INTRODUCTION: Assistive technologies (ATs) offer significant potential to improve the quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). This study explores the concept of integrated user value (IUV), focusing on five key aspects: quality, user experience, cost-effectiveness, safety, and accessibility. Understanding IUV is crucial for enhancing the development and deployment of ATs in ALS disease management.<br><br>METHODS: A systematic search approach was utilized to collect data from Facebook ALS support groups, comprising posts from individuals with ALS and their caregivers. Using a predefined set of keywords, 416 posts were analyzed. The posts were categorized based on the five aspects of IUV, and an in-depth content analysis was conducted to explore patterns, challenges, and experiences associated with AT usage.<br><br>RESULTS: The analysis revealed significant challenges across all aspects of IUV. Quality and user experience were interlinked, with users frequently citing inadequate designs and unmet customization needs. Cost-effectiveness was a key concern, with high costs and limited insurance coverage contributing to financial strain. Accessibility issues, including delays in acquiring devices and insufficient public facilities, further highlighted systemic challenges. Safety concerns emphasized the need for personalized and intuitive AT designs.<br><br>DISCUSSION: The findings underscore the importance of a holistic approach to AT development, integrating all five aspects of IUV. Recommendations include enhancing product quality, ensuring affordability, prioritizing user-centered design, and addressing accessibility gaps. Collaboration between AT designers, healthcare providers, and policymakers is essential to optimize AT value and improve the quality of life for individuals with ALS and their caregivers.}, }
@article {pmid39905402, year = {2025}, author = {Li, J and Guo, S and Sun, Q and An, N and Lin, J and Fei, Q}, title = {Bioinformatics screening and clinical validation of CircRNA and related miRNA in male osteoporosis.}, journal = {BMC musculoskeletal disorders}, volume = {26}, number = {1}, pages = {117}, pmid = {39905402}, issn = {1471-2474}, mesh = {Humans ; Male ; *RNA, Circular/genetics ; *Osteoporosis/genetics/diagnosis ; *Computational Biology ; *MicroRNAs/genetics ; Middle Aged ; Gene Regulatory Networks ; Gene Expression Profiling ; Aged ; RNA, Messenger/genetics/metabolism ; Protein Interaction Maps ; Biomarkers/blood ; Case-Control Studies ; }, abstract = {BACKGROUND: The pathogenesis of male osteoporosis (MOP) remains unclear, with the role of genetic factors attracting the attention of researchers. In the present study, we aimed to investigate critical circRNA biomarkers associated with male osteoporosis.<br><br>METHODS: RNA-sequencing was performed to investigate the circRNA expression profiles between 3 men with osteoporosis and 3 with normal mass density. Then, shared mRNAs between host genes acquired in this present study and mRNAs acquired in previous study were identified to screen vital circRNAs associated with male osteoporosis. PPI networks of shared mRNAs were constructed and the hub genes in the PPI networks were identified with CytoHubba, a plugin in Cytoscape software (3.10.1). Finally, a ceRNA network of four circRNAs derived from three hub genes was constructed. Validation experiments were performed on selected circRNAs and related miRNAs in this ceRNA network using peripheral blood clinical samples.<br><br>RESULTS: In total, 657 circRNAs were detected in male osteoporosis. The shared mRNAs were significantly enriched in the metabolic pathways, RNA transport, Ubiquitin mediated proteolysis and Amyotrophic lateral sclerosis. Then, three genes, including SETD2, ATM and XPO1, were identified as hub genes with four algorithms. Ultimately, the ceRNA network, involving 4 circRNAs, 40 miRNAs, and 592 mRNAs, was obtained. Using 35 clinical samples, three potential circRNAs and three miRNAs associated with male osteoporosis were selected for validation. It was ultimately found that three miRNAs were upregulated in MOP, while hsa-circ-9130, novel_circ_0014940 and hsa-circ-0054894 were upregulated, hsa-circ-2484 and novel_circ_0033084 were downregulated in patients with MOP.<br><br>CONCLUSION: We emphasized the roles of several significantly up- and down-regulated circRNAs and four circRNAs derived from three hub genes in male osteoporosis. Differences in expression were confirmed for three miRNAs and five circRNAs in the ceRNA network among patients with male osteoporosis.}, }
@article {pmid39904421, year = {2025}, author = {Dragoni, F and Garofalo, M and Di Gerlando, R and Rizzo, B and Bordoni, M and Scarian, E and Viola, C and Bettoni, V and Fiamingo, G and Tornabene, D and Scanu, L and Pansarasa, O and Diamanti, L and Gagliardi, S}, title = {Whole transcriptome analysis of unmutated sporadic ALS patients' peripheral blood reveals phenotype-specific gene expression signature.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106823}, doi = {10.1016/j.nbd.2025.106823}, pmid = {39904421}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis ; Female ; Male ; Middle Aged ; *Phenotype ; Aged ; *Transcriptome ; *Gene Expression Profiling/methods ; Adult ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder. According to clinical criteria, ALS patients can be classified into eight subgroups: classic, bulbar, pyramidal, pure lower motor neuron, flail arm, pure upper motor neuron, flail leg, and respiratory. There are no well-established molecular biomarkers for early diagnosis, prognosis, and progression monitoring of this fatal disease. Classification based on clinical phenotypes could be associated with peculiar gene expression patterns shaped during lifespan, allowing the identification of specific sporadic ALS (sALS) subtypes with less heterogeneous clinical and biological features. Our objective was to define a phenotype-specific transcriptomic signature of distinct ALS phenotypes, and lay the foundation for biomarkers development. We characterized 48 sALS patients by clinical and paraclinical parameters, and subdivided them in "Classic" (n = 12), "Bulbar" (n = 10), "Flail Arm" (n = 7), "Flail Leg" (n = 10) and "Pyramidal" (n = 9) phenotypes. RNAs extracted from patients' PBMCs and 19 controls were sequenced. Our analysis allowed the visualization of gene expression differential clusters between patients and controls. Interestingly, only one gene (Y3_RNA, a misc_RNA component of the Ro60 ribonucleoprotein involved in cellular response to interferon-alpha) was upregulated at different levels across all phenotypes, whereas other genes appeared phenotype-specific. The work proposed stress the innovative view of ALS as a multi-systemic disorder rather than a pure motor neuron-associated and 'neurocentric' pathology. The possibility to cluster ALS patients based on their molecular signature pave the way for future personalized clinical trials and early diagnosis.}, }
@article {pmid39902643, year = {2025}, author = {Abad-Yang, N and Raguseo, F and Di Michele, L and Patani, R and Di Antonio, M}, title = {The potential of multimolecular G-quadruplex structures for targeted treatment of Amyotrophic Lateral Sclerosis.}, journal = {Expert opinion on therapeutic targets}, volume = {29}, number = {1-2}, pages = {1-4}, doi = {10.1080/14728222.2025.2463361}, pmid = {39902643}, issn = {1744-7631}, }
@article {pmid39902522, year = {2025}, author = {Yu, WQ and Zhao, LX and Bian, Y and Zhang, PX and Jia, L and Zhao, DM and Fu, Y and Ye, F}, title = {Pharmacophore Recombination Design, Synthesis, and Bioactivity of Ester-Substituted Pyrazole Purine Derivatives as Herbicide Safeners.}, journal = {Journal of agricultural and food chemistry}, volume = {73}, number = {6}, pages = {3341-3352}, doi = {10.1021/acs.jafc.4c07027}, pmid = {39902522}, issn = {1520-5118}, mesh = {*Herbicides/chemistry/pharmacology/chemical synthesis ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; *Purines/chemistry/pharmacology ; *Molecular Docking Simulation ; *Acetolactate Synthase/metabolism/antagonists &amp; inhibitors/chemistry/genetics ; *Drug Design ; Triticum/chemistry/drug effects ; Structure-Activity Relationship ; Sulfonylurea Compounds/chemistry/pharmacology ; Molecular Structure ; Plant Proteins/chemistry/metabolism ; Esters/chemistry/pharmacology ; Enzyme Inhibitors/chemistry/pharmacology/chemical synthesis ; Pharmacophore ; }, abstract = {Mesosulfuron-methyl, an acetolactate synthase (ALS) inhibitor primarily applied to wheat and rye, can injure or even kill wheat crops. Herbicide safeners can improve the herbicide resistance of crops without reducing the herbicidal effect on targeted weed species. Herein, we present a series of pyrazole purine derivatives with the primary structure of the natural product cytokinin and commercialized safener mefenpyridyl, designed using the pharmacophore recombination method. The title compounds were synthesized and characterized using infrared spectroscopy, [1]H and [13]C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. A bioactivity assay proved that most of the target compounds can reduce the wheat phytotoxicity of mesosulfuron-methyl. Measurements of chlorophyll and glutathione contents, along with other enzyme activity assays, confirmed that compounds I-15 and I-13 exhibit higher safety activities compared with the mefenpyr-diethyl safener. Molecular structure comparisons demonstrated that I-15 is more readily absorbed and disseminated through the crop than the commercialized safener mefenpyr-diethyl. Molecular docking models and molecular dynamics simulations elucidated the protective mechanism of safeners; specifically, compound I-15 competitively binds to the ALS active site with mesosulfuron-methyl. The current study reveals the potential of pyrazole purine derivatives in the future discovery of novel herbicide safeners.}, }
@article {pmid39902127, year = {2024}, author = {Ma, J and Wang, H and Gui, Z and Yang, Y}, title = {Unveiling the role of SYNGR4 in breast cancer development: a novel target for immunotherapy.}, journal = {Frontiers in oncology}, volume = {14}, number = {}, pages = {1490073}, pmid = {39902127}, issn = {2234-943X}, abstract = {INTRODUCTION: SYNGR4 is considered to be one of the causative genes for amyotrophic lateral sclerosis, but its role in breast cancer development has not been revealed.<br><br>METHODS: The expression of SYNGR4 in a variety of malignancies including breast cancer was analyzed using Genotype Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA) databases and verified by specimens collected from our center. The effect of SYNGR4 on breast cancer prognosis was analyzed using bioinformatics and possible pathways by which this molecule affects breast cancer prognosis were explored. The effect of SYNGR4 on immune infiltration of breast cancer was analyzed using GSVA, and the effects of SYNGR4 on breast cancer proliferation, migration, and tumor-associated macrophage polarization in cancer foci were verified by cellular and animal experiments, respectively.<br><br>RESULTS: SYNGR4 is highly expressed in a variety of malignant tumors, including breast cancer, and affects the prognosis of breast cancer patients. This may be a volatile effect through Organelle fission, chromosome segregation, nuclear division, etc. SYNGR4 overexpression affects breast cancer proliferation, migration, and tumor immune infiltration, and promotes breast cancer tumor-associated macrophage polarization toward M2.<br><br>DISCUSSION: SYNGR4 overexpression can affect the prognosis of breast cancer patients by promoting M2 polarization of tumor-associated macrophages in breast cancer, and this molecule may be a novel target for breast cancer immunotherapy.}, }
@article {pmid39901730, year = {2025}, author = {Wu, W and Wang, X and Xu, Y and Ma, C and Qian, X and Qiu, W}, title = {Neuropathological comorbidity, genetics and cognition in a Chinese community-based autopsy cohort.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf039}, pmid = {39901730}, issn = {1460-2156}, abstract = {Neurodegenerative comorbidities are common and critical, yet data specific to the Chinese population remains limited. The study aims to investigate the prevalence and associations of neuropathologic changes and comorbidities, and their correlation with genetics and cognition in a community-dwelling autopsy cohort in China. Datasets of 610 participants were obtained from the National Human Brain Bank for Development and Function at the Chinese Academy of Medical Sciences/Peking Union Medical College. Neuropathological changes analysed included Alzheimer's disease neuropathological change (ADNC) (n = 331); α-synucleinopathies (n = 124) with 120 Lewy body disease (LBD) and 4 multiple system atrophy; limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) (n = 341); primary age-related tauopathy (PART) (n = 231); argyrophilic grain disease (AGD) (n = 107); age-related tau astrogliopathy (ARTAG) (n = 144); cerebral amyloid angiopathy (CAA) (n = 183); hippocampus sclerosis (HS) (n = 46). Frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and amygdala-predominant LBD are rare. Descriptive statistics and logistic regression models were used to assess the neuropathological associations. Increased age at death was correlated with increased severity in ADNC, LBD, and LATE-NC, as well as with a higher number of comorbidities. APOE ε4 allele frequency in the present autopsy cohort was 13.63%. The presence of the APOE ε4 allele was linked to an advanced ADNC stage and increased comorbidities. The co-pathology prevalence varied by pathologies, with notable increases in specific subgroups: within the ADNC subgroups, LBD, LATE-NC, CAA, and HS were more frequent in advanced stages; in the LATE-NC subgroups, ADNC, CAA, and ARTAG increased, while PART decreased in higher LATE-NC stages. PART cases presented the highest proportion of pure pathology (37.2%) compared to other groups. Advanced ADNC stages were significantly associated with higher LATE-NC stages, and vice versa. Neocortical LBD was correlated with elevated ADNC levels, and higher LATE-NC stages were associated with worsening LBD pathology. High level ADNC, neocortical LBD, and stage 3 of LATE-NC were identified as independent predictors of severe cognition status. Our study suggests that older age at death and APOE ε4 presence are the risk factors for neuropathologic comorbidities in Chinese people. The findings underscore the importance of considering comorbid neurologic diagnoses and therapies in clinical practice.}, }
@article {pmid39901566, year = {2025}, author = {Park, NY and Heo, Y and Yang, JW and Yoo, JM and Jang, HJ and Jo, JH and Park, SJ and Lin, Y and Choi, J and Jeon, H and Cha, SJ and Bae, G and Kim, D and Kim, J and Zeno, W and Park, JB and Isozumi, N and Saio, T and Kim, SH and Lee, H and Hong, BH and Nahm, M and Lee, YH and Hong, YB}, title = {Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis.}, journal = {ACS nano}, volume = {19}, number = {9}, pages = {8692-8710}, pmid = {39901566}, issn = {1936-086X}, mesh = {*Quantum Dots/chemistry ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; Animals ; *Graphite/chemistry/pharmacology ; *DNA-Binding Proteins/metabolism/chemistry ; Mice ; Humans ; Mice, Transgenic ; TDP-43 Proteinopathies/pathology/metabolism/drug therapy ; Motor Neurons/metabolism/pathology/drug effects ; Amyloid/chemistry/metabolism/antagonists &amp; inhibitors ; Disease Models, Animal ; }, abstract = {Aberrant phase separation- and stress granule (SG)-mediated cytosolic aggregation of TDP-43 in motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we found that graphene quantum dots (GQDs) potentially modulate TDP-43 aggregation during SG dynamics and phase separation. The intrinsically disordered region in the C-terminus of TDP-43 exhibited amyloid fibril formation; however, GQDs inhibited the formation of amyloid fibrils through direct intermolecular interactions with TDP-43. These effects were accompanied by attenuation of the ALS phenotype in animal models. Additionally, GQDs delayed the onset and survival of TDP-43 transgenic mouse models by enhancing motor neuron survival, reducing glial activation, and reducing the cytosolic aggregation of TDP-43 in motor neurons. In this research, we demonstrated the efficacy of GQDs on the SG-mediated aggregation of TDP-43 and the binding property of GQDs with TDP-43. Additionally, we demonstrated the clinical feasibility of GQDs using several animal models and other types of ALS caused by FUS and C9orf72. Therefore, GQDs could offer a new therapeutic approach for proteinopathy-associated ALS.}, }
@article {pmid39901378, year = {2025}, author = {San Gil, R and Walker, AK}, title = {Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {47}, number = {4}, pages = {e202400257}, pmid = {39901378}, issn = {1521-1878}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; Neurodegenerative Diseases/metabolism/genetics/pathology ; }, abstract = {Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo-transmission electron microscopy, and advancements in high-resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP-43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD.}, }
@article {pmid39900510, year = {2025}, author = {van Altena, EJE and Jansen, BHE and Vis, AN}, title = {Reply to Ignacio Puche-Sanz, Ugo Giovanni Falagario, Giorgio Gandaglia, et al's Letter to the Editor re: Evelien J.E. van Altena, Bernard H.E. Jansen, Marieke L. Korbee, et al. Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrences. Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2024.09.015.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.01.011}, pmid = {39900510}, issn = {2588-9311}, }
@article {pmid39899435, year = {2025}, author = {Blake, J and Peryer, G and Dance, R and Parke, S and Aryankhesal, A and Farquhar, M}, title = {How can healthcare professionals work with families to address misaligned expectations of recovery in brain injury rehabilitation? A scoping review.}, journal = {Brain injury}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/02699052.2025.2450603}, pmid = {39899435}, issn = {1362-301X}, abstract = {INTRODUCTION: Most survivors of severe acquired brain injuries will have significant long-term disability. During inpatient rehabilitation, families often have expectations of recovery that do not match healthcare professional opinion. This impacts on patient care, service processes, professional-family relations, and wellbeing. This review aimed to understand how family expectations are managed in this setting, and to explore potential areas of improvement.<br><br>METHOD: A scoping review was conducted by searching CINAHL, Medline, EMBASE and Web of Science. Krieger et al's 'Conceptual Building Blocks' provided a framework to analyze the data using a 'best fit' framework synthesis approach.<br><br>RESULTS: Twenty-one papers were included in the review. Six sub-themes within three overarching themes were generated, which explored recommendations for effective expectation management. The sub-themes within the 'staff behaviors' theme were 'appropriate information provision,' 'open communication' and 'prioritize family.' Sub-themes within 'system behaviors' were 'cultural change' and 'increased resource.' 'Rehabilitation as a shared process' was the third theme.<br><br>DISCUSSION: Misaligned expectations of recovery appear to reflect a range of unmet family needs related to their position within the healthcare hierarchy, professional-family communication, and their involvement in rehabilitation processes. Early identification of family and healthcare professional expectations alongside regular review may prevent misunderstanding and conflict.}, }
@article {pmid39898446, year = {2025}, author = {Boddy, SL and Simpson, RM and Walters, SJ and Bamford, H and Walsh, T and McDermott, CJ and , }, title = {Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2447916}, pmid = {39898446}, issn = {2167-9223}, support = {MCRGS-07-16-13/MCCC_/Marie Curie/United Kingdom ; }, abstract = {Objective: The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a commonly used outcome measure in clinical trials for motor neuron disease (MND) therapies. As such, understanding how differences in scores relate to patient perception of their disease status is important when interpreting ALSFRS-R data. Our study sought to estimate the minimal important difference (MID) for the ALSFRS-R, the smallest difference in scores at which patients perceive a change in their quality of life. Methods: Data were collected as part of a longitudinal, observational saliva management study, ProSec3. These included both the ALSFRS-R and a global rating of change question (GRoC), which asked participants to rate how their disease had progressed since the previous visit. Anchor-based and distribution-based methods have been used to estimate the MID of the ALSFRS-R. The MID was estimated using two methods of calculating the total ALSFRS-R score, the original summation scale method and the recently proposed interval scale method. Results: A total of 145 people with MND had longitudinal ALSFRS-R and GRoC data. Different methods estimated the ALSFRS-R MID to be in the range of 2.02-5.43 for the summation scale and 1.23-3.31 for the interval scale method over a 3-month period, the time between study visits. Using anchor-based methods our MID estimates for the ALSFRS-R are 3.8 points and 2 points, respectively. Conclusions: The results of this study can guide clinicians and researchers in the interpretation of ALSFRS-R data. However, further studies are required to more precisely estimate the ALSFRS-R MID.}, }
@article {pmid39897942, year = {2025}, author = {Quarracino, C and Capani, F and Otero-Losada, M and Rodríguez, GE and Pérez-Lloret, S}, title = {Frequency of orthostatic hypotension in the Pooled Resource Open-Access ALS Clinical Trials database.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1512357}, pmid = {39897942}, issn = {1664-2295}, abstract = {PURPOSE: To explore the frequency of orthostatic hypotension (OH) in a large sample of amyotrophic lateral sclerosis patients (ALS).<br><br>METHODS: From the PRO-ACT database, data of 1,240 ALS patients were analyzed, focusing on blood pressure and heart rate before and after standing. OH was defined as a drop in systolic/diastolic blood pressure&#x202f;>&#x202f;20/10&#x202f;mm Hg within 3&#x202f;min of standing. Neurogenic OH was diagnosed when the heart rate increase was below 15&#x202f;bpm in patients not taking medications that could affect this response.<br><br>RESULTS: At baseline, 138 (11.1%) patients showed OH, 76.1% of whom had neurogenic OH. At follow-up, 163 patients (13.1%) had OH, 71.2% with neurogenic OH. Only 22.5% of the patients with OH at baseline had OH at follow-up.<br><br>CONCLUSION: In a large sample of ALS patients, OH occurred in 11-13%, pointing to a subgroup that might require special care to avoid related complications.}, }
@article {pmid39897290, year = {2025}, author = {McBenedict, B and Hauwanga, WN and Nezam, U and Ko Oo, A and Eapi, S and Pradhan, S and Dang, NB and Cher, PW and Orsini, MA and Lima Pessôa, B}, title = {Amyotrophic Lateral Sclerosis (ALS) Type 8: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76717}, pmid = {39897290}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis type 8 (ALS8) is a rare familial subtype of ALS caused by mutations in the vesicle-associated membrane protein-associated protein B (VAPB) gene, particularly the p.P56S mutation. It is distinguished by slower disease progression and an earlier onset compared to sporadic ALS forms, along with unique clinical features such as severe cramping, fasciculations, postural tremors, and cognitive and behavioral impairments. Although current pharmacological options, such as riluzole, edaravone, and sodium phenylbutyrate/taurursodiol, provide modest benefits, they fail to address the underlying genetic mechanisms of ALS8. Emerging gene therapies, RNA-based interventions, and stem cell approaches hold promise for precision-targeted treatments but face challenges in clinical application. Symptom management strategies, including respiratory, nutritional, and psychological support, are crucial for improving patient outcomes and quality of life. Despite significant progress in understanding the genetic and molecular pathogenesis of ALS8, its rarity, phenotypic variability, and limited clinical data pose challenges to therapeutic advancements. This narrative review highlights current therapeutic strategies, the unique clinical trajectory of ALS8, and potential pathways for innovative, subtype-specific interventions, emphasizing the need for multidisciplinary and targeted approaches to optimize care for this distinct ALS subtype.}, }
@article {pmid39896335, year = {2025}, author = {Eckardt, A and Marble, C and Fern, B and Moritz, H and Kotula, C and Ke, J and Rebancos, C and Robertson, S and Nishimune, H and Suzuki, M}, title = {Muscle-specific Bet1L knockdown induces neuromuscular denervation, motor neuron degeneration, and motor dysfunction in a rat model of familial ALS.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1527181}, pmid = {39896335}, issn = {1662-4548}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by specific loss of motor neurons in the spinal cord and brain stem. Although ALS has historically been characterized as a motor neuron disease, there is evidence that motor neurons degenerate in a retrograde manner, beginning in the periphery at the neuromuscular junctions (NMJs) and skeletal muscle. We recently reported a vesicle trafficking protein Bet1L (Bet1 Golgi Vesicular Membrane Trafficking Protein Like) as a new molecule possibly linked to NMJ degeneration in ALS. In this study, we tested the hypothesis that Bet1L gene silencing in skeletal muscle could influence NMJ integrity, motor neuron function, and survival in a rat model of familial ALS (SOD1[G93A] transgenic). Small interfering RNA (siRNA) targeting the Bet1L gene was injected on a weekly basis into the hindlimb muscle of pre-symptomatic ALS and wild-type (WT) rats. After 3 weeks, intramuscular Bet1L siRNA injection significantly increased the number of denervated NMJs in the injected muscle. Bet1L knockdown decreased motor neuron size in the lumbar spinal cord, which innervated the siRNA-injected hindlimb. Impaired motor function was identified in the hindlimbs of Bet1L siRNA-injected rats. Notably, the effects of Bet1L knockdown on NMJ and motor neuron degeneration were more significant in ALS rats when compared to WT rats. Together, Bet1L knockdown induces denervation of NMJs, but also this knockdown accelerates the disease progression in ALS. Our results provide new evidence to support the potential roles of Bet1L as a key molecule in NMJ maintenance and ALS pathogenesis.}, }
@article {pmid39894843, year = {2025}, author = {Chen, L and Shen, Q and Liu, Y and Zhang, Y and Sun, L and Ma, X and Song, N and Xie, J}, title = {Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {31}, pmid = {39894843}, issn = {2059-3635}, support = {32471049//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32170984//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32200802//National Natural Science Foundation of China (National Science Foundation of China)/ ; ZR2020YQ23//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; ZR2024MC153//Natural Science Foundation of Shandong Province (Shandong Provincial Natural Science Foundation)/ ; }, mesh = {Humans ; *Iron/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Homeostasis ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Copper/metabolism ; Metals/metabolism ; Ferroptosis/genetics ; Oxidative Stress ; Zinc/metabolism ; Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; Animals ; }, abstract = {As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.}, }
@article {pmid39894561, year = {2025}, author = {Ito, T and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR-Induced Oxidative Stress and Protein Translational Impairment.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {48}, number = {2}, pages = {93-100}, doi = {10.1248/bpb.b24-00794}, pmid = {39894561}, issn = {1347-5215}, mesh = {*Oxidative Stress/drug effects ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics ; Animals ; Mice ; *NF-E2-Related Factor 2/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Protein Biosynthesis ; Cell Line ; Motor Neurons/metabolism ; Dipeptides/pharmacology ; Neuroprotective Agents/pharmacology ; C9orf72 Protein/genetics/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR-induced neurotoxicity. In this study, poly-PR-expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS.}, }
@article {pmid39894369, year = {2025}, author = {Jairath, N and Manduca, S and Que, SKT}, title = {Response to Wang et al's limitations and risks of custom GPTs in dermatology. Comment on "ReconGPT: A novel artificial intelligence tool and its potential use in post-Mohs reconstructive decision-making".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.072}, pmid = {39894369}, issn = {1097-6787}, }
@article {pmid39893487, year = {2025}, author = {Pilotto, F and Smeele, PH and Scheidegger, O and Diab, R and Schobesberger, M and Sierra-Delgado, JA and Saxena, S}, title = {Kaempferol enhances ER-mitochondria coupling and protects motor neurons from mitochondrial dysfunction and ER stress in C9ORF72-ALS.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {21}, pmid = {39893487}, issn = {2051-5960}, support = {725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; 725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; 725825//European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program/ ; }, mesh = {*Kaempferols/pharmacology ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics/drug therapy ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; *Mitochondria/drug effects/metabolism/pathology ; *Motor Neurons/drug effects/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *C9orf72 Protein/genetics/metabolism ; *Endoplasmic Reticulum/drug effects/metabolism ; Mice, Transgenic ; Male ; Female ; Mice, Inbred C57BL ; }, abstract = {Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology.}, }
@article {pmid39893047, year = {2025}, author = {Zhu, A and Hu, JC}, title = {Reply to Alireza Ghoreifi, Jaffar Hussain, Wei Phin Tan, et al's Letter to the Editor re: Alec Zhu, Mary O. Strasser, Timothy D. McClure, et al. Comparative Effectiveness of Partial Gland Cryoablation Versus Robotic Radical Prostatectomy for Cancer Control. Eur Urol Focus 2024;10:843-50.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2025.01.013}, pmid = {39893047}, issn = {2405-4569}, }
@article {pmid39891470, year = {2025}, author = {Iazzolino, B and Palumbo, F and Moglia, C and Manera, U and Grassano, M and Matteoni, E and Cabras, S and Brunetti, M and Vasta, R and Pagani, M and Mora, G and Canosa, A and Calvo, A and Chiò, A}, title = {Frequency and Early Predictors of Cognitive Deterioration in Amyotrophic Lateral Sclerosis: A Longitudinal Population-Based Study.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27194}, pmid = {39891470}, issn = {1531-8249}, support = {ALS-Care//EU Joint Programme - Neurodegenerative Disease Research/ ; Brain-Mend//EU Joint Programme - Neurodegenerative Disease Research/ ; 101017598//HORIZON EUROPE Health/ ; RF-2016-02362405//Ministero della Salute/ ; 2017SNW5MB//Ministero dell'Universit&#xe0; e della Ricerca (Department of Excellence)/ ; 20228N7573//Ministero dell'Universit&#xe0; e della Ricerca (Department of Excellence)/ ; 259867//FP7 Health/ ; }, abstract = {OBJECTIVE: The objective is to evaluate cognitive and behavioral progression and identify early predictors of these changes in a cohort of amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: A total of 161 ALS patients were tested at diagnosis (T0), and 107 were re-tested after 1&#x2009;year (T1) using cognitive/behavioral tests. All patients underwent whole-genome sequencing, and 46 patients (ALS-normal cognition [CN]) underwent [18F]Fluorodeoxyglucose positron emission tomography.<br><br>RESULTS: Of the 161 patients, 107 were re-rested at T1; non-retested patients included 10 with frontotemporal dementia and 44 who were either non-testable or deceased. At T0, 67 patients (62.6%) were classified as ALS-CN, whereas 40 (38.4%) showed some degree of cognitive/behavioral impairment. Eighteen ALS-CN patients (26.9%) experienced cognitive decline at T1. Phenoconverters had lower baseline scores in letter fluency (Letter Fluency Test [FAS]) (p&#x2009;<&#x2009;0.001), Edinburgh Cognitive and Behavioral ALS Screen (ECAS) verbal fluency score (p&#x2009;=&#x2009;0.017). Both tests were independently predictive of phenoconversion in binary logistic regression models, with optimal cut-off scores of 28.75 and 14.2, with good sensitivity and specificity. Other predictors included older age, lower education, and ALS-related genetic variants. Phenoconverters were hypometabolic in the left temporal lobe. Thirteen (32.5%) of the 40 patients with cognitive impairment at T0 worsened by T1, with FAS (p&#x2009;=&#x2009;0.02) and the ECAS verbal fluency score (p&#x2009;=&#x2009;0.023) predicting further decline.<br><br>INTERPRETATION: Approximately 30% of ALS patients experienced cognitive/behavioral decline within the first year after diagnosis. FAS and ECAS verbal fluency were predictive of cognitive phenoconversion. Our findings highlight the importance of early detection of at-risk individuals and the need for longitudinal cognitive assessments to monitor disease progression. ANN NEUROL 2025.}, }
@article {pmid39891383, year = {2025}, author = {Chen, M and Cui, H and Zhang, X and Ma, S and Guo, J and Liu, Z and Gu, D and Fan, Y}, title = {Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline-arginine) by Inducing the Expression of KPNA2/KPNB1.}, journal = {Cell biochemistry and function}, volume = {43}, number = {2}, pages = {e70053}, doi = {10.1002/cbf.70053}, pmid = {39891383}, issn = {1099-0844}, support = {//This work was supported by the National Natural Science Foundation of China (31970616, 82070505) and Jiangsu Provincial Natural Science Foundation (BK20211330)./ ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; beta Karyopherins/metabolism ; alpha Karyopherins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.}, }
@article {pmid39891231, year = {2025}, author = {Rakab, MS and Zaid, AB and Hamadein, MA and Hamadein, SA and Ashour, MAE and El-Shamia, AS and Mostafa, DA and Rateb, RM and Elashry, MA and El-Badawy, MM and Shaheen, RSB}, title = {Assessment of ABCDE approach knowledge among residents and interns in multiple Egyptian hospitals, a cross-sectional study.}, journal = {BMC medical education}, volume = {25}, number = {1}, pages = {164}, pmid = {39891231}, issn = {1472-6920}, mesh = {Humans ; Egypt ; *Internship and Residency ; Cross-Sectional Studies ; Male ; Female ; Adult ; *Clinical Competence ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach is crucial in emergency care, but there may be variability in adherence among healthcare professionals. Inconsistent application of this approach may lead to variations in patient care quality and outcomes. Identifying the factors influencing adherence can help improve training to ensure more effective application across emergency settings. This study explores the theoretical knowledge of the ABCDE approach among Egyptian resident doctors and medical interns.<br><br>METHODS: An online survey was conducted in Egypt targeting resident doctors and medical interns. Statistical analyses were performed using SPSS 26 and Excel, descriptive statistics and association tests were used to measure the relationship between knowledge and demographic factors.<br><br>RESULTS: The study included 422 medical residents and interns, with most in university hospitals. The average knowledge score of 59.1% exposed specific gaps in understanding, emphasizing deficiencies in 12 questions answered by less than 50%. Notably, 49.5% acquired ABCDE knowledge from medical school, while 28.2% had ALS/BLS courses. Encouragingly, 91.2% expressed willingness for life support training. Statistical analyses unveiled significant associations between knowledge scores and both medical practice settings and sources of ABCDE knowledge. Surgeons exhibited the lowest knowledge scores among participants, emphasizing the need for tailored interventions across specialties.<br><br>CONCLUSION: This study addresses a critical gap in ABCDE approach knowledge among Egyptian resident doctors and medical interns. The study points to the need for focused education, especially for surgeons, to improve emergency care skills and patient outcomes through continued training.}, }
@article {pmid39889925, year = {2025}, author = {Bian, Y and Fukui, Y and Ota-Elliott, RS and Hu, X and Sun, H and Bian, Z and Zhai, Y and Yu, H and Hu, X and An, H and Liu, H and Morihara, R and Ishiura, H and Yamashita, T}, title = {The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model.}, journal = {Neuroscience research}, volume = {213}, number = {}, pages = {128-137}, doi = {10.1016/j.neures.2025.01.006}, pmid = {39889925}, issn = {1872-8111}, mesh = {Animals ; Male ; *DNA-Binding Proteins/metabolism ; *Mice, Inbred C57BL ; *Disease Models, Animal ; *Stroke/metabolism/pathology ; Mice ; Infarction, Middle Cerebral Artery/metabolism ; Histone Deacetylase 6/metabolism ; Brain/metabolism ; }, abstract = {The disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43-positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.}, }
@article {pmid39889542, year = {2025}, author = {Albrecht, F and Kvist, A and Franzén, E}, title = {Resting-state functional near-infrared spectroscopy in neurodegenerative diseases - A systematic review.}, journal = {NeuroImage. Clinical}, volume = {45}, number = {}, pages = {103733}, pmid = {39889542}, issn = {2213-1582}, mesh = {Humans ; *Spectroscopy, Near-Infrared/methods/standards ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; Brain/diagnostic imaging/physiopathology ; Rest/physiology ; }, abstract = {OBJECTIVE: To systematically review and summarize alterations found in resting-state activity as measured via functional near-infrared spectroscopy (fNIRS) in neurodegenerative diseases.<br><br>BACKGROUND: fNIRS is a novel and emerging neuroimaging method suitable for a variety of study designs. Resting-state is the measure of brain activity in the absence of a task, which has been investigated for yielding information about neurodegenerative diseases, mainly using magnetic resonance imaging. We aimed to systematically review the usage of resting-state fNIRS (rsfNIRS) in neurodegenerative diseases.<br><br>INCLUSION CRITERIA: Studies investigating people diagnosed with a neurodegenerative disease and resting-state activity obtained with fNIRS using at least two channels.<br><br>METHODS: We searched three databases for publications. After the screening, 16 studies were included in the systematic review. The quality of the studies was assessed, and data were extracted. Data were qualitatively synthesized and in the case of at least 10 similar studies, a meta-analysis was planned.<br><br>RESULTS: Most studies investigated Mild cognitive impairment (50%), followed by Alzheimer's disease (25%). Other neurodegenerative diseases encompassed Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. All studies reported oxygenated hemoglobin. Still, studies were heterogeneous in terms of study design, measurement duration, fNIRS device, montage, pre-processing, and analyses. A meta-analysis was not considered possible due to this heterogeneity.<br><br>CONCLUSION: rsfNIRS shows promise in neurodegenerative disease, as most studies have observed resting-state alterations when compared to healthy controls. However, inconsistencies across studies limit data comparison and meta-analysis. Hence, we strongly advocate the application of fNIRS reporting guidelines and the establishment of rsfNIRS-specific guidelines. This will ensure reliable and comparable results in future research.}, }
@article {pmid39889424, year = {2025}, author = {Pascual, A and May, PB and Cárdenas-Martínez, A and Guerra-Hernández, J and Hunka, N and Bruening, JM and Healey, SP and Armston, JD and Dubayah, RO}, title = {Calibration of GEDI footprint aboveground biomass models in Mediterranean forests with NFI plots: A comparison of approaches.}, journal = {Journal of environmental management}, volume = {375}, number = {}, pages = {124313}, doi = {10.1016/j.jenvman.2025.124313}, pmid = {39889424}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Ecosystem ; Spain ; Models, Theoretical ; Calibration ; }, abstract = {Observations from the NASA Global Ecosystem Dynamics Investigation (GEDI) provide global information on forest structure and biomass. Footprint-level predictions of aboveground biomass density (AGBD) in the GEDI mission are based on training data sourced from sparsely distributed field plots coincident with airborne laser scanning surveys. National Forest Inventories (NFI) are rarely used to calibrate GEDI footprint biomass models because their sampling and positional accuracy prevent accurate colocation with GEDI or ALS. This omission can limit the harmonization of jurisdictional biomass estimates from NFI's and GEDI; however, there are methods available to improve the colocation of NFI plots with GEDI footprints. Focusing on Mediterranean forests in Spain, we compared different approaches to the collocation of NFI and GEDI data: (i) simulated waveforms from ALS; (ii) nearest-neighbor on-orbit GEDI waveforms; and (iii) imputed GEDI waveforms imputed to NFI plot locations using a novel geostatistical method. These methods are potential solutions to improve the local performance of biomass models and address potential local systematic deviations between GEDI and NFI estimates. We assess the advantages and limitations of these methods to locally calibrate GEDI biomass models and quantify the impact of geolocation errors in reference NFI plot data. The new biomass models from each method were used to predict footprint level AGBD, which were then gridded for a province in the North-West of Spain. It was found that the imputation approach is not sensitive to common errors in NFI plot geolocation, but it can outperform ALS-based simulation in some cases, highlighting the benefit of information from multiple GEDI footprints proximate to NFI plots for improving biomass predictions. This research provides users with benchmark of available techniques to locally-calibrate GEDI footprint biomass models.}, }
@article {pmid39887552, year = {2025}, author = {Dopler, MB and Abeer, MI and Arezoumandan, S and Cox, K and Petersen, TL and Daniel, EH and Cannon, CL and Bautista, A and Blancher, KD and Bland, AM and Bond, KJ and Davis, DA and Francois, JM and McCray, EJ and Morgan, JM and Pulliam, JL and Robinson, ZA and Taylor, MJ and Dowell, JA and Cairns, NJ and Gitcho, MA}, title = {A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.17413}, pmid = {39887552}, issn = {1742-4658}, support = {52008702//HHMI/ ; 2023004//National Science Foundation/ ; P20GM103446/GM/NIGMS NIH HHS/United States ; 0823//The Paul H. Boerger Fund of the Delaware Community Foundation/ ; R25 GM122722/GM/NIGMS NIH HHS/United States ; P20GM103653/GM/NIGMS NIH HHS/United States ; T32GM144895-03/GM/NIGMS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein-43 (TDP-43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10-15% of ALS cases that are familial, mutations in TDP-43 represent about 5% of those with a family history. We have developed an in vitro overexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP-43 (TARDBP) gene which we define as 3X-TDP-43. This overexpression model TDP-43 shows deficits in autophagy flux and colocalization of TDP-43 with stress granules. We also observe a progressive shift of TDP-43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP-43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time-dependent decreases in 3X-TDP-43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha-1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide-isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP-43. Overall, these results suggest that the 3X-TDP-43 model may provide new insights into pathophysiology and an avenue for drug screening in vitro for those suffering from ALS and related TDP-43 proteinopathies.}, }
@article {pmid39886777, year = {2025}, author = {Alkhazaali-Ali, Z and Sahab-Negah, S and Boroumand, AR and Farkhad, NK and Khodadoust, MA and Ganjali, R and Tavakol-Afshari, J}, title = {Evaluation of Safety and Efficacy of Repeated Mesenchymal Stem Cell Transplantation in Patients with Amyotrophic Lateral Sclerosis (ALS) by Investigating Patient's Specific microRNAs as Novel Biomarkers: A Clinical Trial Study.}, journal = {Current stem cell research &amp; therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/011574888X330199250106081717}, pmid = {39886777}, issn = {2212-3946}, abstract = {BACKGROUND: Since there is currently no cure for amyotrophic lateral sclerosis (ALS), it is essential to search for diagnostic biomarkers and novel treatments to reduce the severity of this disease. One of these treatment approaches is stem cell transplantation.<br><br>OBJECTIVE: This study aims to evaluate the safety and efficacy of repeated transplantation of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS by analyzing clinical and molecular data.<br><br>METHODS: This one-arm, single-center, open-label without a control group, prospective clinical trial, twenty-one confirmed ALS patients entered the study based on defined inclusion and exclusion criteria and underwent repeated stem cell transplantation (3 times BM-MSCs transplantation (1&#xd7;10^6, MSC/Kg BW per injection) concurrently intrathecally (IT) and intravenously (IV), with one-month interval). Clinical assessment using ALS functional rating scale-revised (ALSFRS) and forced vital capacity (FVC) values and also molecular investigation by evaluating specific microRNAs expression (mir206, 133a-3p, 338-3p) in patient's serum and Cerebra spinal fluid (CSF) samples were done three times during the 3-month follow-up period.<br><br>RESULT: No serious adverse effects were reported during the study. Besides, significant improvement in FVC when compared the baseline with the end of the research and the p-value was (0.036), and stability in ALSFRS was observed, and the p-value was (p=0.16) following stem cell transplantation in patients; also, the mentioned microRNA expression was non-significant (p > 0.05) as reported as well.<br><br>CONCLUSION: Our results demonstrated that repeated transplantation of BM-MSCs was a safe procedure in ALS patients, leading to delay in disease progression and improvement in clinical symptoms. Future studies are needed to confirm these results.}, }
@article {pmid39885830, year = {2025}, author = {Marthinsen, A and Gaweł, BA and Warden, GK and Górska-Ratusznik, A and Gaweł, K and Di Sabatino, M and Hallam, B}, title = {Al doped silica glass: investigation of structural response and defect interactions based on crystalline models.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {7}, pages = {3803-3809}, doi = {10.1039/d4cp04581e}, pmid = {39885830}, issn = {1463-9084}, abstract = {High purity quartz glass is an important material in high-tech industries like semiconductors and photovoltaics due to, among other properties, its good mechanical performance at high temperatures. Small amounts of Al in silica glass (in the range between 20 ppm and 100 ppm) have previously been shown to increase the viscosity of the SiO2 glass. The underlying mechanism for this increase is, however, not well understood. In this paper we report on the local structural and electronic effects of the presence of Al in the SiO2 structure by density functional theory (DFT). Comparing the quartz and cristobalite polymorphs, we found that the driving force for Al substitution is larger in the denser quartz structure compared to cristobalite, and that oxygen vacancy (Vo) formation is most stabilized in the nearest neighbour position relative to Al in both polymorphs. Al was not found to inherently strengthen the SiO2 network in the two crystalline polymorphs considered. However, our results suggest that Al preferentially substitutes Si in denser ring configurations, which combined with local Vo formation could lead to locally favourable SiO2 network reconstructions in SiO2 glasses (likely towards 6-membered rings), which could propagate causing an increase in the viscosity. Furthermore, we show that the presence of Al can lower the stability of OH groups due to increased electrostatic interactions between the substitutional Al and H2O which may also be a contributing factor in the increased viscosity of Al doped SiO2 glass. The modelling results are in line with the experimental fluorescence and FT-IR spectroscopy data confirming that the presence of Al in the glass causes formation of oxygen vacancies and correlates with a lower fictive temperature which typically corresponds to a larger average Si-O-Si angle in the glass structure. Our results suggest that Al's contribution to high glass viscosity is not solely due to the substitution of Si atoms by Al atoms in the glass structure but rather due to structural changes of the silica network the substitution causes.}, }
@article {pmid39885728, year = {2025}, author = {Gondim, F and Fernandes, JMA}, title = {Another family with ALS and homozygosity for p.Val120Leu (c.358G &gt; C) mutation of SOD1.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-2}, doi = {10.1080/21678421.2025.2457973}, pmid = {39885728}, issn = {2167-9223}, }
@article {pmid39884586, year = {2025}, author = {Ye, L and Dittlau, KS and Sicart, A and Janky, R and Van Damme, P and Van Den Bosch, L}, title = {Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways.}, journal = {Neurobiology of disease}, volume = {206}, number = {}, pages = {106815}, doi = {10.1016/j.nbd.2025.106815}, pmid = {39884586}, issn = {1095-953X}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Axon Guidance/physiology ; *Axons/pathology/metabolism ; Female ; Neuromuscular Junction/metabolism/pathology ; Male ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.}, }
@article {pmid39884579, year = {2025}, author = {Liu, WW and Wei, JC}, title = {Response to Vera et al's "Interleukin-23 inhibition associates with lower incidence of cardiovascular risk factor type diseases compared to biologic naïve patients with psoriasis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.12.044}, pmid = {39884579}, issn = {1097-6787}, }
@article {pmid39883905, year = {2025}, author = {Hollin, IL and Giler, G and Heiman-Patterson, TD and , }, title = {Health Care Delivery and Financial Considerations in Amyotrophic Lateral Sclerosis Clinics: A Survey of Clinic Directors.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210015}, pmid = {39883905}, issn = {1526-632X}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; *Delivery of Health Care/economics ; Ambulatory Care Facilities/economics ; Surveys and Questionnaires ; Patient Care Team/economics ; United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Clinical care for people living with amyotrophic lateral sclerosis (PLWALS) is directed at slowing disease progression and symptom management. The American Academy of Neurology recommends a multidisciplinary approach to providing ALS health care because observational studies show that multidisciplinary clinics (MDCs) extend survival and improve quality of life. However, providing multidisciplinary care is a challenging financial proposition. To understand how MDCs are financed, we surveyed ALS MDCs across the Northeast ALS Consortium network in the United States.<br><br>METHODS: We surveyed clinic directors in the Northeast ALS Consortium, a group of institutions equipped to provide ALS care and perform research and clinical trials in ALS. Respondents (n = 61; response rate = 49.6%) provided information regarding their care model, services, funding sources, and financial solvency between December 2020 and August 2021.<br><br>RESULTS: In 74% (n = 45) of clinics, PLWALS were seen by the entire multidisciplinary team, and in 26% (n = 16) of clinics, PLWALS were seen by the physician and triaged according to needs. In 79% (n = 48) of clinics, visit duration was &#x2265;3 hours, and on average, 8.4 services were available, compared with 6.8 in clinics lasting <3 hours. Most of the MDCs offer occupational (97%; n = 59), speech (97%; n = 59), and physical (95%; n = 58) therapies on site. The most common source of financial support was third-party nonprofits/philanthropy (92%; n = 56). Fifty-nine percent (n = 36) of clinics received financial support from their parent organizations (e.g., universities). Only 17% (n = 10) of clinics reported no deficit, and all clinics used multiple income sources.<br><br>DISCUSSION: These findings reconfirm the range of services available to PLWALS and highlight the financial challenges facing ALS MDCs. The main limitation is that recruitment was through the NEALS network which primarily includes MDCs, so we were not able to compare with non-MDCs. Since not all centers responded, there may be other differences in the characteristics of the centers that did respond and those that did not leading to some bias. Future work should support the goal of reducing reliance on funding from nonprofits and increase reimbursement from payers, so health care providers can provide high-quality ALS care and cover costs.}, }
@article {pmid39883903, year = {2025}, author = {Fournier, CN and Quinn, CC}, title = {The Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: Broke but Not Broken.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e210189}, doi = {10.1212/WNL.0000000000210189}, pmid = {39883903}, issn = {1526-632X}, }
@article {pmid39882923, year = {2025}, author = {Koltsova, E and Smotraiev, R and Nehrii, A and Zhekeev, M and Ratnaweera, H}, title = {Mechanisms for removing phosphorus species through sequential coagulation using inorganic coagulants and organic polymers.}, journal = {Water science and technology : a journal of the International Association on Water Pollution Research}, volume = {91}, number = {2}, pages = {202-218}, pmid = {39882923}, issn = {0273-1223}, mesh = {*Phosphorus/chemistry ; *Polymers/chemistry ; Water Pollutants, Chemical/chemistry ; Water Purification/methods ; Alum Compounds/chemistry ; Waste Disposal, Fluid/methods ; }, abstract = {The need for stringent phosphorus removal from domestic wastewater is increasing to mitigate eutrophication, while efficient phosphate reuse is critical due to the global phosphate crisis. Combining aluminum sulfate (ALS) with high molecular weight organic polymers achieved 95-99% removal of particles, turbidity, and phosphates, reducing ALS usage by 40%. We propose mechanisms to explain the enhanced treatment efficiency. Particle and turbidity removal is more influenced by polymer charge density than molecular weight, while orthophosphate (OP) removal is linked to a change in zeta potential from negative to positive, allowing additional OP binding through complex formation with hydrolysis products and polymers. Enhanced phospholipid (PL) removal likely results from adsorption and neutralization of micelle PL charges by intermediate positively charged aluminum hydroxyphosphate ions. Higher PL removal with low ALS doses is attributed to a two-stage dosing process that optimizes coagulant and polymer dosages. The combined removal of OP and PL improves phosphorus bioavailability, increasing the sludge's fertilizer value.}, }
@article {pmid39882298, year = {2024}, author = {Johnsen, JT and Rafaela Lima do Vale, M and Bhangaonkar, R and Nyaga, W and Ayyad, S and Ray, S}, title = {COVID-19's impact on food environment in the Indian states of Telangana, Maharashtra, West Bengal, Tamil Nadu and Punjab: a descriptive qualitative study to build further research in India's food environment resilience building.}, journal = {BMJ nutrition, prevention &amp; health}, volume = {7}, number = {2}, pages = {e000844}, pmid = {39882298}, issn = {2516-5542}, abstract = {BACKGROUND AND AIM: Globally, COVID-19 has had a profound impact on food and nutrition security. This paper aims to gather the perspective from Transforming India's Green Revolution by Research and Empowerment for Sustainable food Supplies (TIGR2ESS) Flagship Project 6 (FP-6) team on the impact of COVID-19 on the food systems in India. The responses collected will be used for further research projects after TIGR2ESS ends in March 2022.<br><br>METHOD: Members of the TIGR2ESS FP-6 team in India were invited to complete an online open-ended questionnaire with 21 questions exploring the impact of the COVID-19 pandemic on food systems and environments in India. The questionnaire and data analysis were guided by the food environment framework developed by Turner et al and the adaptations proposed by the United Nations System Standing Committee on Nutrition. Discussions and organisation of codes under the respective themes and subthemes were held online using the virtual platform Miro. 35 individual codes and 65 subcodes were agreed on. Responses were collated and analysed using the template with support from NVivo software and synthesised the relevant themes under Turner et al's framework.<br><br>RESULTS: The organisation representatives from TIGR2ESS FP-6 (n=16) captured the perceived impact of the COVID-19 on food systems and the environment from the Indian states of Maharashtra, Punjab, Tamil Nadu, Telangana and West Bengal. Negative disruptions were caused by the COVID-19 restrictions across all the themes affecting food actors and consumers. Myths and misconception on dietary intake were reported across the state affecting especially the consumption of poultry. Positive aspects such as home cooking and awareness around healthy food emerged.<br><br>CONCLUSION: Potential research areas were identified and involve the effects of supply chain resilience buidling, farmers selling their produce directly to consumer and the revival of local and traditional food's impact on diets, understanding the harm for consumers by implementing restrictions, how indigenous and local food may impact peoples' diets, how to build on the encouragement of healthy home cooking during the pandemic, investigate the negative and positive effects of digital environments during the pandemic and dispelling myths and misconception while advocating for healthy diets.}, }
@article {pmid39881481, year = {2025}, author = {Steenland, K and Tan, Y and Mullins, SM and Kidd, TE and Gong, Q and Lah, JJ}, title = {Survival of Patients at a Neurology Clinic: No Improvement Over 12 Years.}, journal = {Alzheimer disease and associated disorders}, volume = {}, number = {}, pages = {}, doi = {10.1097/WAD.0000000000000658}, pmid = {39881481}, issn = {1546-4156}, abstract = {INTRODUCTION: We previously followed Emory patients with neurodegenerative disease from 1993 to 2006. Here, we follow survivor and new patients for 2007 to 2018.<br><br>METHODS: We studied mortality from 10 different diagnostic groups among 4322 research volunteers, and compared mortality rates to controls with normal cognition, using Cox regression. We assessed mortality through the National Death Index, controlling for sex, education, race, comorbidities, and age. Supplemental analyses considered APOE and cognitive test scores.<br><br>RESULTS: Fifty-nine percent of patients died during follow-up. Mortality rate ratios, compared with controls (n=641) in descending order were 12.54, 6.61, 4.77, 4.92, 3.36, 2.25, 2.21 1.71, 1.39, and 1.17 for diagnostic groups ALS, (n=571), FTD (n=197), LBD (n=134), PD (n=584), AD (n=1118), MCI/dementia (n=82), dementia not specified (n=165), PD symptoms (n=256), vascular dementia (n=234), and MCI (n=340), respectively. Women, non-whites, those with higher education, with no comorbidities, and lower ages had lower mortality rates for most diagnostic groups. Mortality rates were higher in the presence of APOE4 variants for several diagnostic groups. Lower MMSEs predicted worse survival for most diseases. Overall, 41% of patients survived during 12 years of follow-up, compared with an expected 75% in the US population.<br><br>CONCLUSION: Survival times for different diagnostic groups have changed little over several decades.}, }
@article {pmid39880678, year = {2025}, author = {Kozlowski, MM and Strickland, A and Benitez, AM and Schmidt, RE and Bloom, AJ and Milbrandt, J and DiAntonio, A}, title = {Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {13}, pages = {}, pmid = {39880678}, issn = {1529-2401}, support = {R01 NS105645/NS/NINDS NIH HHS/United States ; R37 NS065053/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Schwann Cells/metabolism/drug effects ; Mice ; Female ; *Motor Neurons/drug effects/metabolism ; Male ; *Axons/drug effects ; Cell Survival/drug effects/physiology ; Mice, Transgenic ; Myelin Proteins/metabolism/genetics ; Mice, Inbred C57BL ; Tamoxifen/pharmacology ; }, abstract = {Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both amyotrophic lateral sclerosis (ALS) model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability.}, }
@article {pmid39880333, year = {2025}, author = {Izrael, M and Chebath, J and Molakandov, K and Revel, M}, title = {Clinical perspective on pluripotent stem cells derived cell therapies for the treatment of neurodegenerative diseases.}, journal = {Advanced drug delivery reviews}, volume = {218}, number = {}, pages = {115525}, doi = {10.1016/j.addr.2025.115525}, pmid = {39880333}, issn = {1872-8294}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Pluripotent Stem Cells ; Animals ; Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation/methods ; Clinical Trials as Topic ; }, abstract = {Self-renewal capacity and potential to differentiate into almost any cell type of the human body makes pluripotent stem cells a valuable starting material for manufacturing of clinical grade cell therapies. Neurodegenerative diseases are characterized by gradual loss of structure or function of neurons, often leading to neuronal death. This results in gradual decline of cognitive, motor, and physiological functions due to the degeneration of the central nervous systems. Over the past two decades, comprehensive preclinical efficacy (proof-of-concept) and safety studies have led to the initiation of First-in-Human phase I-II clinical trials for a range of neurodegenerative diseases. In this review, we explore the fundamentals and challenges of neural-cell therapies derived from pluripotent stem cells for treating neurodegenerative diseases. Additionally, we highlight key preclinical investigations that paved the way for regulatory approvals of these trials. Furthermore, we provide an overview on progress and status of clinical trials done so far in treating neurodegenerative diseases such as spinal cord injury (SCI), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), as well as advances in retina diseases such as Stargardt disease (a.k.a fundus flavimaculatus), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). These trials will pave the way for the development of new cell-based therapies targeting additional neurological conditions, including Alzheimer's disease and epilepsy.}, }
@article {pmid39880289, year = {2025}, author = {Chen, SJ and Li, QY and Zhou, J and Wu, Q and Zhang, Y and Zhang, QQ and Hu, H and Xu, XQ and Wu, FY and Niu, Q}, title = {Differed brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis patients.}, journal = {Brain research bulletin}, volume = {221}, number = {}, pages = {111229}, doi = {10.1016/j.brainresbull.2025.111229}, pmid = {39880289}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Imaging/methods ; *Brain/physiopathology/diagnostic imaging ; Aged ; Adult ; Support Vector Machine ; Brain Mapping/methods ; }, abstract = {PURPOSE: To investigate the differences in brain spontaneous neural activity between limb-onset and bulbar-onset amyotrophic lateral sclerosis (ALS-L and ALS-B, respectively) patients using resting-state functional MRI (rs-fMRI) with amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo).<br><br>MATERIALS AND METHODS: The rs-fMRI data were collected from 41 ALS patients (11 ALS-B and 30 ALS-L) and 25 healthy controls (HC). ALFF and ReHo values were calculated, and group differences were assessed using one-way ANCOVA and two-sample t-tests. Correlation analyses with clinical measures were conducted. Support vector machine (SVM) analysis was performed to distinguish ALS subtypes.<br><br>RESULTS: Compared with ALS-L, ALS-B showed increased ALFF values in the right gyrus rectus/ orbital part of right middle frontal gyrus, orbital part of left middle frontal gyrus and left dorsolateral superior frontal gyrus/ left medial superior frontal gyrus and decreased ALFF values in the left superior occipital gyrus (FDR-corrected, P&#x202f;<&#x202f;0.05). Both ALS subtypes demonstrated distinct ALFF alterations compared to HC. Differences in ReHo values were only found between ALS-B and HC. Correlation analyses revealed associations between ALFF in specific brain regions and ALS clinical scores. SVM analysis achieved an accuracy of 90.2&#x202f;%, with an AUC of 0.909 in differentiating ALS-B and ALS-L.<br><br>CONCLUSION: ALS-B and ALS-L patients had distinct alterations in brain spontaneous neural activity, which could serve as potential biomarkers for accurately distinguishing these two subtypes. Our findings offer a new insight into the neural mechanism of ALS, underscoring the importance of personalized diagnostic approaches for this complex neurological disorder.}, }
@article {pmid39880202, year = {2025}, author = {Xu, F and Liu, H and Yin, Z and Xing, X and Chen, X}, title = {Associations of dietary factors with amyotrophic lateral sclerosis: A Mendelian randomization study.}, journal = {Clinical nutrition ESPEN}, volume = {66}, number = {}, pages = {226-235}, doi = {10.1016/j.clnesp.2025.01.042}, pmid = {39880202}, issn = {2405-4577}, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Diet ; Vegetables ; Feeding Behavior ; Risk Factors ; Polymorphism, Single Nucleotide ; Fruit ; }, abstract = {BACKGROUND: An inconsistent yet notable relationship between dietary habits and the risk of amyotrophic lateral sclerosis (ALS) has been previously established, with the causative nature of this relationship remaining uncertain. This study aims to explore the causal connections at a genetic level.<br><br>METHODS: A two-sample Mendelian Randomization (MR) based analysis was conducted utilizing a comprehensive, publicly assessable Genome-wide association study (GWAS) database. Fourteen dietary variables were examined as potential exposure factors, and the ALS outcome data was statistically analyzed. The inverse-variance weighted (IVW) approach was used as the primary analytical method, supplemented by sensitivity analyses to assess the reliability of our findings.<br><br>RESULTS: Our analysis identified significant protective effects against ALS from increased intake of water (fixed-effects IVW: OR&#xa0;=&#xa0;0.700, 95&#xa0;% CI: 0.524-0.935, P&#xa0;=&#xa0;0.016), fresh fruit (random-effects IVW: OR&#xa0;=&#xa0;0.561, 95&#xa0;% CI: 0.361-0.871, P&#xa0;=&#xa0;0.010), and cooked vegetable (fixed-effects IVW: OR&#xa0;=&#xa0;0.200, 95&#xa0;% CI: 0.090-0.445, P&#xa0;=&#xa0;0.000). No significant associations were found for the other 11 dietary factors examined.<br><br>CONCLUSION: The study highlights the protective association of cooked vegetables and fresh fruit intake with ALS risk reduction. Additionally, an intriguing association between water intake and ALS was observed, warranting further investigation to elucidate the underlying mechanisms.}, }
@article {pmid39879721, year = {2025}, author = {Derevyanko, A and Tao, T and Allen, NJ}, title = {Common alterations to astrocytes across neurodegenerative disorders.}, journal = {Current opinion in neurobiology}, volume = {90}, number = {}, pages = {102970}, doi = {10.1016/j.conb.2025.102970}, pmid = {39879721}, issn = {1873-6882}, mesh = {Humans ; *Astrocytes/metabolism/pathology ; *Neurodegenerative Diseases/pathology/metabolism ; Animals ; Brain/pathology/metabolism ; }, abstract = {Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.}, }
@article {pmid39879575, year = {2025}, author = {Jang, DG and Kind, AJ and Patterson, A and Pedde, M and Powell, WR and Feldman, EL and Goutman, SA}, title = {Impact of the Adverse Social Exposome on Survival in Individuals With Amyotrophic Lateral Sclerosis.}, journal = {Neurology}, volume = {104}, number = {4}, pages = {e213362}, pmid = {39879575}, issn = {1526-632X}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 AG070883/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; *Exposome ; Aged, 80 and over ; Survival Analysis ; }, abstract = {BACKGROUND AND OBJECTIVES: An adverse social exposome negatively affects many diseases, but its association with amyotrophic lateral sclerosis (ALS) survival is unknown. This study examined the association between the social exposome measure Area Deprivation Index (ADI) and ALS survival.<br><br>METHODS: This is a retrospective analysis of patients with ALS at the University of Michigan Pranger ALS Clinic diagnosed after January 1, 2012. Extracted data included age, sex, race, residential address, disease characteristics, and survival. National ADI ranking was assigned to each patient's geocoded address. Accelerated failure time survival analysis determined association between the ADI group and survival with adjustment for clinicodemographic covariates.<br><br>RESULTS: 1,085 patients (median age at diagnosis, 72 years; 45% female) met inclusion criteria. The highest ADI decile (most disadvantaged neighborhood group) was associated with 37.0% shorter survival time (95% CI -50.4% to -20.1%). Results were similar when grouping patients by ADI ranking (as opposed to decile) or including only those with a classical ALS phenotype.<br><br>DISCUSSION: Exposure to adverse social exposome, as measured by ADI, associates with poorer ALS survival. Because this is a single-center study, replication in other cohorts is encouraged. Further research is needed to understand the underlying mechanisms, which could influence ALS clinical care.}, }
@article {pmid39879320, year = {2025}, author = {Guillot, SJ and Lang, C and Simonot, M and Beckett, D and Lulé, D and Balz, LT and Knehr, A and Stuart-Lopez, G and Vercruysse, P and Dieterlé, S and Weydt, P and Dorst, J and Kandler, K and Kassubek, J and Wassermann, L and Rouaux, C and Arthaud, S and Da Cruz, S and Luppi, PH and Roselli, F and Ludolph, AC and Dupuis, L and Bolborea, M}, title = {Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.}, journal = {Science translational medicine}, volume = {17}, number = {783}, pages = {eadm7580}, doi = {10.1126/scitranslmed.adm7580}, pmid = {39879320}, issn = {1946-6242}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism ; *Orexins/metabolism ; *Disease Models, Animal ; Humans ; Sleep/drug effects ; Male ; Melanins/metabolism ; Mice ; Wakefulness/drug effects ; Female ; Motor Neurons/drug effects/pathology/metabolism ; Hypothalamic Hormones/metabolism ; Pituitary Hormones/metabolism ; Orexin Receptors/metabolism ; Superoxide Dismutase-1/metabolism/genetics ; Mice, Transgenic ; }, abstract = {Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non-rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (Sod1[G86R], Fus[ΔNLS/+], and TDP43[Q331K]). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of Sod1[G86R] mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.}, }
@article {pmid39877726, year = {2025}, author = {Fournier, CN and Levine, M and Simmons, K and García-Santibáñez, RC and Rowland, A and Quinn, CC and Ho, DT and Bedlack, RS and Glass, JD}, title = {ALS Motor Observational Telemedicine Objective Rasch-Built Assessment: A Quantitative Scale for the Era of Teleneurology.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {2}, pages = {e200432}, pmid = {39877726}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Telemedicine has become a mainstay of ALS clinical care, but there is currently no standardized approach for assessing and tracking changes to the neurologic examination in this format. The goal of this study was to create a standardized telemedicine-based motor examination scale to objectively and reliably track ALS progression and use Rasch methodology to validate the scale and improve its psychometric properties.<br><br>METHODS: A draft telemedicine examination scale with 25 items assessing movement in the bulbar muscles, neck, trunk, and extremities was created by an ALS expert panel, incorporating input from patient advisors. This prospective, observational study was approved by the Emory IRB, and participants provided informed consent. Adults with a diagnosis of ALS who were able to undergo a video telemedicine evaluation by an Emory clinician were eligible for participation. Rasch analyses were performed to determine the final item responses and optimize the scoring structure. Test-retest reliability was assessed in a subset of participants through 2 separate examinations by 2 different examiners within a 7-day period. Construct validity was assessed by calculating correlations with simultaneously administered Rasch-built Overall ALS Disability Scale (ROADS) and revised ALS Functional Rating Scale (ALSFRS-R).<br><br>RESULTS: The ALS Motor Observational Telemedicine Objective Rasch-built assessment was administered to a total of 258 PALS representing the full spectrum of a typical ALS clinic population. After performing Rasch analyses, 3 items were removed and item response categories were consolidated for 8 items. The final 22-item ALS MOTOR scale conformed to Rasch model criteria. The inter-rater reliability was 95%. The ALS MOTOR had a 0.78 (95% CI 0.72-0.83) correlation with ALSFRS-R and 0.81 (95% CI 0.76-0.85) correlation with ROADS.<br><br>DISCUSSION: The ALS MOTOR is a novel, accessible tool for remotely and objectively tracking ALS progression for both clinical care and research studies. Use of Rasch methodology for scale validation allowed for optimization of scale psychometric properties, which is particularly important when using the sum score as an overall outcome measure. Longitudinal and external validation studies are ongoing.}, }
@article {pmid39877010, year = {2024}, author = {Stavrovskaya, AV and Voronkov, DN and Pavlova, AK and Olshanskiy, AS and Belugin, BV and Ivanova, MV and Zakharova, MN and Illarioshkin, SN}, title = {Intraventricular Administration of Exosomes from Patients with Amyotrophic Lateral Sclerosis Provokes Motor Neuron Disease in Mice.}, journal = {Acta naturae}, volume = {16}, number = {4}, pages = {73-80}, pmid = {39877010}, issn = {2075-8251}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe disease of the central nervous system (CNS) characterized by motor neuron damage leading to death from respiratory failure. The neurodegenerative process in ALS is characterized by an accumulation of aberrant proteins (TDP-43, SOD1, etc.) in CNS cells. The trans-synaptic transmission of these proteins via exosomes may be one of the mechanisms through which the pathology progresses. The aim of this work was to study the effect of an intraventricular injection of exosomes obtained from the cerebrospinal fluid (CSF) of ALS patients on the motor activity and CNS pathomorphology of mice. The exosomes were obtained from two ALS patients and a healthy donor. Exosome suspensions at high and low concentrations were injected into the lateral brain ventricles of male BALB/c mice (n = 45). Motor activity and physiological parameters were evaluated twice a month; morphological examination of the spinal cord was performed 14 months after the start of the experiment. Nine months after administration of exosomes from the ALS patients, the animals started exhibiting a pathological motor phenotype; i.e., altered locomotion with paresis of hind limbs, coordination impairment, and increasing episodes of immobility. The motor symptoms accelerated after administration of a higher concentration of exosomes. The experimental group showed a significant decrease in motor neuron density in the ventral horns of the spinal cord, a significant increase in the number of microglial cells, and microglia activation. The TDP43 protein in the control animals was localized in the nuclei of motor neurons. TDP43 mislocation with its accumulation in the cytoplasm was observed in the experimental group. Thus, the triggering effect of the exosomal proteins derived from the CSF of ALS patients in the development of a motor neuron pathology in the experimental animals was established. This confirms the pathogenetic role of exosomes in neurodegenerative progression and makes it possible to identify a new target for ALS therapy.}, }
@article {pmid39876814, year = {2025}, author = {Papadopoulou, M and Stefanou, MI and Fanouraki, S and Moschovos, C and Bakola, E and Salakou, S and Zouvelou, V and Papadimas, GK and Tsivgoulis, G}, title = {Motor neuron diseases are not exclusively motor; the SSR paradigm.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2025.2458694}, pmid = {39876814}, issn = {2167-9223}, abstract = {Motor Neuron Diseases (MNDs), familial and sporadic, are progressive neurodegenerative disorders that, for an extended period in the past, were considered purely motor disorders. During the course of the disease, however, some patients exhibit concomitant non-motor signs; thus, MNDs are currently perceived as multisystem disorders. Assessment of non-motor symptoms is usually performed clinically, although laboratory tests can also be routinely used to objectively evaluate these symptoms. Sympathetic Skin Response (SSR) is an example of a neurophysiological test that has been used in cases of Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, and Monomelic Atrophy, mostly to assess Autonomic Nervous System (ANS) disorders. Dysautonomia affects quality of life and life expectancy, as it is involved in cardiovascular events and incidents of sudden death. SSR abnormalities are present even in subclinical involvement of the ANS in MNDs. In this review, we present published research examining SSR findings in various MNDs, and discuss the correlation of SSR findings with clinical symptoms and disease severity, as well as the potential sources of abnormal findings. The aim of this study is to raise clinician awareness of autonomic dysfunction in MNDs and present the benefits of SSR examination in patient care.}, }
@article {pmid39875596, year = {2025}, author = {Tomar, VR and Sharma, S and Siddhanta, S and Deep, S}, title = {Biophysical and spectroscopical insights into structural modulation of species in the aggregation pathway of superoxide dismutase 1.}, journal = {Communications chemistry}, volume = {8}, number = {1}, pages = {22}, pmid = {39875596}, issn = {2399-3669}, support = {CRG/2020/002091//DST | Science and Engineering Research Board (SERB)/ ; }, abstract = {Superoxide dismutase 1 (SOD1) aggregation is implicated in the development of Amyotrophic Lateral Sclerosis (ALS). Despite knowledge of the role of SOD1 aggregation, the mechanistic understanding remains elusive. Our investigation aimed to unravel the complex steps involved in SOD1 aggregation associated with ALS. Therefore, we probed the aggregation using ThT fluorescence, size-exclusion chromatography, and surface-enhanced Raman spectroscopy (SERS). The removal of metal ions and disulfide bonds resulted in the dimers rapidly first converting to an extended monomers then coming together slowly to form non-native dimers. The rapid onset of oligomerization happens above critical non-native dimer concentration. Structural features of oligomer was obtained through SERS. The kinetic data supported a fragmentation-dominant mechanism for the fibril formation. Quercetin acts as inhibitor by delaying the formation of non-native dimer and soluble oligomers by decreasing the elongation rate. Thus, results provide significant insights into the critical steps in oligomer formation and their structure.}, }
@article {pmid39875548, year = {2025}, author = {Rabhi, C and Babault, N and Martin, C and Desforges, B and Maucuer, A and Joshi, V and Pankivskyi, S and Feng, Y and Bollot, G and Rattenbach, R and Pastré, D and Bouhss, A}, title = {TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {136}, pmid = {39875548}, issn = {2399-3642}, support = {ANR-24-CE44-3867-01-SUFATOP//Agence Nationale de la Recherche (French National Research Agency)/ ; CIFRE Grant//Association Nationale de la Recherche et de la Technologie (National Association for Research and Technology)/ ; }, mesh = {Phosphorylation ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Cytoplasm/metabolism ; *Cell Nucleus/metabolism ; RNA, Messenger/metabolism/genetics ; }, abstract = {Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases.}, }
@article {pmid39874287, year = {2025}, author = {Baek, Y and Kim, H and Lee, D and Kim, D and Jo, E and Roh, SH and Ha, NC}, title = {Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {5}, pages = {e2408582122}, pmid = {39874287}, issn = {1091-6490}, support = {RS-2021-IP321036//Ministry of Agriculture, Food and Rural Affairs (MAFRA)/ ; RS-2024-00344154//Ministry of Science and ICT, South Korea (MSIT)/ ; RS-2023-00245941//National Research Foundation of Korea (NRF)/ ; 2021M3A9I4021220//Ministry of Science and ICT, South Korea (MSIT)/ ; }, mesh = {*Superoxide Dismutase-1/metabolism/genetics/chemistry ; *Cysteine/metabolism/chemistry ; Humans ; *Amyloid/metabolism/chemistry ; *Cryoelectron Microscopy ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Mutation ; Models, Molecular ; }, abstract = {The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.}, }
@article {pmid39872677, year = {2025}, author = {Pulst, SM}, title = {Spinocerebellar Ataxia Type 2: A Review and Personal Perspective.}, journal = {Neurology. Genetics}, volume = {11}, number = {1}, pages = {e200225}, pmid = {39872677}, issn = {2376-7839}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, abstract = {Spinocerebellar ataxias (SCAs) are dominantly inherited diseases that lead to neurodegeneration in the cerebellum and other parts of the nervous system. This review examines the progress that has been made in SCA2 from its initial clinical description to discovery of DNA CAG-repeat expansions in the ATXN2 gene. ATXN2 repeat alleles cover the range from recessive and dominant mendelian alleles to risk alleles for amyotrophic lateral sclerosis. We review studies aimed at defining the normal function of ATXN2 and mutant ATXN2 using cellular and mouse models. Progress in testing small compounds and antisense oligonucleotides in preclinical studies is described as well including our recent focus on staufen-1 (STAU1) and mRNA metabolism and control of autophagy.}, }
@article {pmid39871987, year = {2024}, author = {Ribichini, E and Pallotta, N and Badiali, D and Carlucci, M and Ceccanti, M and Cambieri, C and Libonati, L and Corazziari, ES and Ruoppolo, G and Inghilleri, M}, title = {Assessment of upper GI motor activity and GI symptoms in patients with amyotrophic lateral sclerosis: an observational study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1509917}, pmid = {39871987}, issn = {1664-2295}, abstract = {BACKGROUND/AIMS: Oro-pharyngeal dysfunction has been reported in Amyotrophic Lateral Sclerosis (ALS). We aimed to assess ALS patients upper gastrointestinal (GI) motor activity and GI symptoms according to bulbar and spinal onset and severity of ALS.<br><br>METHODS: ALS bulbar (B) and spinal (S) patients with ALS Functional Rating Scale (ALSFRS-r) &#x2265;35, bulbar sub-score &#x2265;10, and Forced Vital Capacity (FVC) >50%, underwent to: Fiberoptic Endoscopic Evaluation of Swallowing (FEES); esophageal manometry; gastric emptying; Rome symptom questionnaire. Medical Research Council Scale for Muscle Strength (MRC) was performed for the upper and lower limbs. Mann-Whitney's U, Fisher's ranks test, Pearson's test was used.<br><br>RESULTS: Thirteen ALS patients were included (6 F; mean age 61.2 &#xb1; 13.7 years, range: 37-87), 5 with B and 8 with S onset (ALSFRS-R score 39.5 &#xb1; 4.9, MRC score 128.6 &#xb1; 23.3, disease duration 22.8 &#xb1; 17.9 months). FEES detected a high dysphagia score in 5 patients with no difference between S and B phenotype. Lower esophageal sphincter pressure was normal in all patients. Esophageal dysmotility was observed in three S and two B onset patients. Upper esophageal sphincter (UES) pressure was higher in all ALS patients. UES spasms and delayed gastric emptying were detected in two B and one S and in two B and four S patients, respectively. There was no correlation between esophagogastric motor abnormalities and clinical characteristics of ALS, nor GI symptoms.<br><br>CONCLUSIONS: The presence of UES spasm and the delayed gastric emptying in a subgroup of ALS patients may suggest the role of ANS dysfunction in ALS.}, }
@article {pmid39871563, year = {2025}, author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P}, title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266357822250119172351}, pmid = {39871563}, issn = {1873-4294}, abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.}, }
@article {pmid39871559, year = {2025}, author = {Rani, S and Tuteja, M}, title = {Chaperones as Potential Pharmacological Targets for Treating Protein Aggregation Illness.}, journal = {Current protein &amp; peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037338028241230092414}, pmid = {39871559}, issn = {1875-5550}, abstract = {The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders. It is now well understood that the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Creutzfeldt-Jakob disease shares a common mechanism: the accumulation of misfolded proteins, which aggregate and become toxic to cells. Among the family of molecular chaperones, Heat Shock Proteins (HSPs) are highly expressed in response to cellular stress and play a pivotal role in preventing protein aggregation. Specific chaperones, particularly HSPs, are now recognized as critical in halting the accumulation and aggregation of misfolded proteins in these conditions. Consequently, these chaperones are increasingly considered promising pharmacological targets for the treatment of protein aggregation-related diseases. This review highlights research exploring the potential roles of specific molecular chaperones in disorders characterized by the accumulation of misfolded proteins.}, }
@article {pmid39870504, year = {2025}, author = {Wilson, C and Giaquinto, L and Santoro, M and Di Tullio, G and Morra, V and Kukulski, W and Venditti, R and Navone, F and Borgese, N and De Matteis, MA}, title = {A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.}, journal = {Life science alliance}, volume = {8}, number = {4}, pages = {}, pmid = {39870504}, issn = {2575-1077}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Mitochondria/metabolism/genetics ; Humans ; *Endoplasmic Reticulum/metabolism ; *Motor Neurons/metabolism/pathology ; *Mutation ; *Vesicular Transport Proteins/metabolism/genetics ; Animals ; Saccharomyces cerevisiae/metabolism/genetics ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Aggregates ; }, abstract = {Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.}, }
@article {pmid39870443, year = {2025}, author = {Zhang, Q and Walkley, CR}, title = {Mouse models for understanding physiological functions of ADARs.}, journal = {Methods in enzymology}, volume = {710}, number = {}, pages = {153-185}, doi = {10.1016/bs.mie.2024.11.024}, pmid = {39870443}, issn = {1557-7988}, mesh = {Animals ; *Adenosine Deaminase/metabolism/genetics ; Mice ; Humans ; *RNA Editing ; *Disease Models, Animal ; *RNA-Binding Proteins/metabolism/genetics ; Adenosine/metabolism/genetics ; Mutation ; Inosine/metabolism/genetics ; Autoimmune Diseases of the Nervous System/genetics/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Nervous System Malformations/genetics/metabolism ; Mice, Knockout ; }, abstract = {Adenosine-to-inosine (A-to-I) editing, is a highly prevalent posttranscriptional modification of RNA, mediated by the adenosine deaminases acting on RNA (ADAR) proteins. Mammalian transcriptomes contain tens of thousands to millions of A-to-I editing events. Mutations in ADAR can result in rare autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) through to irreversible conditions such as motor neuron disease, amyotrophic lateral sclerosis (ALS). Mouse models have played an important role in our current understanding of the physiology of ADAR proteins. With the advancement of genetic engineering technologies, a number of new mouse models have been recently generated, each providing additional insight into ADAR function. This review highlights both past and current mouse models, exploring the methodologies used in their generation, their respective discoveries, and the significance of these findings in relation to human ADAR physiology.}, }
@article {pmid39868844, year = {2025}, author = {Elyaman, W and Stern, LJ and Jiang, N and Dressman, D and Bradley, P and Klatzmann, D and Bradshaw, EM and Farber, DL and Kent, SC and Chizari, S and Funk, K and Devanand, D and Thakur, KT and Raj, T and Dalahmah, OA and Sarkis, RA and Weiner, HL and Shneider, NA and Przedborski, S}, title = {Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {2}, pages = {e14548}, pmid = {39868844}, issn = {1552-5279}, support = {T32 AI148099/AI/NIAID NIH HHS/United States ; P01 AI106697/AI/NIAID NIH HHS/United States ; R01AI137198/NH/NIH HHS/United States ; R13 AG090018/AG/NIA NIH HHS/United States ; R01 AG067581/AG/NIA NIH HHS/United States ; R01 AG076018/AG/NIA NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; T32AI148099-4/NH/NIH HHS/United States ; AI106697/NH/NIH HHS/United States ; R01 AG055422/AG/NIA NIH HHS/United States ; R01AG067581/NH/NIH HHS/United States ; R13AG090018-01/NH/NIH HHS/United States ; R01AG076018/NH/NIH HHS/United States ; AG R01AG055422/NH/NIH HHS/United States ; R35GM141457/NH/NIH HHS/United States ; R01 AI137198/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/immunology/therapy ; *Neurodegenerative Diseases/immunology/therapy ; *T-Lymphocytes/immunology ; Immunotherapy/methods ; Brain/pathology/immunology ; }, abstract = {This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.}, }
@article {pmid39867453, year = {2024}, author = {Rong, P and Heidrick, L and Pattee, G}, title = {A novel muscle network approach for objective assessment and profiling of bulbar involvement in ALS.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1491997}, pmid = {39867453}, issn = {1662-4548}, abstract = {INTRODUCTION: As a hallmark feature of amyotrophic lateral sclerosis (ALS), bulbar involvement significantly impacts psychosocial, emotional, and physical health. A validated objective marker is however lacking to characterize and phenotype bulbar involvement, positing a major barrier to early detection, progress monitoring, and tailored care. This study aimed to bridge this gap by constructing a multiplex functional mandibular muscle network to provide a novel objective measurement tool of bulbar involvement.<br><br>METHODS: A noninvasive electrophysiological technique-surface electromyography-was combined with graph network analysis to extract 48 features measuring the regulatory mechanisms, connectivity, integration, segregation, assortativity, and lateralization of the functional muscle network during a speech task. These features were clustered into 10 interpretable latent factors. To evaluate the utility of the muscle network as a bulbar measurement tool, a heterogenous ALS cohort, consisting of eight individuals with overt clinical bulbar symptoms and seven without, along with 10 neurologically healthy controls, was employed to train and validate statistical and machine learning algorithms to assess the disease effects on the network features and the relation of the network performance to the current clinical diagnostic standard and behavioral patterns of bulbar involvement.<br><br>RESULTS: Significant disease effects were found on most network features. The most robust effects were manifested by reduced and more variable myoelectric activities, and reduced functional connectivity and integration of the muscle network. The 10 latent factors (1) demonstrated acceptably high efficacy for detecting bulbar neuromuscular changes across all clinically confirmed symptomatic cases and clinically silent prodromal cases (area under the curve = 0.89-0.91; F1 score = 0.85-0.87; precision = 0.84-0.86; recall = 0.87-0.88); and (2) selectively correlated with clinically meaningful behavioral patterns (conditional R [2] = 0.45-0.81).<br><br>CONCLUSION: The functional muscle network shows promise for an objective quantifiable measurement tool to improve early detection and profiling of bulbar involvement across the prodromal and symptomatic stages. This tool has various strengths, including the use of a clinically readily available noninvasive instrument, fully automated data processing and analytics, and generation of interpretable objective outcome measures (i.e., latent factors), together rendering it highly scalable in routine clinical practice for assessing and monitoring of bulbar involvement.}, }
@article {pmid39866212, year = {2025}, author = {Wang, W and Cooper, C}, title = {Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: A dual threat to cardiac dysfunction progression.}, journal = {World journal of cardiology}, volume = {17}, number = {1}, pages = {102467}, pmid = {39866212}, issn = {1949-8462}, abstract = {Metabolic dysfunction-associated steatotic liver disease (MASLD), particularly in patients with type 2 diabetes mellitus (T2DM), is increasingly recognized as a multi-system disease that affects both hepatic and cardiovascular health. This study explores the association between MASLD-related liver fibrosis and cardiac dysfunction, focusing on how liver fibrosis contributes to cardiac remodeling and dysfunction. Cernea et al's research highlights the strong correlation between liver fibrosis and changes in left ventricular mass, left atrial dimensions, and systolic and diastolic function in diabetic patients. Notably, the study suggests a protective role of sex-hormone binding protein against cardiac remodeling. These findings underline the importance of early detection of liver fibrosis using non-invasive markers like fibrosis-4 index and nonalcoholic fatty liver disease fibrosis scores, which may offer dual protection for both liver and heart health in T2DM patients. Moreover, this study calls for further research into the shared pathogenic mechanisms, including inflammation and fibrosis pathways, between the liver and heart. It advocates for the integration of liver fibrosis screening into cardiovascular risk management, urging clinicians to adopt a more holistic approach in treating patients with MASLD and T2DM. The research has broad implications for preventing cardiovascular complications and improving outcomes in this high-risk population.}, }
@article {pmid39865792, year = {2025}, author = {Murakami, E and Shibata, T and Tomemori, M and Kawai, G and Nakatani, K}, title = {The role of spatial arrangement of aromatic rings on the binding of N,N'-diheteroaryl guanidine ligands to the G2C4/G2C4 motif DNA.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {6}, pages = {3341-3350}, doi = {10.1039/d4cp03213f}, pmid = {39865792}, issn = {1463-9084}, mesh = {*DNA/chemistry/metabolism ; Ligands ; *Guanidine/chemistry/analogs &amp; derivatives ; Guanidines/chemistry ; Circular Dichroism ; Humans ; Surface Plasmon Resonance ; Hydrogen Bonding ; Nucleic Acid Conformation ; }, abstract = {Non-canonical DNA structures formed by aberrantly expanded repeat DNA are implicated in promoting repeat instability and the onset of repeat expansion diseases. Small molecules that target these disease-causing repeat DNAs hold promise as therapeutic agents for such diseases. Specifically, 1,3-di(quinolin-2-yl)guanidine (DQG) has been identified to bind to the disease-causing GGCCCC (G2C4) repeat DNA associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In this study, we investigate the structure-binding relationships between DQG analogs and double-stranded DNA (dsDNA) containing a G2C4/G2C4 unit. Our findings, derived from UV melting temperature, circular dichroism spectra, and surface plasmon resonance (SPR) analyses of DQG analogs, highlight the crucial role of the spatial arrangements of aromatic rings in binding to the G2C4/G2C4 unit. Among the tested DQG analogs, N,N'-di(quinazolin-2-yl)guanidine (DQzG) stands out for its ability to form seven planar conformers. These conformers enable ADD-DAA hydrogen bonding with cytosine and multiple spatial arrangements of aromatic rings, including those resembling DQG. Our binding analyses revealed that DQzG exhibits the highest affinity binding for the G2C4/G2C4 unit. NMR analysis of the DQzG-bound G2C4/G2C4-dsDNA further suggested that DQzG binds to the G2C4/G2C4 unit via hydrogen bonding. Moreover, SPR analysis demonstrated that DQzG binds more strongly to G2C4 repeat DNA compared to DQG. These results position DQzG as a promising lead compound for targeting the G2C4 repeat, offering potential therapeutic avenues for the treatment of ALS/FTD and other repeat expansion diseases.}, }
@article {pmid39865616, year = {2025}, author = {Dong, S and Liu, X and Zhou, Y and Li, J and Qi, Z and Wang, Z and Yang, W and Chen, X}, title = {Prognostic Value of Cerebrospinal Fluid and Serum Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Correlation Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70256}, pmid = {39865616}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; Prognosis ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: The diagnostic and prognostic values of serum neurofilament light chain (sNfL), in comparison to cerebrospinal fluid (CSF) neurofilament light chain (cNfL), and other clinical parameters in amyotrophic lateral sclerosis (ALS) at the time of diagnosis remain elusive.<br><br>METHODS: We examine paired serum and CSF samples from 80 ALS patients and 21 control subjects, all obtained at the time of diagnosis. Additional serum samples were collected from 51 other ALS patients. NfL concentrations were quantified using the single molecule array (Simoa) technique.<br><br>RESULTS: Our findings demonstrate a robust correlation between NfL levels in matched CSF and serum samples. Notably, both sNfL (p < 0.0001) and cNfL (p < 0.0001) exhibited significantly elevated levels in ALS patients compared to controls. Furthermore, baseline sNfL concentrations, as well as cNfL levels, emerged as predictive indicators of subsequent disease progression rate (sNfL: p < 0.0001, cNfL: p = 0.0005) and overall survival (sNfL: p = 0.0073, cNfL: p = 0.0044). Employing a Cox regression model, we identified baseline sNfL level (HR = 1.01, p = 0.013), and diagnostic delay (HR = 0.94, p = 0.003) as independent prognostic factors for mortality. Furthermore, we constructed a nomogram model that incorporates both sNfL and pertinent clinical variables, which substantially enhances the accuracy of predicting disease outcomes (Concordance Index, 0.808).<br><br>CONCLUSION: Our study underscores the robust correlation between sNfL and cNfL in ALS patients and establishes baseline sNfL as a potent and independent prognostic marker for mortality.}, }
@article {pmid39863573, year = {2025}, author = {Ting, HC and Guo, YT and Su, HL and Chen, YS and Lin, SZ and Harn, HJ and Chang, CY}, title = {Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy.}, journal = {Cell death discovery}, volume = {11}, number = {1}, pages = {23}, pmid = {39863573}, issn = {2058-7716}, abstract = {The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.}, }
@article {pmid39863163, year = {2025}, author = {Kearney, CA and Needle, CD and Brinks, AL and Gutierrez, D and Lo Sicco, KI}, title = {Response to Sood et al's "Systemic Janus kinase inhibitor treatment for vitiligo: An evidence-based review".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2025.01.059}, pmid = {39863163}, issn = {1097-6787}, }
@article {pmid39863029, year = {2025}, author = {Liu, X and Li, T and Tu, X and Xu, M and Wang, J}, title = {Mitochondrial fission and fusion in neurodegenerative diseases:Ca[2+] signalling.}, journal = {Molecular and cellular neurosciences}, volume = {132}, number = {}, pages = {103992}, doi = {10.1016/j.mcn.2025.103992}, pmid = {39863029}, issn = {1095-9327}, mesh = {*Mitochondrial Dynamics ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Calcium Signaling/physiology ; Mitochondria/metabolism ; Endoplasmic Reticulum/metabolism ; Mitochondrial Proteins/metabolism/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca[2+] signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca[2+] signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca[2+] signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca[2+] signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.}, }
@article {pmid39862884, year = {2025}, author = {Moens, TG and Da Cruz, S and Neumann, M and Shelkovnikova, TA and Shneider, NA and Van Den Bosch, L}, title = {Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {166-178}, doi = {10.1016/S1474-4422(24)00517-9}, pmid = {39862884}, issn = {1474-4465}, support = {SHELKOVNIKOVA/OCT17/968-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; *RNA-Binding Protein FUS/genetics ; *Mutation/genetics ; Animals ; }, abstract = {Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression. Most FUS mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in FUS-ALS and informed therapeutic strategies that are currently in development, including the silencing of FUS expression using an intrathecally administered antisense oligonucleotide.}, }
@article {pmid39862877, year = {2025}, author = {Feldman, EL and Sattler, R and Kiernan, MC and Goutman, SA and Chiò, A and Al-Chalabi, A}, title = {Transforming amyotrophic lateral sclerosis into a liveable disease.}, journal = {The Lancet. Neurology}, volume = {24}, number = {2}, pages = {100-101}, doi = {10.1016/S1474-4422(24)00523-4}, pmid = {39862877}, issn = {1474-4465}, }
@article {pmid39861520, year = {2025}, author = {Tripolskaja, L and Kazlauskaite-Jadzevice, A and Razukas, A and Baksiene, E}, title = {Perennial Grasses on Stony Sandy Loam Arenosol: Summary of Results of Long-Term Experiment in Northern Europe Region (1995-2024).}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, pmid = {39861520}, issn = {2223-7747}, support = {"Improvement of the preparation of highly skilled professionals for development of science-intensive economic entities-NKPDOKT" (project code No: VP1-3.1-&#x160;MM-01-V-03-001)//Lietuvos moksl&#x173; taryba/ ; }, abstract = {Grasses can sustain soil functions despite nutrient depletion, which can have serious consequences for soil processes and ecosystem services. This paper summarizes the results of the long-term experiment (1995-2024) carried out in Arenosol within a temperate climate zone, focusing on the productivity of natural and managed grasslands; their succession changes over time, and so do the effects on soil chemical properties, and soil organic carbon (SOC) sequestration. The results indicated that two land uses-abandoned land (AL) and grassland fertilized with mineral fertilizers (MGf)-can be effectively applied to prevent Arenosol soil degradation. SOC accumulation occurs more rapidly in AL soils, and their chemical properties show less change over time. The ability of grasses to sequester SOC is better reflected by SOC stocks across the Ah horizon, where thickness varies over long-term grassland use. Significant changes in soil properties were observed more than 20 years after converting arable to herbaceous land use. While MGf has the highest biomass productivity, the use of fertilizers leads to soil acidification. The biomass productivity of AL and MGf increased with longer grassland use; however, in MG, productivity decreased without fertilizers, reaching AL's productivity levels after 20 years. As the age of AL increased, plant biodiversity decreased, and drought-resistant plants began to spread.}, }
@article {pmid39860557, year = {2025}, author = {Chmiel, J and Stępień-Słodkowska, M}, title = {Resting-State EEG Oscillations in Amyotrophic Lateral Sclerosis (ALS): Toward Mechanistic Insights and Clinical Markers.}, journal = {Journal of clinical medicine}, volume = {14}, number = {2}, pages = {}, pmid = {39860557}, issn = {2077-0383}, abstract = {Introduction: Amyotrophic lateral sclerosis (ALS) is a complex, progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain, brainstem, and spinal cord. Several neuroimaging techniques can help reveal the pathophysiology of ALS. One of these is the electroencephalogram (EEG), a noninvasive and relatively inexpensive tool for examining electrical activity of the brain with excellent temporal precision. Methods: This mechanistic review examines the pattern of resting-state EEG activity. With a focus on publications published between January 1995 and October 2024, we carried out a comprehensive search in October 2024 across a number of databases, including PubMed/Medline, Research Gate, Google Scholar, and Cochrane. Results: The literature search yielded 17 studies included in this review. The studies varied significantly in their methodology and patient characteristics. Despite this, a common biomarker typical of ALS was found-reduced alpha power. Regarding other oscillations, the findings are less consistent and sometimes contradictory. As this is a mechanistic review, three possible explanations for this biomarker are provided. The main and most important one is increased cortical excitability. In addition, due to the limitations of the studies, recommendations for future research on this topic are outlined to enable a further and better understanding of EEG patterns in ALS. Conclusions: Most studies included in this review showed alpha power deficits in ALS patients, reflecting pathological hyperexcitability of the cerebral cortex. Future studies should address the methodological limitations identified in this review, including small sample sizes, inconsistent frequency-band definitions, and insufficient functional outcome measures, to solidify and extend current findings.}, }
@article {pmid39859339, year = {2025}, author = {Yashooa, RK and Duranti, E and Conconi, D and Lavitrano, M and Mustafa, SA and Villa, C}, title = {Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859339}, issn = {1422-0067}, mesh = {*MicroRNAs/genetics/metabolism ; Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Mitochondria/metabolism/genetics ; Animals ; Gene Expression Regulation ; DNA, Mitochondrial/genetics/metabolism ; }, abstract = {MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.}, }
@article {pmid39859258, year = {2025}, author = {Szablewski, L}, title = {Associations Between Diabetes Mellitus and Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {2}, pages = {}, pmid = {39859258}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/etiology ; *Diabetes Mellitus, Type 2/complications/metabolism ; Parkinson Disease/metabolism/pathology ; Oxidative Stress ; Alzheimer Disease/metabolism/etiology/pathology ; Amyotrophic Lateral Sclerosis/metabolism/etiology/pathology ; Diabetes Mellitus, Type 1/complications/metabolism ; Huntington Disease/metabolism/pathology ; Diabetes Mellitus/metabolism ; Animals ; }, abstract = {Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.}, }
@article {pmid39858428, year = {2024}, author = {Argueti-Ostrovsky, S and Barel, S and Kahn, J and Israelson, A}, title = {VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.}, journal = {Biomolecules}, volume = {15}, number = {1}, pages = {}, pmid = {39858428}, issn = {2218-273X}, support = {#284/19 and #485/24//Israel Science Foundation/ ; }, mesh = {Humans ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Mitochondria/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; Animals ; alpha-Synuclein/metabolism/genetics ; Alzheimer Disease/metabolism/pathology/genetics ; Superoxide Dismutase-1/metabolism/genetics ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Mitochondrial Membranes/metabolism ; }, abstract = {Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.}, }
@article {pmid39857761, year = {2025}, author = {Sun, C and Chen, Y and Xu, L and Wang, W and Zhang, N and Fournier, CN and Li, N and Fan, D}, title = {Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857761}, issn = {2227-9059}, support = {82001347//National Natural Science Foundation of China/ ; 82071426//National Natural Science Foundation of China/ ; 81701067//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; }, abstract = {Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.}, }
@article {pmid39857633, year = {2024}, author = {Zhang, G and Cao, W and Wang, Z and Xia, K and Deng, B and Fan, D}, title = {Associations of Abnormal Sleep Duration and Chronotype with Higher Risk of Incident Amyotrophic Lateral Sclerosis: A UK Biobank Prospective Cohort Study.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857633}, issn = {2227-9059}, support = {82301601 81873784 82071426//National Natural Science Foundation of China/ ; }, abstract = {Background: The occurrence of sleep disturbances in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, there is still a lack of reliable evidence of a relationship between sleep disturbances and the risk of developing ALS. The aim of this study was to prospectively investigate the longitudinal associations between sleep traits and the risk of incident ALS. Methods: We included information from 409,045 individuals from the prospective cohort of the UK Biobank. Sleep traits at baseline were measured using a standardized questionnaire. All sleep traits were analyzed in relation to the subsequent incidence of ALS using Cox proportional hazards models. Results: Multivariate analysis showed that 6-7 h of sleep was related to the lowest risk for ALS. A long sleep duration (≥8 h) was associated with an increased risk of ALS incidence (HR: 1.31, 95% CI: 1.07-1.61; p = 0.009). A short sleep duration (<6 h) was associated with an increased risk of ALS incidence (HR: 1.91, 95% CI: 1.10-3.30, p = 0.021) in females. In participants aged ≥65 years, eveningness was associated with increased ALS risk (HR: 1.32, 95% CI: 1.08-1.61; p = 0.006). Conclusion: Our results hint at a sleep duration that is too short or too long, and certain chronotypes might be related to the risk of developing ALS. Despite the limitations imposed by the study design and the subjectivity of sleep information, our findings suggest that sleep disturbances may influence the risk of developing ALS.}, }
@article {pmid39857620, year = {2024}, author = {Frawley, L and Taylor, NT and Sivills, O and McPhillamy, E and To, TD and Wu, Y and Chin, BY and Wong, CY}, title = {Stem Cell Therapy for the Treatment of Amyotrophic Lateral Sclerosis: Comparison of the Efficacy of Mesenchymal Stem Cells, Neural Stem Cells, and Induced Pluripotent Stem Cells.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, pmid = {39857620}, issn = {2227-9059}, support = {Australian Government New Colombo Plan (NCP) scheme//Australian Government New Colombo Plan (NCP) scheme/ ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.<br><br>METHODS: This review evaluates the efficacy of three stem cell types in ALS treatment: mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs).<br><br>RESULTS: MSCs, derived from various tissues, show neuroprotective and regenerative qualities, with clinical trials suggesting potential benefits but limited by small sample sizes and non-randomised designs. NSCs, isolated from the fetal spinal cord or brain, demonstrate promise in animal models but face functional integration and ethical challenges. iPSCs, created by reprogramming patient-specific somatic cells, offer a novel approach by potentially replacing or supporting neurons. iPSC therapy addresses ethical issues related to embryonic stem cells but encounters challenges regarding genotoxicity and epigenetic irregularities, somatic cell sources, privacy concerns, the need for extensive clinical trials, and high reprogramming costs.<br><br>CONCLUSIONS: This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.}, }
@article {pmid39857328, year = {2025}, author = {Stoccoro, A}, title = {Epigenetic Mechanisms Underlying Sex Differences in Neurodegenerative Diseases.}, journal = {Biology}, volume = {14}, number = {1}, pages = {}, pmid = {39857328}, issn = {2079-7737}, support = {GR-2021-12374436//Italian Ministry of Health, Ricerca Finalizzata/ ; }, abstract = {Neurodegenerative diseases are characterized by profound differences between females and males in terms of incidence, clinical presentation, and disease progression. Furthermore, there is evidence suggesting that differences in sensitivity to medical treatments may exist between the two sexes. Although the role of sex hormones and sex chromosomes in driving differential susceptibility to these diseases is well-established, the molecular alterations underlying these differences remain poorly understood. Epigenetic mechanisms, including DNA methylation, histone tail modifications, and the activity of non-coding RNAs, are strongly implicated in the pathogenesis of neurodegenerative diseases. While it is known that epigenetic mechanisms play a crucial role in sexual differentiation and that distinct epigenetic patterns characterize females and males, sex-specific epigenetic patterns have been largely overlooked in studies aiming to identify epigenetic alterations associated with neurodegenerative diseases. This review aims to provide an overview of sex differences in epigenetic mechanisms, the role of sex-specific epigenetic processes in the central nervous system, and the main evidence of sex-specific epigenetic alterations in three neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Understanding the sex-related differences of these diseases is essential for developing personalized treatments and interventions that account for the unique epigenetic landscapes of each sex.}, }
@article {pmid39855275, year = {2025}, author = {Zhang, W and Zhang, L and Fu, S and Yan, R and Zhang, X and Song, J and Lu, Y}, title = {Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.}, journal = {Pharmacology &amp; therapeutics}, volume = {267}, number = {}, pages = {108803}, doi = {10.1016/j.pharmthera.2025.108803}, pmid = {39855275}, issn = {1879-016X}, mesh = {Humans ; *Inflammasomes/metabolism ; Animals ; *Calcium-Binding Proteins/metabolism ; Nervous System Diseases/drug therapy/metabolism/immunology ; Neurodegenerative Diseases/drug therapy/metabolism ; Pyroptosis ; CARD Signaling Adaptor Proteins ; }, abstract = {The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.}, }
@article {pmid39854930, year = {2025}, author = {Drouet, C and Priou, P and Gagnadoux, F and Trzepizur, W}, title = {Constraints to the initiation of home non-invasive ventilation and short-term efficacy in different diagnostic groups (as a prelude to an ambulatory shift).}, journal = {Respiratory medicine and research}, volume = {87}, number = {}, pages = {101154}, doi = {10.1016/j.resmer.2025.101154}, pmid = {39854930}, issn = {2590-0412}, abstract = {INTRODUCTION: Non-invasive ventilation (NIV) is the reference treatment for chronic respiratory failure (CRF) due to impairment of the ventilatory system. Home initiation is increasingly practiced. To better support this ambulatory shift, we aimed to assess the implementation constraints and short-term efficacy according to different aetiologies of CRF.<br><br>METHODS: This retrospective study with cross-sectional and longitudinal analysis included patients initiated with NIV at Angers University Hospital. Patients were separated according to the following aetiologies: obesity hypoventilation syndrome (OHS), chronic obstruction pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), myopathy and chest wall disease. Implementation constraints were assessed by analysing the variability of NIV settings, the number of masks tried and the duration of hospitalisation. NIV effectiveness was assessed by measuring residual PaCO2 (arterial pressure in CO2), apnoea hypopnea index (AHIflow) and tidal volume (VT) (as displayed by the NIV software).<br><br>RESULTS: Between October 2020 and May 2022, 102 patients were started with NIV, including a majority of ALS patients. We found a moderate variability in NIV settings (pressure, slope, triggers, etc.) within the different etiological groups, particularly in ALS. On the other hand, ALS patients required more interface trials than other groups and often had unmet efficacy criteria at hospital discharge. Interestingly, longitudinal follow-up showed a progressive improvement in efficacy criteria, particularly in patients who were initially inadequately ventilated.<br><br>CONCLUSION: Each aetiological group has specific constraints in the initiation of NIV that should be considered when initiating NIV in the outpatient setting.}, }
@article {pmid39854095, year = {2025}, author = {Hansen, G and Shaw, A and Bolt, K and Verity, R and Nataraj, RT and Schellenberg, KL}, title = {Thoracic Electric Impedance Tomography Detects Lung Volume Changes in Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {4}, pages = {552-557}, pmid = {39854095}, issn = {1097-4598}, support = {//ALS Society of Saskatchewan/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; *Electric Impedance ; Female ; Male ; Middle Aged ; Aged ; Vital Capacity/physiology ; *Tomography/methods ; Lung/physiopathology/diagnostic imaging ; Lung Volume Measurements/methods ; Spirometry ; Supine Position ; Adult ; Respiratory Function Tests ; }, abstract = {INTRODUCTION/AIMS: Spirometry is the conventional means to measure lung function in amyotrophic lateral sclerosis (ALS), but is dependent on patient effort and bulbar strength. We aimed to use electric impedance tomography (EIT), an emerging non-invasive imaging modality, to measure dynamic lung volume changes.<br><br>METHODS: Twenty-one patients with ALS underwent sitting and supine spirometry for forced vital capacity (FVC), and sitting and supine EIT. There were 13 patients in the high FVC group (FVC &#x2265;&#x2009;80% predicted) and 8 in the low FVC group (FVC&#x2009;<&#x2009;80% predicted). Additional demographic and clinical data were collected from clinical records.<br><br>RESULTS: Only the low FVC group had significant loss of lung volumes in the supine position (R [2]&#x2009;=&#x2009;0.89 and p&#x2009;<&#x2009;0.001). The supine volume loss measurement at 10&#x2009;min correlated with sitting (r [2]&#x2009;=&#x2009;0.47) and supine FVC (r [2]&#x2009;=&#x2009;0.36), maximum inspiratory (r [2]&#x2009;=&#x2009;-0.44) and expiratory pressures (r [2]&#x2009;=&#x2009;0.36) (MIP and MEP), and the ALS Functional Rating Scale-Revised (ALSFRS-R) dyspnea subscore (r [2]&#x2009;=&#x2009;0.36).<br><br>DISCUSSION: EIT is an emerging alternative to existing measures of lung function in ALS, but without need for patient effort or bulbar strength. Significant losses in lung volume are seen on supine compared to upright position in patients with respiratory dysfunction. Further study is needed to determine relationships to existing clinical measures.}, }
@article {pmid39853150, year = {2025}, author = {Shune, S and Gray, LT and Perry, S and Kosty, D and Namasivayam-MacDonald, A}, title = {Validation of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) Screening Tool for Neurodegenerative Disease.}, journal = {American journal of speech-language pathology}, volume = {34}, number = {2}, pages = {633-645}, doi = {10.1044/2024_AJSLP-24-00253}, pmid = {39853150}, issn = {1558-9110}, mesh = {Humans ; *Deglutition Disorders/diagnosis ; *Caregivers ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Aged ; *Neurodegenerative Diseases/diagnosis ; Adult ; Aged, 80 and over ; Deglutition ; Surveys and Questionnaires ; Cost of Illness ; Caregiver Burden/psychology ; Amyotrophic Lateral Sclerosis/diagnosis ; Parkinson Disease/diagnosis ; Predictive Value of Tests ; ROC Curve ; Dementia/diagnosis ; }, abstract = {PURPOSE: Swallowing difficulties have a substantial impact on the burden experienced by care partners of individuals with neurodegenerative disease. Given this, there is a clear need to easily identify and quantify the unique aspects of swallowing-related burden. The purpose of this study was to establish the validity and reliability of the Caregiver Analysis of Reported Experiences with Swallowing Disorders (CARES) screening tool in care partners of individuals with neurodegenerative disease.<br><br>METHOD: Survey data were collected from an international sample of 212 individuals caring for family members with amyotrophic lateral sclerosis (n = 49), dementia (n = 110), or Parkinson's disease (n = 53). Respondents completed the CARES, Eating Assessment Tool-10, International Dysphagia Diet Standardisation Initiative-Functional Diet Scale, and Zarit Burden Interview. Reliability and validity of the CARES were evaluated via internal consistency alpha coefficients, Spearman's rho correlations, and logistic regression analyses with receiver operating characteristic (ROC) curves.<br><br>RESULTS: CARES scores demonstrated excellent internal consistency (&#x3b1; = .90-.95) and high test-retest reliability (r = .86-.91). The CARES was found to be valid, as increased swallowing-related burden was associated with increased severity of swallowing difficulties (r = .79 to .84), diet restrictiveness (r = -.50 to -.54), and general caregiver burden (r = .36 to .40). The CARES had excellent discrimination between care partners with and without self-reported swallowing-related burden, with a score of &#x2265; 4 suggesting a heightened risk of experiencing this burden.<br><br>CONCLUSIONS: Results establish the CARES as a valid and reliable screening tool that can detect burden related to swallowing difficulties among care partners of individuals living with neurodegenerative disease (score &#x2265; 4). Clinical implementation of the CARES requires the concerted efforts of the larger multidisciplinary team who can collaboratively identify the presence of burden and target the multifaceted sources of burden that a care partner may be experiencing.}, }
@article {pmid39852553, year = {2025}, author = {Tang, X and Chen, Y and Ren, Y and Yang, W and Yu, W and Zhou, Y and Guo, J and Hu, J and Chen, X and Gu, Y and Wang, C and Dong, Y and Yang, H and Sato, C and He, J and Fan, D and You, L and Zinman, L and Rogaeva, E and Chen, Y and Zhang, M}, title = {Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf025}, pmid = {39852553}, issn = {1460-2156}, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with most sporadic cases lacking clear genetic causes. Abnormal pre-mRNA splicing is a fundamental mechanism in neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) loss-of-function (LOF) causes widespread RNA mis-splicing events in ALS. Additionally, splicing mutations are major contributors to neurological disorders. However, the role of intronic variants driving RNA mis-splicing in ALS remains poorly understood. To address this, we developed Spliformer to predict RNA splicing. Spliformer is a transformer-based deep learning model trained and tested on splicing events from the GENCODE database, as well as RNA-seq data from blood and central nervous system tissues. We benchmarked Spliformer against SpliceAI and Pangolin using testing datasets and paired whole-genome sequencing (WGS) with RNA-seq data. We further developed the Spliformer-motif model to identify splicing regulatory motifs. We analyzed Clinvar dataset to identify the link of splicing variants with disease pathogenicity. Additionally, we analyzed WGS data of ALS patients and controls to identify common intronic splicing variants linked to ALS risk or disease phenotypes. We also profiled rare intronic splicing variants in ALS patients to identify known or novel ALS-associated genes. Minigene assays were employed to validate candidate splicing variants. Finally, we measured spine density in neurons with a specific gene knockdown or those expressing a TDP-43 disease-causing mutant. Spliformer accurately predicts the possibilities of a nucleotide within a pre-mRNA sequence being a splice donor, acceptor, or neither. Spliformer outperformed SpliceAI and Pangolin in both speed and accuracy in tested splicing events and/or paired WGS/RNA-seq data. Spliformer-motif successfully identified canonical and novel splicing regulatory motifs. In Clinvar dataset, splicing variants are highly related to disease pathogenicity. Genome-wide analyses of common intronic splicing variants nominated one variant linked to ALS progression. Deep learning analyses of WGS data from 1,370 ALS patients revealed rare splicing variants in reported ALS genes (such as PTPRN2 and CFAP410, validated through minigene assays and RNA-seq), and TDP-43 LOF related RNA mis-splicing genes (such as PTPRD). Further genetic analysis and minigene assays nominated PCP4 and TMEM63A as ALS-associated genes. Functional assays demonstrated that PCP4 is critical for maintaining spine density and can rescue spine loss in neurons expressing a disease-causing TDP-43 mutant. In summary, we developed Spliformer and Spliformer-motif that accurately predict and interpret pre-mRNA splicing. Our findings highlight an intronic genetic mechanism driving RNA mis-splicing in ALS and nominate PCP4 as an ALS-associated gene.}, }
@article {pmid39852477, year = {2025}, author = {Bennett, SA and Cobos, SN and Fisher, RMA and Son, E and Frederic, R and Segal, R and Yousuf, H and Chan, K and Dansu, DK and Torrente, MP}, title = {Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {39852477}, issn = {2309-608X}, support = {S10 OD010582/OD/NIH HHS/United States ; R35 NS111604/NS/NINDS NIH HHS/United States ; K22NS09131401//NIH NINDS/ ; R35NS111604//NIH NINDS/ ; R15NS125394//NIH NINDS/ ; N/A//Brooklyn College, CUNY/ ; N/A//The Graduate Center, CUNY/ ; K12 GM102778/GM/NIGMS NIH HHS/United States ; R15 NS125394/NS/NINDS NIH HHS/United States ; R15NS125394-01S1//NIH NINDS/ ; K12GM102778//NIH NIGMS/ ; 1S01OD010582-01A1/GF/NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109-responsible for installing H3S10ph and H3K56ac-are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.}, }
@article {pmid39851451, year = {2025}, author = {Milligan, C and Cowley, DO and Stewart, W and Curry, AM and Forbes, E and Rector, B and Hastie, A and Liu, L and Hawkins, GA}, title = {Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.}, journal = {Brain sciences}, volume = {15}, number = {1}, pages = {}, pmid = {39851451}, issn = {2076-3425}, support = {R03 AI137866/AI/NIAID NIH HHS/United States ; Hope for Tomorrow ALS Fund//Wake Forest University School of Medicine/ ; TAB Williams Endowment//Wake Forest University School of Medicine/ ; 1R03AI137866-21A1/NH/NIH HHS/United States ; UM1 TR004929/TR/NCATS NIH HHS/United States ; DoD W81XWH1810377//US Department of the Army/ ; Neuroscience Clinical Trial and Innovation Center//Wake Forest University School of Medicine/ ; }, abstract = {Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1[G93A] mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp[358]Ala variant.}, }
@article {pmid39850989, year = {2025}, author = {Matsuda, C and Nakayama, Y and Haraguchi, M and Morishima, R and Itagaki, Y and Bokuda, K and Kimura, H and Takahashi, K and Shimizu, T}, title = {Patients' choices regarding ventilatory support affect opioid use in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/21678421.2025.2453463}, pmid = {39850989}, issn = {2167-9223}, abstract = {OBJECTIVE: To investigate the impact of different ventilatory support options on opioid use among patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We retrospectively reviewed 889 consecutive patients with ALS and enrolled 399 eligible patients. All patients were followed until death or tracheostomy. Clinical characteristics of patients and the timing of initial opioid administration were evaluated. Patients were categorized into four subgroups: (1) 160 patients who never used a ventilator, (2) 120 patients who used only noninvasive ventilation (NIV), (3) 61 patients who transitioned from NIV to tracheostomy and invasive ventilation (TIV), and (4) 58 patients who underwent TIV without prior NIV. We compared the prevalence of opioid use across these groups and assessed its relationship with ventilatory support options using multivariate logistic analysis.<br><br>RESULTS: A total of 130 patients (32.6%) used opioids. The number of patients who used opioids in each group was as follows: 55 (34.4%) in Group 1, 69 (57.5%) in Group 2, 5 (8.2%) in Group 3, and 1 (1.7%) in Group 4 (p&#x2009;<&#x2009;0.0001). Multivariate logistic analysis revealed that, compared to Group 1, the use of NIV only was positively associated with opioid use (p&#x2009;=&#x2009;0.002). In contrast, transitioning from NIV to TIV (Group 3) and using TIV only (Group 4) were negatively associated with opioid use (p&#x2009;=&#x2009;0.0001 and 0.001, respectively).<br><br>CONCLUSIONS: The choice of ventilatory support significantly influences opioid use in patients with ALS. Patients who opted against TIV required opioids to relieve distress more commonly than those who chose TIV.}, }
@article {pmid39849490, year = {2025}, author = {Álvarez-Sánchez, E and Carbayo, &#xc1; and Valle-Tamayo, N and Muñoz, L and Aumatell, J and Torres, S and Rubio-Guerra, S and García-Castro, J and Selma-González, J and Alcolea, D and Turon-Sans, J and Lleó, A and Illán-Gala, I and Fortea, J and Rojas-García, R and Dols-Icardo, O}, title = {Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {15}, pmid = {39849490}, issn = {1742-2094}, support = {PI21/00791//Instituto de Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; AARF-22-924456/ALZ/Alzheimer's Association/United States ; R01 AG056850/NH/NIH HHS/United States ; Por un mundo sin ELA//Fundaci&#xf3;n Espa&#xf1;ola para el Fomento de la Investigaci&#xf3;n de la Esclerosis Lateral Amiotr&#xf3;fica/ ; INT21/00073//Instituto de Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; PI19/01543//Instituto de Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; PDC-2023-51; #202307//Fondation J&#xe9;r&#xf4;me Lejeune/ ; RF1 AG056850/AG/NIA NIH HHS/United States ; AACSF-21-850193/ALZ/Alzheimer's Association/United States ; FI22/00077//Instituto de Salud Carlos III (Ministerio de Asuntos Econ&#xf3;micos y Transformaci&#xf3;n Digital, Gobierno de Espa&#xf1;a)/ ; GBHI ALZ UK-21-720973//Global Brain Health Institute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/immunology/blood ; Male ; *Killer Cells, Natural/immunology/metabolism ; Female ; Middle Aged ; Aged ; *Single-Cell Analysis ; *Sequence Analysis, RNA/methods ; Leukocytes, Mononuclear/metabolism/immunology ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq).<br><br>METHODS: We aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq.&#xa0;We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions.<br><br>RESULTS: We identified the expansion of CD56[dim] natural killer (NK) cells in ALS (fold change&#x2009;=&#x2009;2; adj. p-value&#x2009;=&#x2009;0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change&#x2009;=&#x2009;3.12; adj. p-value&#x2009;=&#x2009;0.0001), which represent a mature and cytotoxic CD56[dim] NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value&#x2009;=&#x2009;9.2&#x2009;&#xd7;&#x2009;10[-&#x2009;11]) and the regulation of lymphocyte proliferation (adj. p-value&#x2009;=&#x2009;6.46&#x2009;&#xd7;&#x2009;10[-&#x2009;6]). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8&#x2009;+&#x2009;effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value&#x2009;=&#x2009;1.23&#x2009;&#xd7;&#x2009;10[-&#x2009;8]) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56[bright] NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels.<br><br>CONCLUSION: Our results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56[dim] NK subpopulation (NK_2), as well as a possible role of CD56[bright] NK cells in neurodegeneration.}, }
@article {pmid39849126, year = {2025}, author = {Gupta, S and Kishore, A and Rishi, V and Aggarwal, A}, title = {Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.}, journal = {Functional &amp; integrative genomics}, volume = {25}, number = {1}, pages = {26}, pmid = {39849126}, issn = {1438-7948}, mesh = {Humans ; *Epigenesis, Genetic ; *Mitochondria/metabolism/genetics ; *Synapses/metabolism/genetics ; *Mitochondrial Dynamics ; Animals ; Calcium/metabolism ; Synaptic Transmission ; }, abstract = {Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca[2+]) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca[2+] homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca[2+] regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.}, }
@article {pmid39845951, year = {2024}, author = {Zucchi, E and Banchelli, F and Simonini, C and De Biasi, S and Martinelli, I and Gianferrari, G and Lo Tartaro, D and Cossarizza, A and D'Amico, R and Mandrioli, J}, title = {Tregs levels and phenotype modifications during Amyotrophic Lateral Sclerosis course.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1508974}, pmid = {39845951}, issn = {1664-3224}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology ; *T-Lymphocytes, Regulatory/immunology/metabolism ; Male ; Female ; Middle Aged ; *Disease Progression ; *Phenotype ; Aged ; Biomarkers ; Adult ; Immunophenotyping ; }, abstract = {INTRODUCTION: T regulatory cells (Tregs) inversely correlate with disease progression in Amyotrophic Lateral Sclerosis (ALS) and fast-progressing ALS patients have been reported to exhibit dysfunctional, as well as reduced, levels of Tregs. This study aimed to evaluate the longitudinal changes in Tregs among ALS patients, considering potential clinical and biological modifiers of their percentages and concentrations. Additionally, we explored whether measures of ALS progression, such as the decline over time in the revised ALS Functional Rating Scale (ALSFRS-r) or forced vital capacity (FVC) correlated Treg levels and whether Treg phenotype varied during the course of ALS.<br><br>METHODS: Total Tregs (detected by CD3, CD4, FoxP3, CD25, and CD127) were quantified at five time points over 54 weeks in 21 patients in the placebo arm of the RAP-ALS trial; next they were characterized for the expression of surface markers including CD38, CD39, CXCR3, and PD1. Repeated measures mixed models were used to analyze the longitudinal course of Tregs, considering potential associations with other clinical and laboratory characteristics. Correlations between ALSFRS-r or FVC and Tregs over time were similarly investigated.<br><br>RESULTS: Our study showed that Treg levels did not change significantly on average during the observation period in our ALS cohort. However, PD1+Tregs decreased and CD39+Tregs increased over time. Male sex and cholesterol levels were associated with increasing Tregs (%) over time, while monocytes positively affected Treg concentrations. Treg concentrations showed a modesty association with FVC decline but were not associated with ALSFRS-r decline.<br><br>DISCUSSION: Treg levels remained stable during the ALS observation period and were not significantly associated with ALSFRS-r variations, suggesting that Treg numbers alone may have limited utility as a pharmaco-dynamic biomarker for ALS trials. However the observed changes in Treg phenotypes, such as the decrease in PD1+Tregs, indicate that phenotypic variations may warrant further investigation for their potential role in ALS progression and therapeutic targeting.}, }
@article {pmid39845577, year = {2025}, author = {Ludolph, A and Wiesenfarth, M}, title = {Tofersen and other antisense oligonucleotides in ALS.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864251313915}, pmid = {39845577}, issn = {1756-2856}, abstract = {The advent of antisense oligonucleotide (ASO) therapies in neurodegenerative disorders is associated with enormous hope. Nusinersen treatment was a breakthrough intervention in the recessive disease spinal muscular atrophy, and superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS) seems to be the paradigm disease in dominant degenerative diseases. The results of treatment with the ASO tofersen in SOD1-ALS show that the drug has a convincing beneficial effect on ALS caused by SOD1 mutations, that preclinical studies in rodents predicted the therapeutic effect in the human disease, and that clinical efficacy is associated with a specific sequence of effects of the drug on mechanistic and degenerative biomarkers and, subsequently, functional outcomes such as weight stabilization and ALSFRS-R. Therefore, the enthusiasm seems to be justified; but this should be followed by an attempt to obtain further insights with the goal to improve this therapy. In particular, the following issues are only partially resolved: Which mechanisms are responsible for the clinical effect following the downregulation of SOD1 protein by ASOs? Is long-term downregulation of SOD1 function associated with side effects? Is there an autoimmune response caused by this and other ASO? Is prevention of SOD1-associated ALS possible?}, }
@article {pmid39844967, year = {2025}, author = {de Melo, R and Alcantara, L and Sarmet, M and Sheers, NL and Berlowitz, DJ and Maldaner, V}, title = {Use of Lung Volume Recruitment Technique in Patients With Chronic Respiratory Disease Among Brazilian Health Professionals.}, journal = {Pulmonary medicine}, volume = {2025}, number = {}, pages = {4073171}, pmid = {39844967}, issn = {2090-1844}, mesh = {Humans ; Brazil ; Cross-Sectional Studies ; Chronic Disease ; Adult ; Surveys and Questionnaires ; *Allied Health Personnel ; Male ; Respiratory Therapy/methods ; }, abstract = {Background: Lung volume recruitment (LVR) is a stacked-breath assisted inflation technique in which consecutive insufflations are delivered, without exhaling in between, until the maximum tolerable inflation capacity is reached. Although LVR is recommended in some neuromuscular disease guidelines, there is little information detailing when and how allied health professionals (AHPs) prescribe LVR. Objective: This study is aimed at describing the use of LVR in practice across Brazil. Methods: A cross-sectional e-survey (Sep-Nov 2023) explored LVR practices among qualified clinical or home care AHPs in Brazil. It gathered participant data on geographical region, profession, and experience. It delved into LVR specifics: clinical population and indications for use, prescription (frequency, dosage, and interfaces), related side effects, outcomes assessed, and combined therapies. Results were presented descriptively. Results: One hundred two surveys (74 physical therapists (PTs) and 28 speech and language pathologists (SLPs)) from diverse locations were collected. LVR was predominantly prescribed for adults (57%), with the most common diagnosis being amyotrophic lateral sclerosis (84%). Changes in peak cough flow and vital capacity were the most common reasons for LVR prescription. Maximal insufflation capacity was reportedly measured by 58% of PTs and 22% of SLPs. Chest wall soreness and discomfort were the most common side effects, and many respondents did not provide warnings about potential side effects (42% PTs and 50% SLPs). The study highlighted common use of other respiratory therapy devices alongside LVR. Conclusion: LVR is available in routine clinical and home care settings in Brazil. There is a lack of standardization regarding indications, prescription, and outcome measures among PTs and SLPs in Brazil. Clear recommendations and guidelines are needed to standardize these parameters, enabling more objective data and facilitating comparisons between centers.}, }
@article {pmid39844875, year = {2024}, author = {Kõks, S and Rallmann, K and Muldmaa, M and Price, J and Pfaff, AL and Taba, P}, title = {Whole blood transcriptome profile identifies motor neurone disease RNA biomarker signatures.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {249}, number = {}, pages = {10401}, pmid = {39844875}, issn = {1535-3699}, mesh = {Humans ; *Motor Neuron Disease/genetics/blood/diagnosis ; Female ; Male ; *Biomarkers/blood ; *Transcriptome/genetics ; Middle Aged ; *Gene Expression Profiling/methods ; Aged ; RNA/blood/genetics ; Case-Control Studies ; Adult ; }, abstract = {Blood-based biomarkers for motor neuron disease are needed for better diagnosis, progression prediction, and clinical trial monitoring. We used whole blood-derived total RNA and performed whole transcriptome analysis to compare the gene expression profiles in (motor neurone disease) MND patients to the control subjects. We compared 42 MND patients to 42 aged and sex-matched healthy controls and described the whole transcriptome profile characteristic for MND. In addition to the formal differential analysis, we performed functional annotation of the genomics data and identified the molecular pathways that are differentially regulated in MND patients. We identified 12,972 genes differentially expressed in the blood of MND patients compared to age and sex-matched controls. Functional genomic annotation identified activation of the pathways related to neurodegeneration, RNA transcription, RNA splicing and extracellular matrix reorganisation. Blood-based whole transcriptomic analysis can reliably differentiate MND patients from controls and can provide useful information for the clinical management of the disease and clinical trials.}, }
@article {pmid39844762, year = {2025}, author = {Theuriet, J and Bernard, E and Guy, N and Taithe, F and Even, C and Maisonobe, T and Sangaré, A and Lardeux, P and Tilikete, CF and Couratier, P and Lenglet, T and Pegat, A}, title = {Electrophysiological Abnormalities in Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease: Three New Patients and Review of the Literature.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {4}, pages = {644-650}, pmid = {39844762}, issn = {1097-4598}, mesh = {Humans ; Male ; Middle Aged ; *Nystagmus, Pathologic/physiopathology/etiology ; *Muscle Weakness/physiopathology/etiology ; *Electromyography ; *Motor Neuron Disease/physiopathology/complications/diagnosis ; Fingers/physiopathology ; Neural Conduction/physiology ; Female ; Aged ; Adult ; Muscle, Skeletal/physiopathology ; }, abstract = {INTRODUCTION/AIMS: Finger Extension Weakness and DOwnbeat Nystagmus Motor Neuron Disease (FEWDON-MND) is characterized by motor weakness predominantly affecting finger extension, accompanied by downbeat nystagmus. To date, only 11 patients have been reported. The present study adds a further three and aims to provide a more detailed description of the electrodiagnostic features of these patients.<br><br>METHODS: We present the clinical and electrophysiological features of three French patients from specialized motor neuron centers and review the electrophysiological findings of previously reported patients.<br><br>RESULTS: These three patients presented with pure motor weakness affecting finger extension and downbeat nystagmus. They exhibited a slowly progressive disease course without respiratory involvement. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the extensor indicis muscles. Abnormal spontaneous activity on needle electromyography (EMG) was rare in two patients, absent in one, and otherwise limited to weak muscles. Additionally, chronic motor axon loss features suggestive of motor neuronopathy were seen in our patients. Importantly, they were also detected in distant asymptomatic muscles.<br><br>DISCUSSION: The three patients reported here confirm the typical phenotype of FEWDON-MND, characterized by slowly progressive distal motor weakness initially affecting finger extension, associated with downbeat nystagmus. Although chronic motor axon loss features have been found in all reported patients, our three patients show that active denervation can be absent or rare. Thus, finger drop and diffuse chronic neurogenic changes on EMG should lead clinicians to look for downbeat nystagmus and to consider FEWDON-MND.}, }
@article {pmid39843865, year = {2025}, author = {Calancie, B and Alexeeva, N}, title = {Revisiting motor unit recruitment to TMS in amyotrophic lateral sclerosis: cortical inhibition is retained during voluntary contractions.}, journal = {Experimental brain research}, volume = {243}, number = {2}, pages = {51}, pmid = {39843865}, issn = {1432-1106}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Transcranial Magnetic Stimulation ; Male ; Middle Aged ; Female ; Aged ; *Recruitment, Neurophysiological/physiology ; *Neural Inhibition/physiology ; *Electromyography ; Adult ; *Muscle, Skeletal/physiopathology/physiology ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; Muscle Contraction/physiology ; Motor Neurons/physiology ; }, abstract = {Transcranial magnetic stimulation (TMS) has been used for many years to study the pathophysiology of amyotrophic lateral sclerosis (ALS). Based on single- or dual-pulse TMS and EMG and/or single motor unit (MU) recordings, many groups have described a loss of central inhibition as an early marker of ALS dysfunction, reflecting a state of cortical 'hyperexcitability'. This conclusion is not without its detractors, however, leading us to reexamine this issue using 4-pulse TMS, shown previously to be more effective for testing central motor pathway functional integrity. A total of 221 motor units were tested in 13 subjects (6 controls; 7 with ALS) across a total of 798 unique TMS conditions. MUs were studied from hand muscles (usually first dorsal interosseus) and from tibialis anterior (TA). Subjects were required to recruit a MU to fire rhythmically, during which time 4-pulse trains of TMS were delivered. A given motor unit's recruitment was examined for different stimulus intensities and interpulse intervals (IPI). All motor units from control subjects showed short latency excitation to TMS, and short latency inhibition for TMS pulses of slightly weaker intensity (i.e. the threshold for inhibition was lower than that for excitation). The same was largely true for MUs studied in subjects with ALS, with the primary difference between control and ALS subjects being the need for stronger stimulus intensities to effect recruitment in subjects with ALS. We saw no evidence for a loss or reduction of inhibition of central motor output in persons with ALS, at least when tested during voluntary contractions.}, }
@article {pmid39842380, year = {2025}, author = {Faltracco, V and Pain, D and Dalla Bella, E and Riva, N and Telesca, A and Soldini, E and Gandini, G and Radici, A and Poletti, B and Lauria, G and Consonni, M}, title = {Mood disorders in patients with motor neuron disease and frontotemporal symptoms: Validation of the Hospital Anxiety and Depression Scale for use in motor neuron disease.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123378}, doi = {10.1016/j.jns.2024.123378}, pmid = {39842380}, issn = {1878-5883}, mesh = {Humans ; Female ; Male ; *Motor Neuron Disease/psychology/diagnosis/complications ; Middle Aged ; Aged ; *Mood Disorders/diagnosis/etiology/psychology ; *Anxiety/diagnosis/etiology/psychology ; *Depression/diagnosis/etiology/psychology ; Reproducibility of Results ; Psychiatric Status Rating Scales ; Adult ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a heterogeneous neurodegenerative disorder, with nearly 50 % of patients exhibiting cognitive and behavioral symptoms in addition to motor decline. Anxiety and depression, though frequently observed in this population, have been understudied in relation to motor and extra-motor profiles.<br><br>OBJECTIVES: Our study addresses this gap by validating the Hospital Anxiety and Depression Scale for Motor Neuron Disease (HADS-MND) and investigating the interplay between mood, clincial, and frontotemporal symptoms in a large sample of MND patients.<br><br>METHODS: A total of 249 MND patients underwent clinical, genetic, and neuropsychological assessments. The validity, reliability, sensitivity, and specificity of the HADS-MND global score and subscores were explored. Correlation analyses and group comparisons tested the link between mood, motor and extra-motor profiles.<br><br>RESULTS: The bidirectional structure of the HADS-MND was confirmed, but receiver operating characteristics analysis suggests caution for clinical use of the anxiety and depression subscales. The global HADS-MND score is recommended as a measure of psychological distress, with a cut-off point of 10 detecting 38&#xa0;% of patients with altered scores. Moderate symptoms of anxiety and depression were present in 14&#xa0;% and 11&#xa0;% of cases, respectively. Depressive mood was higher in women, patients with frontotemporal symptoms, and severe motor-functional disabilities. Depressive and/or anxiety symptoms were linked to loneliness, behavioral changes, emotional dysregulation, and poor quality of life. Cognitive efficiency was not associated with mood.<br><br>CONCLUSION: Mood disorders appeared independent of cognitive profiles but related to behavioral changes. This is particularly relevant for clinicians discussing end-of-life decisions with patients.}, }
@article {pmid39841674, year = {2025}, author = {Grapperon, AM and El Mendili, MM and Maarouf, A and Ranjeva, JP and Guye, M and Verschueren, A and Attarian, S and Zaaraoui, W}, title = {In vivo mapping of sodium homeostasis disturbances in individual ALS patients: A brain 23Na MRI study.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0316916}, pmid = {39841674}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Middle Aged ; *Homeostasis ; *Sodium/metabolism ; *Brain/diagnostic imaging/metabolism/pathology ; Aged ; Sodium Isotopes ; Adult ; Brain Mapping/methods ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by significant heterogeneity among patients. 23Na MRI maps abnormal sodium homeostasis that reflects metabolic alterations and energetic failure contributing to the neurodegenerative process. In this study, we investigated disease severity at the individual level in ALS patients using brain 23Na MRI.<br><br>METHODS: 1H and 23Na brain MRI were collected prospectively from 28 ALS patients. Individual map of abnormal total sodium concentration (TSC) was computed using voxel-based statistical mapping for each patient compared to a local database of 62 healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), ALSFRS-R slope, ALSFRS-R at 6-month and survival time.<br><br>RESULTS: Individual maps quantifying voxels with TSC increase evidenced a high heterogeneity between patients consistent with clinical presentation. The main areas involved were the corticospinal tracts. Half of patients showed abnormal TSC increase within more than 1% of whole brain voxels. Patients with TSC increase had worse clinical severity: higher ALSFRS-R slope (p = 0.02), lower ALSFRS-R at 6-month (p = 0.04), and shorter survival (p = 0.04). ALS patients with limited TSC increase had slower progression of disability or predominant lower motor neuron phenotype or shorter disease duration.<br><br>DISCUSSION: This study mapping sodium homeostasis disturbances at the individual level in ALS patients through 23Na MRI evidenced heterogeneity of TSC increase among patients associated with clinical presentation and disease severity. These findings suggest that TSC increase detected at the individual level by 23Na MRI may be a useful marker of the clinical heterogeneity of ALS patients, a factor that is likely to greatly influence the results of therapeutic trials.}, }
@article {pmid39841625, year = {2025}, author = {Hoengenaert, L and Anders, C and Van Doorsselaere, J and Vanholme, R and Boerjan, W}, title = {Transgene-free genome editing in poplar.}, journal = {The New phytologist}, volume = {}, number = {}, pages = {}, doi = {10.1111/nph.20415}, pmid = {39841625}, issn = {1469-8137}, support = {//Universiteit Gent/ ; G011620N//Fonds Wetenschappelijk Onderzoek/ ; //Energy Transition Fund/ ; //Advanced ERC grant POPMET/ ; }, abstract = {Precise gene-editing methods are valuable tools to enhance genetic traits. Gene editing is commonly achieved via stable integration of a gene-editing cassette in the plant's genome. However, this technique is unfavorable for field applications, especially in vegetatively propagated plants, such as many commercial tree species, where the gene-editing cassette cannot be segregated away without breaking the genetic constitution of the elite variety. Here, we describe an efficient method for generating gene-edited Populus tremula × P. alba (poplar) trees without incorporating foreign DNA into its genome. Using Agrobacterium tumefaciens, we expressed a base-editing construct targeting CCoAOMT1 along with the ALS genes for positive selection on a chlorsulfuron-containing medium. About 50% of the regenerated shoots were derived from transient transformation and were free of T-DNA. Overall, 7% of the chlorsulfuron-resistant shoots were T-DNA free, edited in the CCoAOMT1 gene and nonchimeric. Long-read whole-genome sequencing confirmed the absence of any foreign DNA in the tested gene-edited lines. Additionally, we evaluated the CodA gene as a negative selection marker to eliminate lines that stably incorporated the T-DNA into their genome. Although the latter negative selection is not essential for selecting transgene-free, gene-edited Populus tremula × P. alba shoots, it may prove valuable for other genotypes or varieties.}, }
@article {pmid39840922, year = {2025}, author = {Saucier, D and Bélanger, M and Liu, Z and Lavigne, E and O'Connell, C}, title = {Associations between water exposure and the development of amyotrophic lateral sclerosis: a matched case-control study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2025.2453450}, pmid = {39840922}, issn = {2167-9223}, abstract = {OBJECTIVE: Previous studies have hinted at an association between water exposure and the development of ALS. However, proximity measures to these water sources have been limited to questionnaires or large buffers due to a lack of fine geospatial measures. They also do not distinguish the various classes of hydrographic features. Thus, we created a robust database to investigate the association between proximity to water bodies at place of residence and the development of ALS.<br><br>METHODS: A matched (sex and year of birth) case-control study was conducted in New Brunswick, Canada from January 2003 to February 2021. Study population included 304 ALS patients and 1207 controls with their historical postal codes linked to spatial proximity datasets and air pollution index indicators (proxy measures for contamination by run-off).<br><br>RESULTS: Odds of ALS were not significantly associated with proximity to water bodies, even within a 250&#x2009;m buffer from place of residence (Oceans: 1.10, 0.60-2.00 [95% CI], Reservoirs/Ponds/Lakes: 1.24, 0.47-3.30 [95% CI]). As for interaction models investigating proximity to potentially contaminated water bodies, none of the final fitted models observed an association between proximity to water bodies with indicators of potential run-off sources and the development of ALS.<br><br>CONCLUSIONS: No significant association between proximity to water bodies at place of residence and the development of ALS were observed in the current study. Future studies should consider taking direct measurements of water quality or utilize geomaps of spraying activities and cyanobacteria blooms alongside proximity measures. Household water quality is another avenue to explore, particularly well water use.}, }
@article {pmid39840885, year = {2025}, author = {McKinnon, S and Qiang, Z and Keerie, A and Wells, T and Shaw, PJ and Alix, JJP and Mead, RJ}, title = {Maximizing the translational potential of neurophysiology in amyotrophic lateral sclerosis: a study on compound muscle action potentials.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2448540}, pmid = {39840885}, issn = {2167-9223}, abstract = {Mouse models of amyotrophic lateral sclerosis (ALS) enable testing of novel therapeutic interventions. However, treatments that have extended survival in mice have often failed to translate into human benefit in clinical trials. Compound muscle action potentials (CMAPs) are a simple neurophysiological test that measures the summation of muscle fiber depolarization in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression. We assessed the translational potential of CMAPs and ascertained time points when human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1[G93A] and control mice at different ages across different muscles. The relative CMAP amplitude difference between SOD1[G93A] and control mice in tibialis anterior (TA) and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1[G93A] TA CMAP amplitude between 70 and 140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a "translational window", from which to make comparisons between the SOD1[G93A] model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.}, }
@article {pmid39840019, year = {2024}, author = {De Cleene, N and Schwarzová, K and Labrecque, S and Cerejo, C and Djamshidian, A and Seppi, K and Heim, B}, title = {Olfactory dysfunction as potential biomarker in neurodegenerative diseases: a narrative review.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505029}, pmid = {39840019}, issn = {1662-4548}, abstract = {Neurodegenerative diseases represent a group of disorders characterized by progressive degeneration of neurons in the central nervous system, leading to a range of cognitive, motor, and sensory impairments. In recent years, there has been growing interest in the association between neurodegenerative diseases and olfactory dysfunction (OD). Characterized by a decline in the ability to detect or identify odors, OD has been observed in various conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). This phenomenon often precedes the onset of other clinical symptoms, suggesting its potential utility as an early marker or prodromal symptom of neurodegenerative diseases. This review provides a vast literature overview on the current knowledge of OD in PD, AD, ALS, and HD in order to evaluate its potential as a biomarker, particularly in the early and prodromal stages of these diseases. We summarize the most common methods used to measure olfactory function and delve into neuropathological correlations and the alterations in neurotransmitter systems associated with OD in those neurodegenerative diseases, including differences in genetic variants if applicable, and cater to current pitfalls and shortcomings in the research.}, }
@article {pmid39840015, year = {2024}, author = {Yang, J and Li, W and Tian, M and Zhang, L and Du, F and Li, X and Liu, Q and Li, R and Li, Z and Dong, H and Liu, Y}, title = {Cortical thickness correlated with peripheral inflammatory cytokines in amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1514554}, pmid = {39840015}, issn = {1662-4548}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS.<br><br>METHODS: We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-&#x3b1;, IL-1&#x3b2;, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-&#x3b1;, IL-6, IL-10, IL-8, IL-17, and IFN-&#x3b3; and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (&#x394;FS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or &#x394;FS scores.<br><br>RESULTS: IL-4, IFN-&#x3b1;, IL-1&#x3b2;, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with &#x394;FS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with &#x394;FS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level.<br><br>CONCLUSION: These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.}, }
@article {pmid39839899, year = {2025}, author = {Goyal, MK and Goyal, O}, title = {Can Emax and platelet count truly differentiate between benign and malignant liver lesions?.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {98758}, pmid = {39839899}, issn = {2219-2840}, mesh = {Humans ; *Liver Neoplasms/blood/pathology/diagnosis ; Platelet Count ; *Carcinoma, Hepatocellular/blood/diagnosis/pathology ; Diagnosis, Differential ; Liver/pathology ; Liver Cirrhosis/blood/diagnosis/pathology ; Nomograms ; Blood Platelets ; }, abstract = {This letter critically evaluates Jiang et al's article on the differentiation of benign and malignant liver lesions using Emax and platelet count. Despite notable findings, significant methodological and interpretative limitations are identified. The study lacks detailed assay conditions for Emax measurement, employs inadequate statistical methods without robust multivariate analysis, and does not provide clinically relevant threshold values. The nomogram's reliance on Emax as a major diagnostic contributor is questionable due to attenuation in hepatocellular carcinoma patients with cirrhosis. Moreover, the study's limitations, such as selection bias and confounding factors, are not adequately addressed. Future research should adopt more rigorous methodologies, including prospective studies with larger cohorts and standardized protocols for biomarker measurement, to enhance validity and clinical applicability.}, }
@article {pmid39839897, year = {2025}, author = {Jiang, QR and Zeng, DW}, title = {Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt: Mechanistic and clinical implications.}, journal = {World journal of gastroenterology}, volume = {31}, number = {3}, pages = {100752}, pmid = {39839897}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Hypertension, Portal/diagnosis/etiology/microbiology ; *Portasystemic Shunt, Transjugular Intrahepatic/adverse effects ; *Hepatic Encephalopathy/etiology/microbiology/diagnosis ; *Liver Cirrhosis/microbiology/virology/diagnosis ; Hepatitis B virus/isolation &amp; purification ; Hepatitis B/diagnosis/complications/microbiology ; Dysbiosis ; Animals ; }, abstract = {In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.}, }
@article {pmid39839311, year = {2024}, author = {Zhang, J and Li, Y and Shi, Q}, title = {Decremental response in patients with amyotrophic lateral sclerosis during repetitive nerve stimulation and its relationships with impaired homeostasis.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1502025}, pmid = {39839311}, issn = {1663-4365}, abstract = {BACKGROUND: Previous studies have suggested that neuromuscular junction (NMJ) denervation plays a critical role in amyotrophic lateral sclerosis (ALS). Repetitive nerve stimulation (RNS) has been used as a technique to test neuromuscular transmission, but the sensitivity and stability of its parameters have not been investigated in patients with ALS. In addition, the impact of impaired homeostasis on NMJ stability in patients with ALS remains unclear.<br><br>METHODS: A total of 421 patients with ALS were enrolled. Data on their clinical, biochemical and electrophysiological indicators were divided into a training set (collected from June 2019 to June 2022) and a test set (collected from July 2022 to June 2023). The coefficient of variation (CV) was used to assess the extent of variability. Stepwise regression was used in independent variable selection and model building.<br><br>RESULTS: In patients with ALS, area decrement had a higher rate of abnormal result and a lower CV than amplitude decrement. No significant difference in the rate of abnormal decrement was found when the first compound muscle action potential (CMAP) was compared with either the fourth or fifth one. Moreover, multivariate regression analysis suggests high-density lipoprotein cholesterol (HDL-C) had the greatest impact on decremental response, followed by serum uric acid (UA) and forced vital capacity (FVC). Females had a larger range of area decrement than males.<br><br>CONCLUSION: During RNS test, assessing area decrement significantly enhances our ability to detect the impairment of neuromuscular transmission in patients with ALS. Independent factors contributing to decremental response need to be considered in drug development and clinical trials targeting NMJ in patients with ALS.}, }
@article {pmid39838960, year = {2025}, author = {Min, SM and Bashore, FM and Smith, JL and Havener, TM and Howell, S and Li, H and Couñago, RM and Popov, KI and Axtman, AD}, title = {Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {3282-3308}, pmid = {39838960}, issn = {1520-4804}, support = {S10 OD032476/OD/NIH HHS/United States ; }, mesh = {Humans ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/chemistry/chemical synthesis/pharmacokinetics ; Animals ; Phosphatidylinositol 3-Kinases/metabolism ; Mice ; Morpholines/chemistry/pharmacokinetics/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Crohn Disease/drug therapy ; COVID-19 Drug Treatment ; Molecular Probes/chemistry/pharmacokinetics ; Hydrazones ; Pyrimidines ; }, abstract = {We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.}, }
@article {pmid39838927, year = {2025}, author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G}, title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.}, journal = {Movement disorders : official journal of the Movement Disorder Society}, volume = {}, number = {}, pages = {}, doi = {10.1002/mds.30123}, pmid = {39838927}, issn = {1531-8257}, support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.<br><br>METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.<br><br>RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.<br><br>CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. &#xa9; 2025 International Parkinson and Movement Disorder Society.}, }
@article {pmid39838446, year = {2025}, author = {Ou, K and Jia, Q and Li, D and Li, S and Li, XJ and Yin, P}, title = {Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {4}, pmid = {39838446}, issn = {2047-9158}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Huntington Disease/genetics/drug therapy/therapy ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; Genetic Therapy/methods/trends ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.}, }
@article {pmid39838017, year = {2025}, author = {McCaig, CD}, title = {Neurological Diseases can be Regulated by Phase Separation.}, journal = {Reviews of physiology, biochemistry and pharmacology}, volume = {187}, number = {}, pages = {273-338}, pmid = {39838017}, issn = {0303-4240}, mesh = {Humans ; *Nervous System Diseases ; Animals ; Superoxide Dismutase/metabolism ; Motor Neuron Disease ; Neurons/metabolism ; Phase Separation ; }, abstract = {Several neurological diseases arise from abnormal protein aggregation within neurones and this is closely regulated by phase separation. One such is motor neurone disease and aberrant aggregation of superoxide dismutase. Again these events are regulated by electrical forces that are examined.}, }
@article {pmid39837582, year = {2025}, author = {Brubacher, LJ and Yellappa, V and Lestari, BW and Heitkamp, P and Aguilera Vasquez, N and Sassi, A and Olusola-Faleye, B and Thapa, P and Shyam Klinton, J and Sheokand, S and Pai, M and Oga-Omenka, C}, title = {Health and tuberculosis systems resilience, the role of the private sector and pandemic preparedness: insights from a cross-country qualitative study with policy-makers in India, Indonesia and Nigeria.}, journal = {BMJ global health}, volume = {10}, number = {1}, pages = {}, pmid = {39837582}, issn = {2059-7908}, mesh = {Humans ; *COVID-19/epidemiology ; India ; Nigeria ; Indonesia ; *Tuberculosis/prevention &amp; control ; *Qualitative Research ; *Private Sector ; Delivery of Health Care/organization &amp; administration ; Administrative Personnel ; SARS-CoV-2 ; Pandemics ; Health Policy ; Pandemic Preparedness ; }, abstract = {INTRODUCTION: The COVID-19 pandemic was an unprecedented challenge to health systems worldwide and had a severe impact on tuberculosis (TB) case notifications and service delivery. India, Indonesia and Nigeria are high TB-burden countries where the majority of initial care-seeking happens in the private health sector. The objectives of this study were to (1) explore policy-makers' perspectives on the impact of the COVID-19 pandemic on private sector TB service delivery in India, Indonesia and Nigeria and (2) identify cross-cutting insights for pandemic preparedness with respect to TB service delivery.<br><br>METHODS: From May to November 2021, 33 interviews were conducted with key policy-makers involved in health service administration, TB service delivery and/or the COVID-19 response in India, Indonesia and Nigeria (n=11 in each country). Interviews focused on the impact of COVID-19 on TB services and lessons learnt for pandemic preparedness with respect to TB in each study context. Data were analysed thematically using a hybrid inductive-deductive approach, informed by Haldane et al's Determinants of Health Systems Resilience Framework.<br><br>RESULTS: Policy-makers highlighted the crucial role of intersectoral collaboration, effective governance, innovative financing strategies, health workforce reallocation and technological advancements such as virtual consultations and mHealth in strengthening TB service delivery amid the COVID-19 pandemic. India relied on patient-provider support agencies to implement a joint strategy for TB care across sectors and states. Indonesia engaged networks of private provider professional associations to facilitate coordination of the COVID-19 response. Nigeria implemented a pandemic policy for public-private referral for the continuity of TB care.<br><br>CONCLUSIONS: Countries implemented varied measures to support TB service delivery during the COVID-19 pandemic. This study presents insights from three countries (India, Indonesia and Nigeria) that together offer a 'menu' of possibilities for supporting pandemic preparedness with respect to TB care vis-&#xe0;-vis strengthening health systems resilience.}, }
@article {pmid39837305, year = {2025}, author = {Tan, Y and Yang, T and Cheng, Y and Zhang, S and Xiao, Y and Liu, J and Shang, H}, title = {Association between Psychiatric Disorders and Amyotrophic Lateral Sclerosis: A Prospective Cohort Study from the UK Biobank.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-13}, doi = {10.1159/000543473}, pmid = {39837305}, issn = {1423-0208}, abstract = {INTRODUCTION: Psychiatric disorders have been reported to be associated with amyotrophic lateral sclerosis (ALS). However, evidence for the association remains inconsistent, and it is unclear whether specific categories of psychiatric disorders constitute risk factors for ALS. The study aimed to investigate the association between different categories of psychiatric disorders and the risk of ALS.<br><br>METHODS: We utilized data from the UK Biobank to conduct a population-based prospective cohort study. Cox proportional hazards models were employed to evaluate the association between a history of various psychiatric disorders including schizophrenia, bipolar disorder, depression, anxiety, stress-related disorders, and the risk of ALS. Analyses were adjusted for covariates including sociodemographic factors, lifestyle factors, and medical history.<br><br>RESULTS: Among the 484,065 participants initially included, 558 participants were diagnosed with ALS during a median follow-up of 13.63 years. With complete adjustment, previous schizophrenia (hazard ratio [HR] 6.32; 95% confidence interval [CI]: 2.60-15.36; p < 0.001) and depression (HR 1.37; 95% CI: 1.03-1.81; p = 0.03) were found to be significantly associated with ALS.<br><br>CONCLUSION: This large prospective cohort study indicated the association between schizophrenia, depression, and a higher risk of subsequent ALS. These findings suggest potential implications for early process of global neurodegeneration in ALS, underlining the need for further research to explore the underlying mechanisms.}, }
@article {pmid39836386, year = {2025}, author = {Babu, S and Sharfstein, JM and Feldman, EL}, title = {Reimagining Care and Research for Amyotrophic Lateral Sclerosis.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2024.4757}, pmid = {39836386}, issn = {2168-6157}, }
@article {pmid39836043, year = {2025}, author = {Berry, JD and Hagan, M and Zhang, J and Liu, Y and Ciepielewska, M}, title = {Longer disease progression milestone-free time in people with amyotrophic lateral sclerosis treated versus not treated with intravenous edaravone: results from an administrative claims analysis.}, journal = {Journal of comparative effectiveness research}, volume = {14}, number = {2}, pages = {e240007}, pmid = {39836043}, issn = {2042-6313}, mesh = {Humans ; *Edaravone/therapeutic use/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Administration, Intravenous ; Insurance Claim Review ; Free Radical Scavengers/therapeutic use/administration &amp; dosage ; }, abstract = {Aim: To estimate time-to-progression milestones in people with amyotrophic lateral sclerosis (PALS) treated versus not treated with intravenous (IV) edaravone (Radicava[®] IV, Mitsubishi Tanabe Pharma America [MTPA], hereafter "IV edaravone") in a real-world setting. Background: IV edaravone is US FDA approved for the treatment of ALS and was shown in clinical trials to slow the rate of physical functional decline. Patients &amp; methods: This retrospective observational analysis included PALS continuously enrolled in Optum's Clinformatics[®] Data Mart between 8 August 2017 and 31 December 2021. Cases treated with IV edaravone and controls not treated with IV edaravone were propensity score matched for: age, sex, race, US region of residence, pre-index disease duration, insurance, riluzole prescription; and pre-index claims for cardiovascular disease, artificial nutrition/gastrostomy tube, noninvasive ventilation and all-cause hospitalization. The index date was the first IV edaravone claim for cases; for controls, the index date was randomly assigned after IV edaravone market availability. Restricted mean time lost was calculated for the following disease progression milestones: new use of canes/walkers/wheelchairs, artificial nutrition, noninvasive ventilation, invasive ventilation, speech-generating devices and hospice. Results: Cases (n = 395) were matched to controls (n = 395). Cases had less restricted mean time lost, indicating longer disease progression milestone-free time, for all disease progression milestones. From 0 to 24 months post index, more cases (n = 129) than controls (n = 103) reported no milestones and more controls (n = 232) than cases (n = 131) reported deaths. Conclusion: In a US-based real-world setting, IV edaravone-treated PALS had a longer time to disease progression milestone events and fewer deaths in 2 years compared with PALS not treated with IV edaravone.}, }
@article {pmid39835561, year = {2025}, author = {Rai, A and Shukla, S and Gupta, RK and Mishra, A}, title = {ALS: A Silent Slayer of Motor Neurons. Traditional Chinese Herbal Medicine as an Effective Therapy.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128329141241205063352}, pmid = {39835561}, issn = {1873-4286}, abstract = {Amyotrophic Lateral Sclerosis (ALS), is a progressive neurodegenerative disease characterized by motor symptoms, and cognitive impairment. The complexity in treating ALS arises from genetic and environmental factors, contributing to the gradual decline of lower and upper motor neurons. The anticipated pharmaceutical market valuation for ALS is projected to reach $1,038.94 million by 2032. This projection underscores the escalating impact of ALS on global healthcare systems. ALS prevalence is expected to surge to 376,674 cases by 2040. In 2022, India ranked among the top 3 Asian-Pacific nations, while North America dominated the global ALS market. Ongoing investigations explore the potential of neuroprotective drugs like riluzole and edaravone in ALS treatment. Recently approved drugs, Relyvrio (sodium phenylbutyrate and taurursodiol) and Tofersen (Qalsody) have completed the trials, and others are currently undergoing extensive clinical trials. Continuous research and exploration of therapeutic avenues, including gene therapy and neuroprotective treatments, are imperative to address the challenges posed by ALS and other neurodegenerative diseases. Traditional Chinese Medicine (TCM) approaches and clinical trials are being explored for treating ALS symptoms, targeting neuroinflammation, oxidative damage, and muscle weakness, showcasing the potential benefits of integrating traditional and modern approaches in ALS management.}, }
@article {pmid39835009, year = {2024}, author = {Frolov, A and D'sa, E and Henderson, C and Guzman, MA and Hayat, G and Martin, JR}, title = {Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e76027}, pmid = {39835009}, issn = {2168-8184}, abstract = {A significantly diverse clinical presentation of amyotrophic lateral sclerosis (ALS), even in its best-studied familial form, continues to hinder current efforts to develop effective disease-modifying drugs for the cure of this rapidly progressive, fatal neuromuscular disease. We have previously shown that clinical heterogeneity of sporadic ALS (sALS) could be explained, at least in part, by its polygenic nature as well as by the presence of mutated genes linked to non-ALS neurological diseases and genes known to mediate ALS-related pathologies. We hypothesized that a similar genetic framework could also be present in patients with familial ALS (fALS). To test this hypothesis, we conducted post-mortem genetic screening of an individual with fALS and a mutation in the C9ORF72 gene. C9ORF72 mutations are highly penetrant and are present in the majority of fALS patients. Genetic screening by whole exome sequencing (WES) on the next generation sequencing (NGS) Illumina platform (San Diego, CA, USA) followed by examination of the respective rare (minor allele frequency (MAF) ≤ 0.01) pathological/deleterious genetic variants yielded results consistent with our hypothesis of the presence of a complex genetic framework in fALS. Additional members of this genetic framework were identified when the low-frequency (0.01 < MAF < 0.05) pathological/deleterious genetic variants were analyzed with the low-frequency biallelic AHNAK2, GLI3, PTIRM1, and ZNF254 variants, warranting a closer look at their potentially important role in fALS as C9ORF72 genetic modifiers as well as their link to both neuromuscular disorders/ALS and cancer. Therefore, in addition to the current genetic screening using a standard panel of ALS-related genes, a supplementary screening by WES could be very beneficial for the development of personalized treatment of ALS patients as well as in search of the respective efficient disease-modifying drugs.}, }
@article {pmid39834841, year = {2024}, author = {Coutinho, KMD and Fernandes, F and Medeiros, KC and Coutinho, KD and Dias, AP and Valentim, RAM and Leite-Lais, L and Lima, KC}, title = {Data Report: Educational pathway addressing food and nutrition in amyotrophic lateral sclerosis on the AVASUS platform.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1476293}, pmid = {39834841}, issn = {2673-253X}, }
@article {pmid39834554, year = {2025}, author = {Sarallah, R and Jahani, S and Soltani Khaboushan, A and Moaveni, AK and Amiri, M and Majidi Zolbin, M}, title = {The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {43}, number = {}, pages = {100932}, pmid = {39834554}, issn = {2666-3546}, abstract = {Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.}, }
@article {pmid39834320, year = {2025}, author = {Lero, CM and Park, S and Mroz, EL}, title = {Mapping the evidence of self-compassion in caregiver wellbeing for caregivers of persons with neurodegenerative disease: A scoping review.}, journal = {Palliative &amp; supportive care}, volume = {23}, number = {}, pages = {e38}, doi = {10.1017/S1478951524001639}, pmid = {39834320}, issn = {1478-9523}, mesh = {Humans ; *Caregivers/psychology ; *Neurodegenerative Diseases/psychology/complications ; *Empathy ; }, abstract = {OBJECTIVES: Caregivers of those with neurodegenerative disease (ND) manage complex symptoms which impact their wellbeing. Self-compassion can promote maintenance of wellbeing during challenging experiences, including caregiving. Little guidance exists for observationally studying self-compassion or targeted interventions for this population. Our objective was to complete a scoping review of research describing self-compassion in the context of caregiver wellbeing of caregivers of those living with ND.<br><br>METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for Scoping Reviews (PRISMA-ScR) guidelines, 3 online databases identified 350 peer-reviewed articles, 18 of which were included in this study. Eligibility included being written in English, targeting caregivers of those living with ND, and examination of self-compassion. Articles were organized by the incorporation or characterization of self-compassion in the study design.<br><br>RESULTS: Alzheimer's disease predominated study samples of care recipients. Across study types self-compassion appeared as a theoretical concept, emerging theme, variable associated with other outcomes, and main outcome variable. Self-compassion is frequently measured using the Self-Compassion Scale, full or short form .<br><br>SIGNIFICANCE OF RESULTS: The study of self-compassion with caregivers of individuals living with ND is growing. Current literature is somewhat unfocussed, leading to gaps in understanding conceptualization to achieve maximum intervention benefits. Clarifying the role of self-compassion in caregiver wellbeing will provide a lens through which non-pharmacologic, psychotherapeutic, and behavioral intervention development may be framed to reduce negative psychological outcomes. The most frequently represented ND is Alzheimer's disease or other dementia, obscuring other NDs like amyotrophic lateral sclerosis, Parkinson's disease, and others.}, }
@article {pmid39834142, year = {2025}, author = {Stikvoort García, DJL and van den Berg, LH and Sleutjes, BTHM and Goedee, HS}, title = {Diagnostic Accuracy of Median Nerve Cross-Sectional Area in Suspected Amyotrophic Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {4}, pages = {680-684}, pmid = {39834142}, issn = {1097-4598}, support = {//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis/pathology ; Female ; Male ; *Median Nerve/diagnostic imaging/physiopathology ; Middle Aged ; Aged ; *Ultrasonography ; Prospective Studies ; Retrospective Studies ; Adult ; ROC Curve ; Wrist/diagnostic imaging/innervation ; }, abstract = {INTRODUCTION/AIMS: Reduced nerve sizes obtained by nerve ultrasound (NUS) have been proposed as a potential diagnostic marker for amyotrophic lateral sclerosis (ALS). However, prospective studies evaluating patients with suspected ALS are currently lacking. We, therefore, evaluated the diagnostic accuracy of a standardized NUS protocol in a large sample of suspected ALS patients.<br><br>METHODS: We prospectively recruited 193 patients with suspected ALS, all of whom underwent the relevant ancillary tests. They also underwent a standardized NUS protocol, evaluating median nerve cross-sectional area (CSA) at upper arm, forearm and wrist. Additionally, we selected, retrospectively, a random sample of incident patients with multifocal motor neuropathy (MMN, n&#x2009;=&#x2009;42). We determined diagnostic accuracy using receiver operating characteristic (ROC) analysis.<br><br>RESULTS: Ultimately, 143/193 patients received a final diagnosis of ALS, at a median disease duration of 10&#x2009;months. Fifty patients were classified as non-ALS. Diagnostic yield of NUS to distinguish between patients with and without ALS was low (highest area under the curve (AUC) at the wrist: 0.57). In contrast, abnormal nerve sizes accurately discriminated MMN from patients with ALS, with AUCs ranging from 0.65 at the wrist to 0.86 at the upper arm.<br><br>DISCUSSION: Our study shows that reductions in nerve size are unlikely to have diagnostic utility during routine evaluation of suspected patients with ALS. However, when the differential diagnosis includes both ALS and MMN, median nerve size demonstrates high diagnostic accuracy.}, }
@article {pmid39833708, year = {2025}, author = {Bidarolli, M and Das, B and Rawat, VS and Manocha, S and Sony, HT and Agnihotri, A and Gupta, M and Agera, F}, title = {Polypharmacy and anticholinergic burden scales in older adults: a cross-sectional study among psychiatric outpatients in a tertiary care hospital.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {43}, pmid = {39833708}, issn = {1471-2318}, mesh = {Humans ; Male ; *Polypharmacy ; Female ; Aged ; Cross-Sectional Studies ; *Cholinergic Antagonists/adverse effects ; Middle Aged ; *Tertiary Care Centers/trends ; *Mental Disorders/drug therapy/epidemiology ; India/epidemiology ; Outpatients ; Aged, 80 and over ; Psychotropic Drugs/adverse effects ; }, abstract = {INTRODUCTION: Mental disorders are prevalent among older adults, often leading to the use of multiple medications, many with anticholinergic properties. Polypharmacy, common in this population, is a major contributor to anticholinergic burden, which is linked to cognitive and physical decline. This study investigates the relationship between polypharmacy and anticholinergic burden across seven anticholinergic burden scales in elderly patients attending the psychiatric outpatient.<br><br>METHODS: Study was conducted at a psychiatry outpatient clinic at All India Institute of Medical Sciences, Rishikesh, India, from December 2021 to March 2023. Elderly patients (aged&#x2009;&#x2265;&#x2009;60 years) who were on at least one psychotropic medication and had a primary working diagnosis of psychiatric illness were included. All psychotropic medications, including antidepressants, antipsychotics, mood stabilizers, and hypnotics, were evaluated. Anticholinergic burden scales were calculated by the respective tools. Univariate analysis was adopted to determine the factors that may affect polypharmacy.<br><br>RESULTS: Study included 1165 elderly patients aged&#x2009;&#x2265;&#x2009;60 years. The prevalence of polypharmacy was 20.43% (n&#x2009;=&#x2009;238). Clonazepam (n&#x2009;=&#x2009;364, 17.28%), escitalopram (n&#x2009;=&#x2009;197, 9.35%), metformin (n&#x2009;=&#x2009;165, 7.83%), sertraline (n&#x2009;=&#x2009;141, 6.69%), mirtazapine (n&#x2009;=&#x2009;129, 6.12%), and lorazepam (n&#x2009;=&#x2009;110, 5.22%) were among the most frequently prescribed anticholinergic drugs. Univariate analysis demonstrated that all anticholinergic risk assessment scales were closely correlated with polypharmacy, with the strongest association observed for the Anticholinergic Load Scale (ALS) (Odds Ratio&#x2009;=&#x2009;4.3; p&#x2009;<&#x2009;0.001). Polypharmacy was also positively associated with adverse drug reactions (Odds Ratio&#x2009;=&#x2009;1.81; 95% Confidence Interval&#x2009;=&#x2009;1.27-2.56).<br><br>CONCLUSION: The anticholinergic burden in this cohort of elderly psychiatry patients was high, with 95.1% (n&#x2009;=&#x2009;1108) experiencing a significant burden. Adverse drug events and anticholinergic burden scales were positively associated with polypharmacy, with a stronger correlation between polypharmacy and ALS scores than with other anticholinergic burden scales in older adults.}, }
@article {pmid39832811, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Ahmadzadeh, AM and Darmiani, K and Arab Bafrani, M and Jashirenezhad, N and Helfi, M and Alibabaei, S and Azadi, S and Heidary, S and Fatehi, F}, title = {Thalamic Magnetic Susceptibility (χ) Alterations in Neurodegenerative Diseases: A Systematic Review and Meta-Analysis of Quantitative Susceptibility Mapping Studies.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {}, number = {}, pages = {}, doi = {10.1002/jmri.29698}, pmid = {39832811}, issn = {1522-2586}, abstract = {BACKGROUND: Quantitative Susceptibility Mapping (QSM) provides a non-invasive post-processing method to investigate alterations in magnetic susceptibility (χ), reflecting iron content within brain regions implicated in neurodegenerative diseases (NDDs).<br><br>PURPOSE: To investigate alterations in thalamic &#x3c7; in patients with NDDs using QSM.<br><br>STUDY TYPE: Systematic review and meta-analysis.<br><br>POPULATION: A total of 696 patients with NDDs and 760 healthy controls (HCs) were included in 27 studies.<br><br>FIELD STRENGTH/SEQUENCE: Three-dimensional multi-echo gradient echo sequence for QSM at mostly 3 Tesla.<br><br>ASSESSMENT: Studies reporting QSM values in the thalamus of patients with NDDs were included. Following PRISMA 2020, we searched the four major databases including PubMed, Scopus, Web of Science, and Embase for peer-reviewed studies published until October 2024.<br><br>STATISTICAL TESTS: Meta-analysis was conducted using a random-effects model to calculate the standardized mean difference (SMD) between patients and HCs.<br><br>RESULTS: The pooled SMD indicated a significant increase in thalamic &#x3c7; in NDDs compared to HCs (SMD&#x2009;=&#x2009;0.42, 95% CI: 0.05-0.79; k&#x2009;=&#x2009;27). Notably, amyotrophic lateral sclerosis patients showed a significant increase in thalamic &#x3c7; (1.09, 95% CI: 0.65-1.53, k&#x2009;=&#x2009;2) compared to HCs. Subgroup analyses revealed significant &#x3c7; alterations in younger patients (mean age&#x2009;&#x2264;&#x2009;62&#x2009;years; 0.56, 95% CI: 0.10-1.02, k&#x2009;=&#x2009;11) and studies using greater coil channels (coil channels&#x2009;>&#x2009;16; 0.64, 95% CI: 0.28-1.00, k&#x2009;=&#x2009;9). Publication bias was not detected and quality assessment indicated that studies with a lower risk of bias presented more reliable findings (0.75, 95% CI: 0.32-1.18, k&#x2009;=&#x2009;9). Disease type was the primary driver of heterogeneity, while other factors, such as coil type and geographic location, also contributed to variability.<br><br>DATA CONCLUSION: Our findings support the potential of QSM for investigating thalamic involvement in NDDs. Future research should focus on disease-specific patterns, thalamic-specific nucleus analysis, and temporal evolution.<br><br>PLAIN LANGUAGE SUMMARY: Our research investigated changes in iron levels within the thalamus, a brain region crucial for motor and cognitive functions, in patients with various neurodegenerative diseases (NDDs). The study utilized a specific magnetic resonance imaging technique called Quantitative Susceptibility Mapping (QSM) to measure iron content. It identified a significant increase in thalamic iron levels in NDD patients compared to healthy individuals. This increase was particularly prominent in patients with Amyotrophic Lateral Sclerosis, younger individuals, and studies employing advanced imaging equipment.<br><br>LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.}, }
@article {pmid39831450, year = {2025}, author = {Hoehne, SN and Cary, JA and Bailey, LN and Davidow, EB and Martin, LG and DeJong, TL}, title = {An exploratory study on the effect of rescuer team size on basic and advanced life support technical skills in a high-fidelity simulation of canine cardiopulmonary arrest.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {35}, number = {1}, pages = {9-18}, pmid = {39831450}, issn = {1476-4431}, support = {//Converse Fund, Washington State University College of Veterinary Medicine 2021-2022 CVM Intramural Research Grants/ ; }, mesh = {Animals ; Dogs ; *Heart Arrest/veterinary/therapy ; *Cardiopulmonary Resuscitation/veterinary/methods/education ; Prospective Studies ; *Advanced Cardiac Life Support/veterinary/education ; Humans ; Clinical Competence ; Dog Diseases/therapy ; Simulation Training/methods ; Female ; }, abstract = {OBJECTIVE: To evaluate the effect of rescuer team size on objective skill measures of basic life support (BLS) and advanced life support (ALS) using high-fidelity canine CPR simulation.<br><br>DESIGN: Prospective, experimental study.<br><br>SETTING: Veterinary clinical simulation center.<br><br>SUBJECTS: Forty-eight Reassessment Campaign on Veterinary Resuscitation CPR-certified veterinary students.<br><br>MEASUREMENTS AND MAIN RESULTS: Five groups of participants each conducted 3 CPR simulations in configurations of 4, 6, and 8 rescuers. Simulations represented a shock patient declining into asystole, followed by ventricular fibrillation and return of spontaneous circulation. Resuscitation efforts were video-recorded to evaluate BLS and ALS tasks. Mean (&#xb1;SD) was derived and data were compared among team sizes using ANOVA and Tukey's post hoc analysis. Significance was set at P&#xa0;<&#xa0;0.05. Among teams of 4, 6, and 8 rescuers, time to first chest compression (13&#xa0;s [&#xb1;6], 9&#xa0;s [&#xb1;2], 8&#xa0;s [&#xb1;4]; P&#xa0;=&#xa0;0.24) and positive-pressure breath (101&#xa0;s [&#xb1;37], 56&#xa0;s [&#xb1;15], 67&#xa0;s [&#xb1;24]; P&#xa0;=&#xa0;0.05) were not significantly different. Chest compression (100/min [&#xb1;5], 108/min [&#xb1;6], 107/min [&#xb1;6]; P&#xa0;=&#xa0;0.12) and ventilatory rates (9/min [&#xb1;1], respectively, P&#xa0;=&#xa0;0.52) were not significantly different. Time without chest compressions/total length of CPR was not significantly different (72&#xa0;s [&#xb1;16], 61&#xa0;s [&#xb1;16], 54&#xa0;s [&#xb1;8]; P&#xa0;=&#xa0;0.15). Capnography and ECG monitoring were used by all teams. Time to first vasopressor administration was significantly different among team sizes (268&#xa0;s [&#xb1;70], 164&#xa0;s [&#xb1;65], 174&#xa0;s [&#xb1;34]; P&#xa0;=&#xa0;0.04), with vasopressors being most quickly administered by teams of 6 rescuers. Time to electrical defibrillation was not significantly different (486&#xa0;s [&#xb1;45], 424&#xa0;s [&#xb1;22], 488&#xa0;s [&#xb1;181]; P&#xa0;=&#xa0;0.57). Incorrect ALS interventions occurred in 60%, 0%, and 40% of CPR events in 4, 6, and 8 rescuer teams, respectively.<br><br>CONCLUSIONS: Although the achievement of BLS tasks was comparable in teams of 4 rescuers, teams of 6 rescuers may be preferable based on differences in the rate of guideline-incompliant treatments and ALS task efficiency. Teams of 8 rescuers were neither more efficient nor more accurate at conducting BLS and ALS tasks.}, }
@article {pmid39831399, year = {2025}, author = {Wang, F and Jing, Z and Wang, Q and Li, M and Lu, B and Huo, A and Zhao, C and Zhou, H and Liang, W and Hu, W and Fu, X}, title = {Bidirectional Mendelian Randomization Analysis of the Association Between Mitochondrial Proteins and Neurodegenerative Diseases.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70283}, pmid = {39831399}, issn = {2162-3279}, support = {82303029//National Natural Science Foundation of China/ ; 2024YLZDJH027//the Zhengzhou Science and Technology Innovation Project for Healthcare/ ; YXKC2022020//Health Commission of Henan Province/ ; 232102311134//Science and Technology Department of Henan Province/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics ; *Mitochondrial Proteins/genetics ; *Genome-Wide Association Study ; Alzheimer Disease/genetics ; }, abstract = {BACKGROUND: Neurodegenerative diseases involve progressive neuronal dysfunction and cognitive decline, posing substantial global challenges. Although the precise causes remain unclear, several studies highlight the role of protein metabolism abnormalities in disease development. This study investigates the causal links between variations in mitochondrial protein genes and neurodegenerative diseases, aiming to elucidate their potential contributions to disease progression and identify novel therapeutic strategies.<br><br>METHODS: Herein, we utilized data from genome-wide association studies (GWAS) on mitochondrial proteins and neurodegenerative diseases. Bidirectional Mendelian randomization (MR), employing instrumental variables (IVs), was used to assess causal relationships. The primary method for estimating causal effects was the inverse variance-weighted (IVW) method, supplemented by additional MR approaches.<br><br>RESULTS: Bidirectional MR revealed significant associations between mitochondrial protein gene variants and neurodegenerative diseases. Specifically, associations were found with Alzheimer's disease (AD) (three proteins), Parkinson's disease (PD) (four proteins), amyotrophic lateral sclerosis (ALS) (six proteins), multiple sclerosis (two proteins), and dementia with Lewy bodies (four proteins). Conversely, analyses indicated significant associations of neurodegenerative diseases with mitochondrial protein gene variants, notably with AD, dementia with Lewy bodies, and multiple sclerosis, affecting multiple mitochondrial protein levels. Bidirectional causality was observed between dementia with Lewy bodies and C21orf33.<br><br>CONCLUSIONS: Using MR, we identified significant links between mitochondrial protein gene mutations and the risk of neurodegenerative diseases. These results highlight reciprocal relationships where certain neurodegenerative diseases influence mitochondrial protein expression levels. These findings underscore the pivotal role of mitochondrial proteins in neurodegenerative diseases, offering critical insights into disease mechanisms and potential therapeutic avenues.}, }
@article {pmid39831374, year = {2025}, author = {Risi, B and Imarisio, A and Cuconato, G and Padovani, A and Valente, EM and Filosto, M}, title = {Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70014}, pmid = {39831374}, issn = {1468-1331}, mesh = {Humans ; *DNA, Mitochondrial/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid/blood ; *Neurodegenerative Diseases/cerebrospinal fluid/genetics/diagnosis/blood ; Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid/blood/diagnosis ; }, abstract = {BACKGROUND: Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration.<br><br>METHODS: Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria.<br><br>RESULTS: Fifty-nine original studies met our a priori-defined inclusion criteria. The majority of CSF-focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell-free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results.<br><br>CONCLUSIONS: Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.}, }
@article {pmid39831022, year = {2025}, author = {Okpete, UE and Byeon, H}, title = {Brain-derived neurotrophic factor alterations and cognitive decline in schizophrenia: Implications for early intervention.}, journal = {World journal of psychiatry}, volume = {15}, number = {1}, pages = {102131}, pmid = {39831022}, issn = {2220-3206}, abstract = {This manuscript explores the recent study by Cui et al which assessed the interplay between inflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in first-episode schizophrenia patients. The study revealed that higher levels of interleukin-6 and tumor necrosis factor-α correlated with reduced BDNF levels and poorer cognitive performance. Schizophrenia is a severe psychiatric disorder impacting approximately 1% of the global population, characterized by positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation and cognitive impairments) and disorganized thoughts and behaviors. Emerging research highlights the role of BDNF as a potential biomarker for early diagnosis and therapeutic targeting. The findings from Cui et al's study suggest that targeting neuroinflammation and enhancing BDNF levels may improve cognitive outcomes. Effective treatment approaches involve a combination of pharmacological and non-pharmacological interventions tailored to individual patient needs. Hence, monitoring cognitive and neuroinflammatory markers is essential for improving patient outcomes and quality of life. Consequently, this manuscript highlights the need for an integrated approach to schizophrenia management, considering both clinical symptoms and underlying neurobiological changes.}, }
@article {pmid39829394, year = {2025}, author = {Buddenhagen, CE and Ngow, Z and Wynne-Jones, B and Rolston, MP}, title = {Resistance to the herbicides haloxyfop and iodosulfuron is common in commercial ryegrass (Lolium) seed lines.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8665}, pmid = {39829394}, issn = {1526-4998}, support = {//AgResearch Ltd via its contribution to the Better Border Biosecurity (B3) research collaboration, www.b3nz.org/ ; }, abstract = {BACKGROUND: Ryegrass (Lolium spp.) is a key forage providing a $14 billion contribution to New Zealand's gross domestic product (GDP). However, ryegrass can also act as a weed and evolve resistance to herbicides used for its control. Farmers suspected that imported seed might contribute to resistance issues. Herbicide resistance frequencies were investigated in commercial ryegrass seed lines intended for multiplication in New Zealand. Samples from 56 basic seed lots and 52 unique cultivars sourced from regions including New Zealand, United States, Europe and Japan were planted in field trials. Seedlings were then sprayed with three common herbicides: glyphosate, iodosulfuron, and haloxyfop. Surviving plants were retested to confirm resistance.<br><br>RESULTS: Resistance to haloxyfop and or iodosulfuron was detected in 79% of seed lines. However, frequencies were not significantly higher in imported lines (from United States and Europe) compared with New Zealand lines. Resistance was detected at frequencies between 0.00112% and 10% for haloxyfop and between 0.00212% and 14.28% for iodosulfuron Resistance to glyphosate was not found. There was no significant difference between the resistance detected in seed samples sourced from different seed companies.<br><br>CONCLUSIONS: It was found that 63% of resistant lines had resistance frequencies rarer than 0.1%, but this is potentially problematic considering typical sowing rates. Imported versus domestic seed sources were not significantly different; they pose similar levels of resistance risk to farmers. Lolium multiflorum had a higher resistance frequency compared to Lolium perenne (although only six L. multiflorum lots were evaluated). Breeders should screen progeny of early crosses for herbicide resistance. &#xa9; 2025 The Author(s). Pest Management Science published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.}, }
@article {pmid39829368, year = {2025}, author = {Bedlack, R}, title = {Stitching strength: things I've learned about hope and how I am trying to weave them into my in ALS practice.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2025.2454903}, pmid = {39829368}, issn = {2167-9223}, }
@article {pmid39829311, year = {2025}, author = {Falanga, AP and Piccialli, I and Greco, F and D'Errico, S and Nolli, MG and Borbone, N and Oliviero, G and Roviello, GN}, title = {Nanostructural Modulation of G-Quadruplex DNA in Neurodegeneration: Orotate Interaction Revealed Through Experimental and Computational Approaches.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16296}, pmid = {39829311}, issn = {1471-4159}, support = {IR0000010 "ELIXIRxNextGenIT"//European Commission/ ; PNRRMUR-M4C2-I//European Commission/ ; FOE 2020-ISBE-IT Joint Research Unit//Ministero dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {*G-Quadruplexes/drug effects ; Humans ; *Orotic Acid/pharmacology ; DNA/genetics ; Molecular Docking Simulation ; Neurodegenerative Diseases/genetics/metabolism ; Nanostructures/chemistry ; }, abstract = {The natural compound orotic acid and its anionic form, orotate, play a pivotal role in various biological processes, serving as essential intermediates in pyrimidine de novo synthesis, with demonstrated connections to dietary, supplement, and neurodrug applications. A novel perspective on biomolecular aggregation at the nanoscale, particularly pertinent to neurodegeneration, challenges the established paradigm positing that peptide (amyloid beta) and protein (tau) aggregation mainly govern the molecular events underlying prevalent neuropathologies. Emerging biological evidence indicates a notable role for G-quadruplex (G4) DNA aggregation in neurodegenerative processes affecting neuronal cells, particularly in the presence of extended (G4C2)n repeats in nuclear DNA sequences. Our study concerns d[(GGGGCC)3GGGG], a G4-forming DNA model featuring G4C2 repeats that is in correlation with neurodegeneration. Through different investigations utilizing spectroscopic techniques (CD, UV, and thermal denaturations), PAGE electrophoresis, and molecular docking, the study explores the influence of orotate on the aggregation of this neurodegeneration-associated DNA. A computational approach was employed to construct an in silico model of the DNA aggregate, which involved the docking of multiple G4 units and subsequent integration of the ligand into both the DNA monomer and its in silico aggregated model. The convergence of computational analyses and empirical data collectively supports the hypothesis that orotate possesses the capability to modulate the aggregation of neurodegeneration-related DNA. Notably, the findings suggest the potential utility of orotate as a neurodrug, especially for the therapy of amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD), with its current status as a dietary supplement indicating minimal safety concerns. Additionally, orotate demonstrated a slight increase in mitochondrial dehydrogenase activity as assessed by the MTT assay, which is beneficial for a neurodrug as it suggests a potential role in enhancing mitochondrial function and supporting neuronal health.}, }
@article {pmid39828328, year = {2025}, author = {Yorimoto, K and Ariake, Y and Kawaguchi, T and Hara, T}, title = {Long-term lung volume recruitment therapy maintains ventilator weaning in a patient with ALS following tracheostomy.}, journal = {BMJ case reports}, volume = {18}, number = {1}, pages = {}, doi = {10.1136/bcr-2024-262945}, pmid = {39828328}, issn = {1757-790X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Tracheostomy ; Middle Aged ; *Ventilator Weaning/methods ; Male ; Respiratory Therapy/methods ; Vital Capacity ; }, abstract = {We report a case of amyotrophic lateral sclerosis (ALS) in a patient in their 50s, presenting with spastic paraparesis and bulbar palsy, treated with lung volume recruitment therapy (LVRT). From early stage in the disease, vital capacity (VC), lung insufflation capacity (LIC) and ALS Functional Rating Scale-Revised scores were regularly measured, and LVRT was continuously performed at home. After 10 years, the patient had complete limb function loss and required nutritional management via gastrostomy and full assistance with daily activities. Despite this, the gap between VC and LIC remained approximately 2000 mL, and the patient was not ventilator-dependent during the day after tracheostomy. Chest CT showed improvement in lower lobe atelectasis due to LVRT. Typically, respiratory physiotherapy is challenging in patients with bulbar palsy or post-tracheostomy, but in this case, LVRT successfully maintained lung mobility. Early LVRT implementation may improve ALS patients' survival prognosis and warrants further exploration.}, }
@article {pmid39828029, year = {2025}, author = {Fantini, J and Azzaz, F and Di Scala, C and Aulas, A and Chahinian, H and Yahi, N}, title = {Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow.}, journal = {Pharmacology &amp; therapeutics}, volume = {267}, number = {}, pages = {108797}, doi = {10.1016/j.pharmthera.2025.108797}, pmid = {39828029}, issn = {1879-016X}, mesh = {*Intrinsically Disordered Proteins/chemistry/metabolism ; Humans ; *Drug Discovery/methods ; *Peptides/chemistry/pharmacology/therapeutic use ; *Protein Conformation ; Animals ; Drug Design ; }, abstract = {The traditional model of protein structure determined by the amino acid sequence is today seriously challenged by the fact that approximately half of the human proteome is made up of proteins that do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered proteins (IDPs), are involved in numerous physiological functions and are associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), and type 2 diabetes. Targeting these proteins is challenging for two reasons: i) we need to preserve their physiological functions, and ii) drug design by molecular docking is not possible due to the lack of reliable starting conditions. Faced with this challenge, the solutions proposed by artificial intelligence (AI) such as AlphaFold are clearly unsuitable. Instead, we suggest an innovative approach consisting of mimicking, in short synthetic peptides, the conformational flexibility of IDPs. These peptides, which we call adaptive peptides, are derived from the domains of IDPs that become structured after interacting with a ligand. Adaptive peptides are designed with the aim of selectively antagonizing the harmful effects of IDPs, without targeting them directly but through selected ligands, without affecting their physiological properties. This "target the target, not the arrow" strategy is promised to open a new route to drug discovery for currently undruggable proteins.}, }
@article {pmid39828018, year = {2025}, author = {Sharma, D and Singh, V and Kumar, A and Singh, TG}, title = {Genistein: A promising ally in combating neurodegenerative disorders.}, journal = {European journal of pharmacology}, volume = {991}, number = {}, pages = {177273}, doi = {10.1016/j.ejphar.2025.177273}, pmid = {39828018}, issn = {1879-0712}, mesh = {*Genistein/pharmacology/therapeutic use ; Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.}, }
@article {pmid39827940, year = {2025}, author = {Jinno, J and Abdelhamid, RF and Morita, J and Saga, R and Yamasaki, Y and Kadowaki, A and Ogawa, K and Kimura, Y and Ikenaka, K and Beck, G and Baba, K and Nagai, Y and Kasahara, E and Sekiyama, A and Hirayama, T and Hozumi, I and Hasegawa, T and Araki, T and Mochizuki, H and Nagano, S}, title = {TDP-43 transports ferritin heavy chain mRNA to regulate oxidative stress in neuronal axons.}, journal = {Neurochemistry international}, volume = {184}, number = {}, pages = {105934}, doi = {10.1016/j.neuint.2025.105934}, pmid = {39827940}, issn = {1872-9754}, mesh = {*Oxidative Stress/physiology ; *Apoferritins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Axons/metabolism/pathology ; Animals ; Humans ; Neurons/metabolism ; Iron/metabolism ; Ferritins ; Oxidoreductases ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.}, }
@article {pmid39827337, year = {2025}, author = {Mwale, PF and Hsieh, CT and Yen, TL and Jan, JS and Taliyan, R and Yang, CH and Yang, WB}, title = {Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {7}, pmid = {39827337}, issn = {1750-1326}, support = {NSTC 112-2320-B-038 -018 -MY3//National Science and Technology Council/ ; CGH-MR-A11315//Cathay General Hospital/ ; CGH-MR-A11314//Cathay General Hospital/ ; }, mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism ; Animals ; }, abstract = {Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood-brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.}, }
@article {pmid39825381, year = {2025}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Correction: Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {18}, number = {1}, pages = {5}, pmid = {39825381}, issn = {1756-0381}, }
@article {pmid39824815, year = {2025}, author = {Leau, C and Wang, Y and Gervillié-Mouravieff, C and Boles, ST and Zhang, XH and Coudray, S and Boussard-Plédel, C and Tarascon, JM}, title = {Tracking solid electrolyte interphase dynamics using operando fibre-optic infra-red spectroscopy and multivariate curve regression.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {757}, pmid = {39824815}, issn = {2041-1723}, abstract = {As batteries drive the transition to electrified transportation and energy systems, ensuring their quality, reliability, lifetime, and safety is crucial. While the solid electrolyte interphase (SEI) is known to govern these performance characteristics, its dynamic nature makes understanding its nucleation, growth, and composition an ambitious, yet elusive aspiration. This work employs chalcogenide fibres embedded in negative electrode materials for operando Infra-red Fibre-optic Evanescent Wave Spectroscopy (IR-FEWS), combined with Multivariate Curve Resolution by Alternating Least Squares (MCR-ALS) algorithms for spectra analysis. By establishing molecular fingerprints that can be used to identify reaction products, IR-FEWS combined with MCR-ALS enables improved understanding of SEI evolution during cell formation with notable differences stemming from electrolyte or anode material. For example, despite operating at an elevated potential, lithium titanate's SEI has intrinsic instability, evidenced by continued carbonate formation. This approach leads the hunt for the SEI down a new path, giving empirical formulations theoretical roots.}, }
@article {pmid39824736, year = {2025}, author = {Chow, G and Scher, M and Krisciunas, GP and Tracy, LF}, title = {Comprehensive Review of Multilingual Patient-Reported Outcome Measures for Dysphonia.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2025.01.005}, pmid = {39824736}, issn = {1873-4588}, abstract = {INTRODUCTION: Patient-reported outcome measures (PROMs) represent an important part of a comprehensive voice assessment for clinical care and research. Access to multilingual PROMs enables inclusion of information from diverse patient populations. This review compares available translated and validated PROMs for adult dysphonia.<br><br>METHODS: A comprehensive review of Cochrane Library, PubMed, and OnBase was performed for PROMs evaluating adult dysphonia in all languages. References were additionally queried. PROM development process, available languages, and study group demographics were compared between PROMs available in at least one language other than English. Cultural validation for each PROM was assessed against Beaton et al's six-stage cross-cultural adaptation guidelines.<br><br>RESULTS: Of 21 PROMs assessing adult dysphonia, 13 (62%) were available in one or more language other than English, and nine (43%) were available in seven or more. Voice Handicap Index (VHI) and VHI-10 were the most widely available translated questionnaires (n&#xa0;=&#xa0;29, n&#xa0;=&#xa0;15) followed by Vocal Fatigue Index (VFI), Singing-VHI (S-VHI), and Voice-Related Quality of Life (V-RQOL) (n&#xa0;=&#xa0;11). Identified questionnaires were available in English (n&#xa0;=&#xa0;21), Persian (n&#xa0;=&#xa0;9), Kannada (n&#xa0;=&#xa0;8), and Turkish (n&#xa0;=&#xa0;7) as the most common languages. Females averaged 60% (range 13%-81%) of dysphonic subject groups and 59% of non-dysphonic subject groups (range 20%-88%). Of the 113 articles that reported cultural validation techniques, 16 (14%) adequately fulfilled the cross-cultural adaptation guidelines used.<br><br>CONCLUSION: Multilingual PROMs for dysphonia are widely available, but linguistic representation varied. VHI, VFI, S-VHI, and V-RQOL are the most widely translated. The most represented languages were Persian, Kannada, and Turkish. Few studies adequately followed cross-cultural adaptation standards. Efforts to translate and validate questionnaires into different languages may allow more diverse assessment and comparison of larger populations with dysphonia. This review identifies translated PROMs for dysphonia and analyzes their level of cultural validation for future use.}, }
@article {pmid39824655, year = {2025}, author = {Jia, M and Li, P and Yan, Y and Liu, X and Gao, L and Zhu, G and Chen, Z}, title = {Antimicrobial susceptibility and genomic characterization of Vibrio cholerae non-O1/non-O139 isolated from clinical and environmental samples in Jiaxing City, China.}, journal = {FEMS microbiology letters}, volume = {372}, number = {}, pages = {}, doi = {10.1093/femsle/fnaf009}, pmid = {39824655}, issn = {1574-6968}, support = {2024KY1697//Medical Science and Technology Project of Zhejiang Province/ ; 2023AY31028//Science and Technology Bureau of Jiaxing City/ ; }, mesh = {China ; Humans ; *Anti-Bacterial Agents/pharmacology ; *Multilocus Sequence Typing ; *Microbial Sensitivity Tests ; Vibrio cholerae non-O1/genetics/drug effects/isolation &amp; purification ; Genome, Bacterial ; Environmental Microbiology ; Virulence/genetics ; Cholera/microbiology ; Drug Resistance, Bacterial/genetics ; Genetic Variation ; Virulence Factors/genetics ; }, abstract = {Non-O1/non-O139 (NOVC) strains inhabit aquatic environments and sporadically induce human illnesses. This study involved the virulence and antimicrobial genetic characterization of 176 NOVC strains, comprising 25 from clinical samples and 151 from environmental sources, collected between 2021 and 2023. The antimicrobial susceptibility of the examined NOVC population was predominantly high, exhibiting only poor susceptibility to colistin, with 89.2% resistance. The examination of virulence genes revealed that the majority of strains were positive for glucose metabolism (als gene) (169/176, 96.0%). Through multilocus sequence typing, the 176 NOVC strains were categorised into 121 sequence types, 79 of which were novel. NOVC strains demonstrate significant genetic variability and frequently engage in recombination. This work offers genetic characterization of the pathogenicity and antimicrobial resistance of a NOVC community. Our findings offer insights that may aid in the development of preventative and treatment methods for this pathogen.}, }
@article {pmid39823474, year = {2025}, author = {Zhang, Y and He, L and Gundelach, J and Ge, A and Edlund, H and Norlin, S and Bram, RJ}, title = {Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.}, journal = {PLoS genetics}, volume = {21}, number = {1}, pages = {e1011547}, pmid = {39823474}, issn = {1553-7404}, mesh = {Animals ; Mice ; *Motor Neurons/metabolism ; Mice, Transgenic ; Humans ; Endoplasmic Reticulum/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Neuromuscular Junction/metabolism ; Qa-SNARE Proteins/metabolism/genetics ; Spinal Cord/metabolism ; Disease Models, Animal ; Protein Transport ; Dystonin ; Intracellular Signaling Peptides and Proteins ; }, abstract = {Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans.}, }
@article {pmid39823433, year = {2025}, author = {Tindale, A and Cretu, I and Gomez, N and Haynes, R and Meng, H and Mason, MJ and Francis, DP}, title = {Central venous pressure as a method of optimising atrio-ventricular delay after cardiac surgery.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0310905}, pmid = {39823433}, issn = {1932-6203}, mesh = {Humans ; *Central Venous Pressure/physiology ; *Cardiac Surgical Procedures/methods ; Female ; Male ; Aged ; Middle Aged ; Hemodynamics ; Pacemaker, Artificial ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Haemodynamic atrioventricular delay (AVD) optimisation has primarily focussed on signals that are not easy to acquire from a pacing system itself, such as invasive left ventricular catheterisation or arterial blood pressure (ABP). In this study, standard clinical central venous pressure (CVP) signals are tested as a potential alternative.<br><br>METHODS: Sixteen patients with a temporary pacemaker after cardiac surgery were studied. AV delay optimisation was performed by alternating between a reference AVD of 120ms and tested settings ranging from 40 to 280ms, with 8 replicates for each setting. Alongside (a) the raw data, three methods of correcting for respiration were tested: (b) limiting analysis to a respiratory cycle, (c) asymmetric least squares (ALS) and (d) discrete wavelet transform (DWT). The utility of a quality control step was tested.<br><br>RESULTS: CVP signals were a mirror image of the systolic ABP signals: The four R values were -0.674, -0.692, -0.631, -0.671 respectively (all p<0.001). With quality control, the mirror image was best for DWT (R = -0.76, p<0.001), with the CVP and ABP optima agreeing well (R = 0.78, p<0.001). The automated quality control signal correctly predicted the gap between the AVD optima calculated from ABP and CVP (R = 0.8, p<0.001).<br><br>CONCLUSIONS: Central venous pressure signals could be used to optimise AVD, because they have a reliable inverse relationship with ABP when pacemaker settings undergo protocolised testing. However, protocols need careful design to circumvent spontaneous biological variability.}, }
@article {pmid39822067, year = {2025}, author = {Zhu, Y and Verkhratsky, A and Chen, H and Yi, C}, title = {Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.}, journal = {Acta physiologica (Oxford, England)}, volume = {241}, number = {2}, pages = {e14283}, pmid = {39822067}, issn = {1748-1716}, support = {RCJC20231211090018040//Shenzhen Fundamental Research Program/ ; ZDSYS20220606100801003//Shenzhen Fundamental Research Program/ ; 2022B1515020012//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 32170980//National Natural Science Foundation of China/ ; }, mesh = {*Blood-Brain Barrier/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism ; Animals ; *Insulin/metabolism ; *Glucose/metabolism ; Brain/metabolism ; }, abstract = {The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.}, }
@article {pmid39821843, year = {2025}, author = {Zhang, J and Guo, R and Zhou, Z and Fu, Z and Akogo, HY and Li, Y and Zhang, X and Wang, N and Liu, Y and Li, H and Feng, B and Cui, H and Ma, J}, title = {Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6521-6536}, pmid = {39821843}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/pathology ; *Neural Stem Cells/transplantation ; Animals ; Humans ; *Stem Cell Transplantation/methods ; Treatment Outcome ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.}, }
@article {pmid39820998, year = {2025}, author = {Hamad, AA and Alkhawaldeh, IM and Nashwan, AJ and Meshref, M and Imam, Y}, title = {Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {39820998}, issn = {1590-3478}, abstract = {OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS.<br><br>METHODS: A comprehensive search of three databases was conducted from inception through October 2024. Eligible studies included clinical trials, observational studies, and case studies. Meta-analyses were conducted using a random-effects model in RevMan.<br><br>RESULTS: Twelve studies involving 195 patients treated with tofersen met the inclusion criteria, comprising two randomized controlled trials (RCTs), five cohort studies, one case series, and four case reports. Tofersen demonstrated promising effects, notably reducing SOD1 levels in cerebrospinal fluid and neurofilament light chain (NfL) in plasma, a biomarker strongly correlated with ALS progression and survival. Meta-analysis of RCTs showed a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline in the tofersen group compared to placebo (SMD&#x2009;=&#x2009;0.44, 95% CI [0.05 to 0.83], P&#x2009;=&#x2009;0.03) and a significant reduction in the decline of predicted Slow Vital Capacity (P&#x2009;=&#x2009;0.005). In a pre-post meta-analysis of five studies, a significant decrease in ALS progression rate (ALSFRS-R decline rate) was observed (MD = -0.28, 95% CI [-0.40 to -0.15], P&#x2009;<&#x2009;0.0001). Reported adverse events were consistent with ALS progression or procedural effects.<br><br>CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.}, }
@article {pmid39820861, year = {2025}, author = {van Zundert, B and Montecino, M}, title = {Epigenetics in Neurodegenerative Diseases.}, journal = {Sub-cellular biochemistry}, volume = {108}, number = {}, pages = {73-109}, pmid = {39820861}, issn = {0306-0225}, mesh = {Humans ; *Epigenesis, Genetic ; Animals ; *Neurodegenerative Diseases/genetics/metabolism ; Alzheimer Disease/genetics/metabolism ; DNA Methylation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).}, }
@article {pmid39820267, year = {2025}, author = {Martinez-Thompson, JM and Mazurek, KA and Parra Cantu, C and Naddaf, E and Gogineni, V and Botha, H and Jones, DT and Laughlin, RS and Barnard, L and Staff, NP}, title = {Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf014}, pmid = {39820267}, issn = {1460-2156}, abstract = {Nerve conduction F-wave studies contain critical information about subclinical motor dysfunction which may be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial Intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46,802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular, and tibial nerves. Wavelet coefficient statistics, onset age, sex, and BMI were features for training a Gradient Boosting Machine model on 40,095 (5,329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis (IBM), cervical radiculopathy, lumbar radiculopathy, or peripheral neuropathy which can mimic ALS symptoms. Factors affecting survival were estimated through cox proportional hazards regression. The model trained using wavelet-features on the full waveform had 90% recall, 87% precision, and 88% accuracy. Similar model performance was measured using features only from the M-Wave or F-Wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (p<0.001, ANOVA, Tukey's post-hoc), Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient's likelihood of ALS and their survival risks. Although the model can make predictions at specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS compared to other mimicking diagnoses such as IBM, cervical or lumbar radiculopathy, or peripheral neuropathy. These probabilities provide clinicians with additional information they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians diagnose ALS sooner and manage treatment based on estimated survival, which may improve outcomes and patients' quality of life.}, }
@article {pmid39819944, year = {2025}, author = {Kristensen, RK and Andersen, PT and Bilenberg, N and Milling, ED and Dalgaard Guldager, J}, title = {Mapping the landscape and evidence of cross-sectoral collaboration models targeting individuals referred for assessment of attention-deficit hyperactivity disorder or autism spectrum disorder: protocol for a scoping review.}, journal = {BMJ open}, volume = {15}, number = {1}, pages = {e088850}, pmid = {39819944}, issn = {2044-6055}, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity ; *Autism Spectrum Disorder ; Research Design ; Review Literature as Topic ; Cooperative Behavior ; Referral and Consultation ; }, abstract = {INTRODUCTION: Neurodevelopmental disorders, notably attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), present substantial challenges in mental health. Individuals referred for assessment in a psychiatric unit experience complex needs. This implies that their needs necessitate coordination across multiple sectors. Cross-sectoral collaboration models have emerged as essential strategies for addressing the complexities of these disorders. However, evidence of their existence, implementation and success remains limited. This protocol aims to outline a scoping review where we will explore existing collaboration models, evaluate their implementation and gain an understanding of how cross-sectoral collaboration models can be developed to ultimately benefit individuals referred for assessment of ADHD or ASD.<br><br>METHODS AND ANALYSIS: This proposed scoping review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive search will be conducted across PubMed, CINAHL, Embase, PsycINFO and Google Scholar, as well as grey literature sources, between 1 December 2024 and 1 January 2025. Inclusion criteria will encompass studies focusing on cross-sectoral collaboration for individuals referred for assessment of ADHD or ASD, published in English, Danish, Norwegian or Swedish. The search will use a three-block search string, with iterative refinement guided by familiarity with the evidence base. Data extraction will involve study characteristics and implementation details, using the Consolidated Framework for Implementation Research in combination with Proctor et al's implementation outcomes framework. Results will be synthesised into descriptive tables, providing a comprehensive mapping of existing models and emphasising implementation feasibility.<br><br>ETHICS AND DISSEMINATION: Ethical approval is not required for this protocol since it involves the review of existing literature without the involvement of human participants or personal data. Findings will be disseminated at national and international conferences and will be integrated into future efforts to develop cross-sectoral collaboration models in Denmark.}, }
@article {pmid39819841, year = {2025}, author = {Cintora-Sanz, AM and Horrillo-García, C and Quesada-Cubo, V and Pérez-Alonso, AM and Gutiérrez-Misis, A}, title = {Prevalence and Economic Impact of Acute Respiratory Failure in the Prehospital Emergency Medical Service of the Madrid Community: Retrospective Cohort Study.}, journal = {JMIR public health and surveillance}, volume = {11}, number = {}, pages = {e66179}, pmid = {39819841}, issn = {2369-2960}, mesh = {Humans ; Spain/epidemiology ; Retrospective Studies ; *Emergency Medical Services/economics/statistics &amp; numerical data ; *Respiratory Insufficiency/epidemiology/therapy ; Male ; Aged ; Female ; *COVID-19/epidemiology ; Prevalence ; Middle Aged ; Aged, 80 and over ; Adult ; Health Care Costs/statistics &amp; numerical data ; Cohort Studies ; Acute Disease ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and acute pulmonary edema (APE) are serious illnesses that often require acute care from prehospital emergency medical services (EMSs). These respiratory diseases that cause acute respiratory failure (ARF) are one of the main reasons for hospitalization and death, generating high health care costs. The prevalence of the main respiratory diseases treated in a prehospital environment in the prepandemic period and during the COVID-19 pandemic in Spain is unknown. The Madrid Community EMS is a public service that serves all types of populations and represents an epidemiological reference for supporting a population of 6.4 million inhabitants. The high volume of patients treated by Madrid's medical advanced life supports (ALSs) allows us to analyze this little-studied problem.<br><br>OBJECTIVES: Our goal was to lay the groundwork for comprehensive data collection and surveillance of respiratory failure, with an emphasis on the most prevalent diseases that cause it, an aspect that has been largely overlooked in previous initiatives. By achieving these objectives, we hope to inform efforts to address respiratory failure and establish a standardized methodology and framework that can facilitate expansion to a continuous community-wide registry in Madrid, driving advances in emergency care and care practices in these pathologies. The aim of this retrospective observational study was to determine the pathologies that have mainly caused respiratory failure in patients and required medicalized ALS and to evaluate the cost of care for these pathologies collected through this pilot registry.<br><br>METHODS: A multicenter descriptive study was carried out in the Madrid Community EMS. The anonymized medical records of patients treated with medical ALS, who received any of the following medical diagnoses, were extracted: ARF not related to chronic respiratory disease, ARF in chronic respiratory failure, exacerbations of COPD, APE, CHF, and bronchospasm (not from asthma or COPD). The prevalence of each pathology, its evolution from 2014 to 2020, and the economic impact of the Medical ALSs were calculated.<br><br>RESULTS: The study included 96,221 patients. The most common pathology was exacerbation of COPD, with a prevalence of 0.07% in 2014; it decreased to 0.03% in 2020. CHF followed at 0.06% in 2014 and 0.03% in 2020. APE had a prevalence of 0.01% in 2014, decreasing to 0.005% in 2020 with the pandemic. The greatest economic impact was on exacerbation of COPD in 2015, with an annual cost of &#x20ac;2,726,893 (which equals to US $2,864,628).<br><br>CONCLUSIONS: COPD exacerbations had the higher prevalence in the Madrid region among the respiratory diseases studied. With the COVID-19 pandemic, the prevalence and costs of almost all these diseases decreased, except for ARF not related to chronic disease. The cost of these pathologies over 5 years was &#x20ac;58,791,031 (US $61,832,879).}, }
@article {pmid39819742, year = {2025}, author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J}, title = {Peripheral proteinopathy in neurodegenerative diseases.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {2}, pmid = {39819742}, issn = {2047-9158}, support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; }, abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.}, }
@article {pmid39819257, year = {2025}, author = {Barton, M and Roman, A and Spencer, K and Cheng, L and Baylor, C}, title = {Examining the perspectives of augmentative and alternative communication (AAC) specialists on conducting AAC evaluations with people with amyotrophic lateral sclerosis via telehealth.}, journal = {Augmentative and alternative communication (Baltimore, Md. : 1985)}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/07434618.2024.2443669}, pmid = {39819257}, issn = {1477-3848}, abstract = {The purpose of this study was to explore what speech-language pathologists (SLPs) who are AAC specialists see as advantages and disadvantages of providing AAC services via telehealth, how well tele-AAC assessments align with guidelines for in-person assessments, and how SLPs' perspectives of tele-AAC services changed post-COVID. Fifteen SLPs who are AAC specialists and experienced working with people with amyotrophic lateral sclerosis watched videos of speech generating device (SGD) assessments conducted via telehealth for eight people with amyotrophic lateral sclerosis. Using a checklist based on the AAC Clinical Assessment Project (AAC-CAP), the SLPs rated how comparable remote assessment was to in-person assessment, and described advantages and challenges. Across checklist elements, most participants rated AAC assessment via telemedicine as "same/comparable" to in-person assessment. The most common advantages of tele-AAC assessment were that tele-AAC was more functional, increased care partner availability, and increased clients' comfort at home. The most common challenges were technical difficulties and a limited comprehensive assessment due to the remote modality. Tele-AAC should be considered a viable assessment option as it may increase equitable access to care for more people with amyotrophic lateral sclerosis. Tools such as the AAC-CAP may help generalist SLPs increase their comfort and proficiency providing AAC services.}, }
@article {pmid39818026, year = {2025}, author = {Choi, Y and Jung, HJ and Jung, HK and Jeong, E and Kim, S and Kim, JY and Lee, EJ and Lim, YM and Kim, H}, title = {In vivo imaging markers of glymphatic dysfunction in amyotrophic lateral sclerosis: Analysis of ALPS index and choroid plexus volume.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123393}, doi = {10.1016/j.jns.2025.123393}, pmid = {39818026}, issn = {1878-5883}, mesh = {*Glymphatic System/diagnostic imaging/pathology ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; *Choroid Plexus/diagnostic imaging ; Organ Size ; *Biomarkers/analysis ; Humans ; Male ; Female ; Middle Aged ; Aged ; Sensitivity and Specificity ; Diffusion Tensor Imaging ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: The glymphatic system, essential for brain waste clearance, has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Emerging imaging markers, such as the analysis along the perivascular space (ALPS) index and choroid plexus volume (CPV), may provide insights into glymphatic function, but their relevance to ALS remains unclear.<br><br>OBJECTIVE: To assess glymphatic dysfunction in ALS patients using the ALPS index and CPV.<br><br>METHODS: In this prospective single-center study, we analyzed 51 ALS patients and 51 age- and sex-matched healthy controls (HC). The ALPS index was calculated using diffusion tensor imaging, and 3D T1-weighted MRI was used for automated estimation of CPV and its fraction (CPV/total intracranial volume). Diagnostic performance was assessed using area under the receiver operating curve (AUC). Correlations between imaging markers and clinical parameters were also examined.<br><br>RESULTS: ALS patients had a significantly lower ALPS index (ALS: 1.45&#xa0;&#xb1;&#xa0;0.15; HC: 1.55&#xa0;&#xb1;&#xa0;0.16; p&#xa0;=&#xa0;0.002) and higher CPV fraction (ALS: 0.12&#xa0;&#xb1;&#xa0;0.04&#xa0;%; HC: 0.10&#xa0;&#xb1;&#xa0;0.02&#xa0;%; p&#xa0;<&#xa0;0.001). The ALPS index and CPV fraction had AUCs of 0.70 and 0.72, respectively. A significant inverse correlation was observed between the ALPS index and CPV fraction (r&#xa0;=&#xa0;-0.31, p&#xa0;=&#xa0;0.002). Both markers correlated with aging but not with clinical disability or progression rate.<br><br>CONCLUSION: This study identifies glymphatic dysfunction in ALS, as evidenced by changes in the ALPS index and CPV. Larger studies are warranted to validate these findings and assess their potential as biomarkers for ALS.}, }
@article {pmid39817908, year = {2025}, author = {Aikio, M and Odeh, HM and Wobst, HJ and Lee, BL and Chan, &#xda; and Mauna, JC and Mack, KL and Class, B and Ollerhead, TA and Ford, AF and Barbieri, EM and Cupo, RR and Drake, LE and Smalley, JL and Lin, YT and Lam, S and Thomas, R and Castello, N and Baral, A and Beyer, JN and Najar, MA and Dunlop, J and Gitler, AD and Javaherian, A and Kaye, JA and Burslem, GM and Brown, DG and Donnelly, CJ and Finkbeiner, S and Moss, SJ and Brandon, NJ and Shorter, J}, title = {Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115205}, pmid = {39817908}, issn = {2211-1247}, support = {K99 AG075242/AG/NIA NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R21 AG065854/AG/NIA NIH HHS/United States ; R35 GM142505/GM/NIGMS NIH HHS/United States ; F32 NS108598/NS/NINDS NIH HHS/United States ; R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 LM013617/LM/NLM NIH HHS/United States ; F31 AG060672/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; F31 NS087676/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Phosphorylation ; *Protein-Arginine N-Methyltransferases/metabolism ; Methylation ; *DNA-Binding Proteins/metabolism ; *TDP-43 Proteinopathies/metabolism/pathology ; *Mitogen-Activated Protein Kinase 14/metabolism ; *Arginine/metabolism ; Repressor Proteins/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Animals ; Motor Neurons/metabolism/pathology ; Mice ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.}, }
@article {pmid39817235, year = {2024}, author = {Cicardi, ME and Trotti, D}, title = {C9orf72 role in myeloid cells: new perspectives in the investigation of the neuro-immune crosstalk in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Annals of translational medicine}, volume = {12}, number = {6}, pages = {120}, pmid = {39817235}, issn = {2305-5839}, }
@article {pmid39817215, year = {2025}, author = {Liu, SQ and Wang, D and Tang, CC}, title = {Association between age at diagnosis of diabetes and ocular disease: Insights from a recent article.}, journal = {World journal of diabetes}, volume = {16}, number = {1}, pages = {94846}, pmid = {39817215}, issn = {1948-9358}, abstract = {In this article, we discuss Ye et al's recent article on the association between age at diabetes diagnosis and subsequent risk of age-related ocular diseases. The study, which utilized United Kingdom Biobank data, highlighted a strong link between early diabetes onset and major eye conditions, such as cataracts, glaucoma, age-related macular degeneration, and vision loss, independent of glycemic control and disease duration. This finding challenges the previous belief that diabetic eye disease primarily correlates with hyperglycemia. As lifestyles evolve and the age of diabetes diagnosis decreases, understanding this relationship may reveal the complex pathogenesis underlying diabetes-related complications. This editorial summarizes potential mechanisms connecting the age of diabetes onset with four types of ocular diseases, emphasizing the significance of early diagnosis.}, }
@article {pmid39817143, year = {2025}, author = {Chew, FY and Tsai, CH and Chang, KH and Chang, YK and Chou, RH and Liu, YJ}, title = {Exosomes as promising frontier approaches in future cancer therapy.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {100713}, pmid = {39817143}, issn = {1948-5204}, abstract = {In this editorial, we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology. They explored an innovative approach to enhancing gemcitabine (GEM) delivery and efficacy using human bone marrow mesenchymal stem cells (HU-BMSCs)-derived exosomes. The manufacture of GEM-loaded HU-BMSCs-derived exosomes (Exo-GEM) has been optimized. The Tang et al's study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM, highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer. Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.}, }
@article {pmid39817131, year = {2025}, author = {Lampridis, S}, title = {Unraveling the landscape of pediatric pancreatic tumors: Insights from Japan.}, journal = {World journal of gastrointestinal oncology}, volume = {17}, number = {1}, pages = {101477}, pmid = {39817131}, issn = {1948-5204}, abstract = {Pediatric pancreatic tumors, though rare, pose significant diagnostic and management challenges. The recent, 22-year nationwide survey on pediatric pancreatic tumors in Japan by Makita et al offers valuable insights into this uncommon entity, revealing striking geographical variations and questioning current treatment paradigms. This editorial commentary analyzes the study's key findings, including the predominance of solid pseudopapillary neoplasms and their younger age of onset, which contrast sharply with Western data. It explores the implications for clinical practice and research, emphasizing the need for population-specific approaches to diagnosis and treatment. The revealed limited institutional experience and surgical management patterns prompt a reevaluation of optimal care delivery for these complex cases, suggesting benefits of centralizing healthcare services. Furthermore, the commentary advocates for international collaborative studies to elucidate the genetic, environmental, and lifestyle factors influencing the development and progression of pediatric pancreatic tumors across diverse populations. It also outlines future directions, calling for advancements in precision medicine and innovative care delivery models to improve global patient outcomes. Unraveling Makita et al's findings within the broader landscape of pediatric oncology can stimulate further research and clinical advancements in managing pancreatic and other rare tumors in children.}, }
@article {pmid39816800, year = {2025}, author = {Shokr, MM and Badawi, GA and Elshazly, SM and Zaki, HF and Mohamed, AF}, title = {Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.}, journal = {ACS pharmacology &amp; translational science}, volume = {8}, number = {1}, pages = {47-65}, pmid = {39816800}, issn = {2575-9108}, abstract = {Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.}, }
@article {pmid39816195, year = {2025}, author = {Yildiz, O and Hunt, GP and Schroth, J and Dhillon, G and Spargo, TP and Al-Chalabi, A and Koks, S and Turner, MR and Shaw, PJ and Henson, SM and Iacoangeli, A and Malaspina, A}, title = {Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {7}, number = {1}, pages = {fcae402}, pmid = {39816195}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1n-3 DPA were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b[+] integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8[+] T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.}, }
@article {pmid39814005, year = {2025}, author = {Teive, HAG and Coutinho, L and Cardoso, FEC and Tsuji, S}, title = {Neurology pioneers in Japan.}, journal = {Arquivos de neuro-psiquiatria}, volume = {83}, number = {1}, pages = {1-3}, pmid = {39814005}, issn = {1678-4227}, mesh = {*Neurology/history ; Japan ; History, 20th Century ; History, 19th Century ; Humans ; }, abstract = {The pioneers of neurology in Japan were professors Hiroshi Kawahara and Kinnosuke Miura. Kawahara published the first description of progressive bulbar palsy and wrote the first neurology textbook in Japan. Miura, on the other hand, published studies about amyotrophic lateral sclerosis, in addition to participating in the founding of the Japanese Society of Neurology. The influence of European neurology, particularly French and German, in the figures of Professor Jean-Martin Charcot and Professor Erwin Bälz, was fundamental in the consolidation of neurology in Japan.}, }
@article {pmid39813104, year = {2025}, author = {Corti, S and Hedlund, E}, title = {Intrinsic neuronal resilience as a tool for therapeutic discovery.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1058-1061}, pmid = {39813104}, issn = {1460-2156}, support = {RF-2018-12366357//MoH/ ; //Ricerca Corrente 2024/ ; 2020-01049//The Swedish Research Council/ ; //Radala Foundation for ALS Research/ ; FO2023-0346//The Swedish Brain Foundation/ ; //Olov Thon's Foundation/ ; 233021//&#xc5;hlen Foundation/ ; //Ollie &amp; Elof Ericssons Foundation to E.H./ ; }, abstract = {Corti and Hedlund argue that understanding the molecular underpinnings of neuronal resilience and vulnerability to neurodegenerative diseases such as ALS is key to identifying new therapeutic targets.}, }
@article {pmid39813072, year = {2025}, author = {Raines, C and Mefferd, A}, title = {Disease-Specific Speech Movement Characteristics of the Tongue and Jaw.}, journal = {Journal of speech, language, and hearing research : JSLHR}, volume = {}, number = {}, pages = {1-14}, doi = {10.1044/2024_JSLHR-24-00351}, pmid = {39813072}, issn = {1558-9102}, support = {R01 DC019648/DC/NIDCD NIH HHS/United States ; R03 DC015075/DC/NIDCD NIH HHS/United States ; }, abstract = {PURPOSE: To advance our understanding of disease-specific articulatory impairment patterns in speakers with dysarthria, this study investigated the articulatory performance of the tongue and jaw in speakers with differing neurological diseases (Parkinson's disease [PD], amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease).<br><br>METHOD: Fifty-seven speakers with dysarthria and 30 controls produced the sentence "Buy Kaia a kite" five times. A three-dimensional electromagnetic articulography was used to record the articulatory movements of the posterior tongue and jaw. Sentence-length kinematic measures (e.g., duration, tongue range of motion [ROM], jaw ROM, tongue speed, jaw speed) were extracted.<br><br>RESULTS: Results revealed significant group effects for the duration, jaw ROM, and tongue speed but not for tongue ROM. Post hoc pairwise comparisons revealed more significant between-groups differences for duration and jaw ROM than for tongue speed. Statistically significant findings between clinical groups were predominantly driven by the difference between speakers with PD and speakers of other clinical groups.<br><br>CONCLUSIONS: Reduced jaw ROM and trends toward reduced tongue ROM confirm hypokinesia as a distinguishing motor feature of speakers with PD. However, deviancies in speed or movement duration did not emerge as a distinguishing motor feature for any of the four studied clinical groups. Nevertheless, movement duration, but not movement speed, may be useful to index dysarthria severity.}, }
@article {pmid39812841, year = {2025}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {Predicting ALS informant distress from cognitive and behavioural change in people with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {2}, pages = {144}, pmid = {39812841}, issn = {1432-1459}, support = {Goldstein/Oct17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/psychology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/etiology/diagnosis ; *Caregivers/psychology ; *COVID-19/complications ; Depression/etiology/diagnosis ; Psychological Distress ; Anxiety/etiology/diagnosis ; Adult ; }, abstract = {BACKGROUND: The cognitive and behavioural changes that occur in around 50% of people with amyotrophic lateral sclerosis (ALS) may significantly affect people around them, contributing to heightened burden, anxiety, and depression. Despite existing evidence linking behavioural impairment to caregiver distress, the role of cognitive impairment remains less clear, with mixed findings on its impact.<br><br>METHODS: This study assessed the influence of cognitive and behavioural impairments in people with ALS on the distress of their nominated informants. The data were collected face-to-face and remotely due to the COVID-19 pandemic. The cognitive and behavioural impairments were measured using established screening tools. Informants' distress was evaluated through composite measures of burden, anxiety, and depression. Regression analyses were employed to determine the predictive value of cognitive and behavioural impairment on informant distress.<br><br>RESULTS: A total of 98 ALS patients and 84 informants participated. Behavioural impairment predicted informant distress across various tools. In contrast, cognitive impairment was a less consistent predictor of informant distress across screening measures and did not significantly interact with behavioural impairment in predicting distress. Administration mode did not affect predictive relationships.<br><br>CONCLUSIONS: Behavioural impairment in ALS significantly predicts informant distress, with varying predictive power across different screening tools. Cognitive impairment also affects informant distress, but its impact is less substantial compared to behavioural factors. The interaction between cognitive and behavioural impairments did not significantly predict informant distress.}, }
@article {pmid39812044, year = {2025}, author = {Liu, B and Chen, L and Chen, H and Pan, J and Yu, C}, title = {Bioinformatics Analysis Reveals Microrchidia Family Genes as the Prognostic and Therapeutic Markers for Colorectal Cancer.}, journal = {Endocrine, metabolic &amp; immune disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715303367767241231113110}, pmid = {39812044}, issn = {2212-3873}, abstract = {AIM: The aim of this study is to examine the role of the microrchidia (MORC) family, a group of chromatin remodeling proteins, as the therapeutic and prognostic markers for colorectal cancer (CRC).<br><br>BACKGROUND: MORC protein family genes are a highly conserved nucleoprotein superfamily whose members share a common domain but have distinct biological functions. Previous studies have analyzed the roles of MORCs as epigenetic regulators and chromatin remodulators; however, the involvement of MORCs in the development and pathogenesis of CRC was less examined.<br><br>OBJECTIVE: The current work examined the role of the MORCs as the therapeutic and prognostic markers for CRC.<br><br>METHODS: The expressions and prognostic significance of MORC family genes in CRC were explored. The role of these genes in tumor immunity was comprehensively analyzed in terms of their functions in immune cell infiltration, tumor microenvironment (TME), and their interaction with immune regulatory genes such as immunosuppressive genes, immune checkpoints and immunostimulatory genes. The relations between MORC family genes, tumor mutation burden (TMB), DNA, mismatch repair (MMR), RNA methylation, microsatellite instability (MSI), and drug sensitivity were investigated using the R statistical software. The expressions of MORC4 in 150 CRC tissues and 60 paracancer tissues were detected by immunohistochemical method. CRC cell proliferation, migration, and invasion were measured by cell counting kit-8 (CCK-8), scratch assay, and transwell cell invasion assay.<br><br>RESULTS: The expressions of MORC2 and MORC4 were significantly upregulated, whereas those of MORC1 and MORC3 were noticeably downregulated in CRC in comparison to their expressions in normal colorectal mucosal tissues. Patients with high-expressed MORC2 showed a more unfavorable prognosis than those with a low MORC2 level. Functional annotation analysis identified 100 MORC family genes with the most significant negative or positive correlations to diabetic cardiomyopathy, amyotrophic lateral sclerosis, oxidative phosphorylation, Huntington's disease, thermogenesis, Parkinson's disease, olfactory transduction, Alzheimer's disease, prion disease. MORC3 expression was positively correlated with Stromal score, Immune score and ESTIMATE score, while MORC2 expression was negatively related to the three scores in CRC, these correlations were not statistically significant. Additionally, the MORC family genes were significantly positively correlated with tumor-infiltrating immune cells such as T helper cells and exhibited close relations to some immunosuppressive genes such as CXCR4 and PVR, immunostimulatory genes such as TGFBR1, KDR, and CD160 as well as some immune checkpoint genes. It was found that the expressions of some members of MORC family genes were positively correlated with DNA methylation, MSI, TMB, MMRs, and drug sensitivity in CRC and that the mRNA and protein levels of MORC4 were remarkably upregulated in CRC tissues than in adjacent normal tissues (P<0.05). In the MORC4 knockdown group, DLD-1 cell proliferation was more inhibited than in the negative control (NC) and siRNA groups (P<0.05). Furthermore, the migratory capacity of DLD-1 cells and the number of cells crossing the basement membrane in the MORC4 knockdown group were reduced compared to the NC and siRNA groups (all P<0.05).<br><br>CONCLUSION: The expressions of MORC family genes were significantly different in CRC samples, which was related to the immune cell infiltration and prognosis of CRC. Thus, the MORC family genes were considered as markers for indicating the clinical immunotherapy and prognostic outcome of CRC.}, }
@article {pmid39811452, year = {2024}, author = {Li, R and Bao, T and Li, B and Xia, P and Zhang, T and Zhang, H and Huang, F}, title = {Effectiveness and safety of traditional Chinese therapies intreating patients with amyotrophic lateral sclerosis: a protocol for systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1519513}, pmid = {39811452}, issn = {1664-2295}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic, progressive disease that affects both upper and lower motor neurons. Some physicians have used traditional Chinese therapies (TCT) to treat ALS. However, there has been no systematic review or meta-analysis to evaluate the effectiveness and safety of TCT interventions. This review aims to analyze the effects of TCT interventions for patients with amyotrophic lateral sclerosis.<br><br>METHODS AND ANALYSIS: This study will include randomized, non-randomized, and quasi-experimental clinical trials, with participants being any age Amyotrophic Lateral Sclerosis (ALS) patients who have undergone TCT treatment. Two researchers will independently search databases including CENTRAL, PubMed, PEDro, EMBASE, CNKI, CBM, and SPORTDiscus, without restrictions on language or publication date. These researchers will independently screen titles and abstracts and extract data from the included studies. If deemed suitable for meta-analysis, data synthesis will be conducted using Review Manager V.5.3 software; any discrepancies will be resolved by a third researcher. The meta-analysis will compare the effects of TCT with placebo or other interventions. The main endpoint evaluated was the decrease in the overall score of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; scoring from 0 to 48, where higher scores denote greater functionality) over a period of 24&#x202f;weeks. Additional endpoints included the reduction rates in isometric muscle power, levels of phosphorylated axonal neurofilament H subunits in plasma, and slow vital capacity measurements. Furthermore, the study monitored the duration until occurrence of death, tracheostomy, or the need for long-term ventilation, as well as the time until death, tracheostomy, long-term ventilation, or hospital admission.<br><br>ETHICS AND DISSEMINATION: Throughout the entire process of this systematic review, no personal information was used, hence ethical review is not required. The results of this meta-analysis will be disseminated through publication in peer-reviewed journals and/or conference presentations.}, }
@article {pmid39810199, year = {2025}, author = {Eck, RJ and Valdmanis, PN and Liachko, NF and Kraemer, BC}, title = {Alternative 3' UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD.}, journal = {Molecular brain}, volume = {18}, number = {1}, pages = {1}, pmid = {39810199}, issn = {1756-6606}, support = {RF1 AG078374/AG/NIA NIH HHS/United States ; F99AG088436/NH/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; IK6 BX006467/BX/BLRD VA/United States ; I01 BX005762/BX/BLRD VA/United States ; IK6BX006467//U.S. Department of Veterans Affairs/ ; R21AG082032/NH/NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; RF1AG078374/NH/NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Polyadenylation ; *3' Untranslated Regions/genetics ; *Disease Models, Animal ; Humans ; DNA-Binding Proteins/metabolism/genetics ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Mice ; }, abstract = {Recent research has highlighted widespread dysregulation of alternative polyadenylation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Here, we identify significant disruptions to 3` UTR polyadenylation in the ALS/FTLD-TDP mouse model rNLS8 that correlate with changes in gene expression and protein levels through the re-analysis of published RNA sequencing and proteomic data. A subset of these changes are shared with TDP-43 knock-down mice suggesting depletion of endogenous mouse TDP-43 is a contributor to polyadenylation dysfunction in rNLS8 mice. Some conservation exists between alternative polyadenylation in rNLS8 mice and human disease models including in disease relevant genes and biological pathways. Together, these findings support both TDP-43 loss and toxic gain-of-function phenotypes as contributors to the neurodegeneration in rNLS8 mice, nominating its continued utility as a preclinical model for investigating mechanisms of neurodegeneration in ALS/FTLD-TDP.}, }
@article {pmid39810183, year = {2025}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Souza, CDS and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {10}, pmid = {39810183}, issn = {1755-8794}, support = {CEGS 5P50HG00773504//NIH (USA)/ ; 899-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; NF-SI-0617-10077//National Institute for Health and Care Research/ ; /WT_/Wellcome Trust/United Kingdom ; IS-BRC-1215-20017//NIHR Sheffield Biomedical Research Centre/ ; 216596/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/blood ; Humans ; *Motor Neurons/metabolism/pathology ; *Biomarkers/blood ; *DNA Methylation ; Cell-Free Nucleic Acids/blood/genetics ; Induced Pluripotent Stem Cells/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, }
@article {pmid39809929, year = {2025}, author = {Antico, O and Thompson, PW and Hertz, NT and Muqit, MMK and Parton, LE}, title = {Targeting mitophagy in neurodegenerative diseases.}, journal = {Nature reviews. Drug discovery}, volume = {24}, number = {4}, pages = {276-299}, pmid = {39809929}, issn = {1474-1784}, mesh = {Humans ; *Mitophagy/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism/genetics ; Animals ; Mitochondria/drug effects/metabolism ; Protein Kinases ; }, abstract = {Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.}, }
@article {pmid39809899, year = {2025}, author = {Cui, Y and Arnold, FJ and Li, JS and Wu, J and Wang, D and Philippe, J and Colwin, MR and Michels, S and Chen, C and Sallam, T and Thompson, LM and La Spada, AR and Li, W}, title = {Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain.}, journal = {Nature genetics}, volume = {57}, number = {2}, pages = {369-378}, pmid = {39809899}, issn = {1546-1718}, mesh = {Humans ; *Quantitative Trait Loci ; *Brain/metabolism ; *Gene Expression Regulation ; Tandem Repeat Sequences/genetics ; Phenotype ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein/genetics ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Multiomics ; }, abstract = {Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3'-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer's disease.}, }
@article {pmid39806943, year = {2024}, author = {Lee, K and Kim, SI and Shim, YM and Kim, EE and Yoo, S and Won, JK and Park, SH}, title = {Current Status and Future Perspective of Seoul National University Hospital-Dementia Brain Bank with Concordance of Clinical and Neuropathological Diagnosis.}, journal = {Experimental neurobiology}, volume = {33}, number = {6}, pages = {295-311}, pmid = {39806943}, issn = {1226-2560}, abstract = {This paper introduces the current status of Seoul National University Hospital Dementia Brain Bank (SNUH-DBB), focusing on the concordance rate between clinical diagnoses and postmortem neuropathological diagnoses. We detail SNUH-DBB operations, including protocols for specimen handling, induced pluripotent stem cells (iPSC) and cerebral organoids establishment from postmortem dural fibroblasts, and adult neural progenitor cell cultures. We assessed clinical-neuropathological diagnostic concordance rate. Between 2015 and September 2024, 162 brain specimens were collected via brain donation and autopsy. The median donor age was 73 years (1-94) with a male-to -female ratio of 2:1. The median postmortem interval was 9.5 hours (range: 2.5-65). Common neuropathological diagnoses included pure Lewy body disease (10.6%), Lewy body disease (LBD) with other brain diseases (10.6%), pure Alzheimer's disease-neuropathological change (ADNC) (6.0%), ADNC with other brain diseases (10.7%), vascular brain injury (15.2%), and primary age-related tauopathy (7.3%). APOE genotype distribution was following: ε3/ε3: 62.3%, ε2/ε3: 9.6%, ε2/ε4: 3.4%, ε3/ε4: 24.0%, and ε4/ε4: 0.7%. Concordance rates between pathological and clinical diagnoses were: ADNC/AD at 42.4%; LBD at 59.0%; PSP at 100%; ALS at 85.7%; Huntington's disease 100%. The varying concordance rates across different diseases emphasize the need for improved diagnostic criteria and biomarkers, particularly for AD and LBD. Tissues have been distributed to over 40 national studies. SNUH-DBB provides high-quality brain tissues and cell models for neuroscience research, operating under standardized procedures and international guidelines. It supports translational research in dementia and neurodegenerative diseases, potentially advancing diagnostic and therapeutic strategies.}, }
@article {pmid39806490, year = {2025}, author = {Shen, Y and Zhang, X and Liu, S and Xin, L and Xuan, W and Zhuang, C and Chen, Y and Chen, B and Zheng, X and Wu, R and Lin, Y}, title = {CEST imaging combined with [1]H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.}, journal = {Alzheimer's research &amp; therapy}, volume = {17}, number = {1}, pages = {20}, pmid = {39806490}, issn = {1758-9193}, support = {240428226498013//Shantou Science and Technology Project/ ; 213769/SNSF_/Swiss National Science Foundation/Switzerland ; 82020108016//National Natural Science Foundation of China/ ; 82071973//National Natural Science Foundation of China/ ; 2023A1515010326//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022ZDZX2020//Key Research Platform and Project of Guangdong University/ ; }, mesh = {Animals ; *Riluzole/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Neuroprotective Agents/pharmacology ; Mice ; *Mice, Transgenic ; *Glutamic Acid/metabolism ; *gamma-Aminobutyric Acid/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Brain/drug effects/metabolism/diagnostic imaging ; Disease Models, Animal ; Male ; Magnetic Resonance Imaging/methods ; Neurotransmitter Agents/metabolism ; }, abstract = {BACKGROUND: The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy ([1]H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.<br><br>METHODS: GluCEST, GABACEST and [1]H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5&#xa0;mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.<br><br>RESULTS: GluCEST, GABACEST and [1]H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (A&#x3b2;) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.<br><br>CONCLUSIONS: CEST imaging combined with [1]H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.}, }
@article {pmid39805247, year = {2025}, author = {Uzunçakmak-Uyanık, H and Yıldız, FG and Tan, E and Temuçin, &#xc7;M}, title = {Thoracic paraspinal muscle concentric needle electrode jitter analysis in electrophysiological diagnosis of ALS.}, journal = {Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology}, volume = {81}, number = {}, pages = {102975}, doi = {10.1016/j.jelekin.2025.102975}, pmid = {39805247}, issn = {1873-5711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electromyography/methods ; Male ; Female ; Middle Aged ; *Paraspinal Muscles/physiopathology ; *Electrodes ; Aged ; Needles ; Adult ; }, abstract = {OBJECTIVES: Jitter analysis with concentric needle electrode of the thoracic 9 (T9) paraspinal muscle (PM), where the needle EMG examination at rest is difficult, was performed in both amyotrophic lateral sclerosis (ALS) patients and the controls.<br><br>METHODS: For the T9 PM, both upper limit for mean and individual mean consecutive difference (MCD) values and spike numbers were calculated according to jitter values of pairs from controls. In addition to the descriptive statistics, differences between two groups and T9 PM needle EMG and jitter analysis findings of patients were compared (p&#xa0;=&#xa0;0.05).<br><br>RESULTS: Mean MCD median values of T9 PM were 62.8 and 26.2&#xa0;&#xb5;s in patient and controls respectively. Upper limit of mean and individual MCDs for the T9 PM were determined as 36.95&#xa0;&#x3bc;s, 57.95&#xa0;&#x3bc;s respectively. The differences between controls and patients in terms of all jitter analysis parametres (p&#xa0;<&#xa0;0.001) and the comparison of patients' T9 PM needle EMG and jitter analysis findings grading were statistically significant (p&#xa0;=&#xa0;0.029).<br><br>CONCLUSION: The T9 PM jitter analysis performed during routine EMG can be used to support the electrophysiological diagnosis of ALS in challenging cases and may contribute to minimizing the number of muscles examined. Furthermore, our study contributed to the T9 PM reference values for jitter analysis.}, }
@article {pmid39804774, year = {2025}, author = {Agnihotri, D and Lee, CC and Lu, PC and He, RY and Huang, YA and Kuo, HC and Huang, JJ}, title = {C9ORF72 poly-PR induces TDP-43 nuclear condensation via NEAT1 and is modulated by HSP70 activity.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115173}, doi = {10.1016/j.celrep.2024.115173}, pmid = {39804774}, issn = {2211-1247}, mesh = {*HSP70 Heat-Shock Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *C9orf72 Protein/metabolism/genetics ; *RNA, Long Noncoding/metabolism/genetics ; Cell Nucleus/metabolism ; }, abstract = {The toxicity of C9ORF72-encoded polyproline-arginine (poly-PR) dipeptide is associated with its ability to disrupt the liquid-liquid phase separation of intrinsically disordered proteins participating in the formation of membraneless organelles, such as the nucleolus and paraspeckles. Amyotrophic lateral sclerosis (ALS)-related TAR DNA-binding protein 43 (TDP-43) also undergoes phase separation to form nuclear condensates (NCs) in response to stress. However, whether poly-PR alters the nuclear condensation of TDP-43 in ALS remains unclear. In this study, we find that the poly-PR dipeptide enhances the formation of TDP-43 NCs with decreased fluidity. While the non-coding RNA, nuclear-enriched abundant transcript 1 (NEAT1), is essential for the formation of TDP-43 NCs, heat shock protein 70 (HSP70) chaperone maintains their fluidity. Under prolonged poly-PR stress, HSP70 delocalizes from TDP-43 NCs, leading to the oligomerization of TDP-43 within these condensates. This phenomenon is accompanied with TDP-43 mislocalization and increasing cytotoxicity. Our study demonstrates the role of NEAT1 and HSP70 in the aberrant phase transition of TDP-43 NCs under poly-PR stress.}, }
@article {pmid39804470, year = {2025}, author = {Edgar, S and Zulhairy-Liong, NA and Ellis, M and Trivedi, S and Zhu, D and Odongo, JO and Goh, KJ and Capelle, DP and Shahrizaila, N and Kennerson, ML and Ahmad-Annuar, A}, title = {ATXN2 polyglutamine intermediate repeats length expansions in Malaysian patients with amyotrophic lateral sclerosis (ALS).}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {19}, pmid = {39804470}, issn = {1364-6753}, support = {FRGS/1/2018/SKK08/UM/01/1//Malaysian Ministry of Education Fundamental Research Grant Scheme/ ; IF091-2022//ALS Association Seed Grant/ ; IF095-2023//ALS Association Seed Grant/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Malaysia ; *Ataxin-2/genetics ; Male ; Female ; Middle Aged ; *Trinucleotide Repeat Expansion/genetics ; Adult ; Aged ; Peptides/genetics ; Asian People/genetics ; Genetic Predisposition to Disease ; }, abstract = {Intermediate CAG repeats from 29 to 33 in the ATXN2 gene contributes to the risk of amyotrophic lateral sclerosis (ALS) in European and Asian populations. In this study, 148 ALS patients of multiethnic descent: Chinese (56.1%), Malay (24.3%), Indian (12.8%), others (6.8%) and 100 neurologically normal controls were screened for the ATXN2 CAG repeat expansion. The most common repeat length in both the controls and patients was 22. No familial ALS patients were positive for the intermediate repeat sizes (29-33), while four sporadic patients (2.8%) were positive, with one harbouring a rare ATXN2 homozygous 32 repeat expansion, and a likely pathogenic variant in SPAST. All four patients had limb-onset ALS. Despite representing the smallest ethnic group in our patient cohort, three of the four patients with intermediate repeat sizes were of Indian ancestry. This study, which is the first in Malaysia and Southeast Asia, shows that ATXN2 intermediate risk expansions are relevant to ALS in these populations and will help to inform future genetic testing strategies in the clinic.}, }
@article {pmid39803328, year = {2025}, author = {Niu, T and Wang, P and Zhou, X and Liu, T and Liu, Q and Li, R and Yang, H and Dong, H and Liu, Y}, title = {An overlap-weighted analysis on the association of constipation symptoms with disease progression and survival in amyotrophic lateral sclerosis: a nested case-control study.}, journal = {Therapeutic advances in neurological disorders}, volume = {18}, number = {}, pages = {17562864241309811}, pmid = {39803328}, issn = {1756-2856}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and rare neurodegenerative disease. Therefore, evaluating the risk factors affecting the survival of patients with ALS is crucial. Constipation, a common but overlooked symptom of ALS, can be effectively managed. It is currently unknown whether constipation contributes to the progression and survival of ALS.<br><br>OBJECTIVES: This study aimed to investigate the association between constipation and ALS development and survival using a novel overlap-weighted (OW) method to enhance the robustness and reliability of results.<br><br>DESIGN: This prospective matching nested case-control (NCC) study was conducted within an ongoing ALS cohort at the Second Hospital of Hebei Medical University. Baseline data were collected from patients meeting the inclusion and exclusion criteria, with constipation as the exposure factor. A 9-month follow-up was conducted, with death as the endpoint event.<br><br>METHODS: We primarily used the OW method in NCC studies to examine the association between constipation and ALS development and survival. Weighted Cox proportional hazards model was used to assess risk factors associated with overall survival. Survival differences between the two groups were analyzed using Kaplan-Meier's plots and log-rank tests. Finally, the bioinformatic analysis explored common pathways between ALS and constipation.<br><br>RESULTS: Among the 190 patients included, the prevalence of constipation was 50%. Patients with ALS constipation exhibited faster disease progression (p&#x2009;<&#x2009;0.001), with a positive correlation between constipation severity and progression rate (r&#x2009;=&#x2009;0.356, p&#x2009;<&#x2009;0.001). The constipation group had poorer survival before and after OW (log-rank test, p&#x2009;<&#x2009;0.0001). In the Cox proportional hazards model of 114 patients, constipation was a risk factor for ALS both before (hazard ratio (HR)&#x2009;=&#x2009;5.840, 95% confidence interval (CI)&#x2009;=&#x2009;1.504-22.675, p&#x2009;=&#x2009;0.011) and after (HR&#x2009;=&#x2009;5.271, 95% CI&#x2009;=&#x2009;1.241-22.379, p&#x2009;=&#x2009;0.024) OW.<br><br>CONCLUSION: Constipation in individuals with ALS is associated with faster disease progression and reduced survival rates, potentially through the peroxisome proliferator-activated receptor pathway.}, }
@article {pmid39802934, year = {2025}, author = {Ogonah, MGT and Botchway, S and Yu, R and Schofield, PW and Fazel, S}, title = {An umbrella review of health outcomes following traumatic brain injury.}, journal = {Nature. Mental health}, volume = {3}, number = {1}, pages = {83-91}, pmid = {39802934}, issn = {2731-6076}, abstract = {While numerous reviews have assessed the association between traumatic brain injury (TBI) and various mental and physical health outcomes, a comprehensive evaluation of the scope, validity, and quality of evidence is lacking. Here we present an umbrella review of a wide range of health outcomes following TBI and outline outcome risks across subpopulations. On 17 May 2023, we searched Embase, Medline, Global Health, PsycINFO, and Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses. We compared risk ratios across different outcomes for risks compared with people without TBI and examined study quality, including heterogeneity, publication bias, and prediction intervals. The study was registered with PROSPERO (CRD42023432255). We identified 24 systematic reviews and meta-analyses covering 24 health outcomes in 31,397,958 participants. The current evidence base indicates an increased risk of multiple mental and physical health outcomes, including psychotic disorders, attention-deficit/hyperactivity disorder, suicide, and depression. Three outcomes-dementia, violence perpetration, and amyotrophic lateral sclerosis-had meta-analytical evidence of at least moderate quality, which suggest targets for more personalized assessment. Health-care services should review how to prevent adverse long-term outcomes in TBI.}, }
@article {pmid39801873, year = {2025}, author = {Kumar, AJ and Sathiyaseelan, N and Vinodh, JB and Vignesh, A and Rathi, NK}, title = {Recent Advances in Managing Ankylosing Spondylitis with Andersson Lesion: A Clinical Overview and Case Report.}, journal = {Journal of orthopaedic case reports}, volume = {15}, number = {1}, pages = {21-25}, pmid = {39801873}, issn = {2250-0685}, abstract = {INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disorder that primarily affects the spine and sacroiliac joints, leading to pain, stiffness, and progressive thoracolumbar kyphotic deformity. A key complication in advanced AS is the development of Andersson lesions (AL), degenerative vertebral lesions resulting from the disease's progression. These lesions can cause significant mechanical pain, often mistaken for the chronic discomfort associated with AS. The exact cause of AL remains unclear, with hypotheses ranging from spinal stress fractures to delays in the ankylosing process. Understanding AL's pathophysiology is essential for timely diagnosis and effective management.<br><br>CASE REPORT: A 52-year-old male presented with a 20-year history of diffuse abdominal pain, later developing insidious lower back pain over the past 2 months. The pain was aggravated by walking and prolonged standing. Physical examination revealed tenderness in the D11 region of the spine, with limited chest expansion and positive findings on the modified Schober's test. Radiographic studies showed irregularities and erosions at the D11-D12 vertebral levels, and magnetic resonance imaging confirmed the presence of an AL associated with asymmetrical bilateral sacroiliitis. The patient tested positive for human leukocyte antigen-B27, supporting a diagnosis of AS with an AL. Medical management, including methotrexate, sulfasalazine, non-steroidal anti-inflammatory drugs, and corticosteroids, led to significant pain reduction and improved mobility. The patient's condition remained stable with continued treatment over a 2-year follow-up period.<br><br>CONCLUSION: AL s are chronic, often overlooked complications of AS that can lead to spinal instability and neurological deficits if untreated. Early recognition and management are critical to preventing progressive kyphotic deformities and associated complications. While conservative treatment remains the cornerstone for managing AL, surgical intervention may be required in cases of severe pain, deformity, or neurological involvement. Understanding AL's presentation and treatment options is vital for improving patient outcomes in AS.}, }
@article {pmid39801792, year = {2024}, author = {Ansari, U and Wen, J and Syed, B and Nadora, D and Sedighi, R and Nadora, D and Chen, V and Lui, F}, title = {Analyzing the potential of neuronal pentraxin 2 as a biomarker in neurological disorders: A literature review.}, journal = {AIMS neuroscience}, volume = {11}, number = {4}, pages = {505-519}, pmid = {39801792}, issn = {2373-7972}, abstract = {Neuronal pentraxin 2 (NP2) plays a significant role in synaptic plasticity, neuronal survival, and excitatory synapse regulation. Emerging research suggests that NP2 is implicated in the pathogenesis of various neurological disorders, including neurodegenerative diseases, neuropsychiatric disorders, and neuropathies. This literature review extensively analyzes NP2's role in these conditions, thereby highlighting its contributions to synaptic dysfunction, neuroinflammation, and neurotoxic protein aggregation. In Alzheimer's and Parkinson's diseases, NP2 is linked to amyloid-beta aggregation and dopaminergic neuron degeneration, respectively. Additionally, altered NP2 expression is observed in schizophrenia and bipolar disorder, thus suggesting its involvement in synaptic dysfunction and neurotransmitter imbalance. In neuropathic pain and epilepsy, NP2 modulates the synaptic plasticity and inflammatory responses, with altered levels correlating with disease severity. Furthermore, NP2's involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) emphasizes its broad impact on neuronal health. Understanding NP2's multifaceted roles may reveal novel therapeutic targets and improve the clinical outcomes for these neurological disorders. Though the precise role of NP2 remains uncertain, its clinical potential and initial findings justify further investigations into neuronal pentraxins and other related neuroproteins.}, }
@article {pmid39801778, year = {2025}, author = {Ngo, HM and Khatib, T and Thai, MT and Kahveci, T}, title = {QOMIC: quantum optimization for motif identification.}, journal = {Bioinformatics advances}, volume = {5}, number = {1}, pages = {vbae208}, pmid = {39801778}, issn = {2635-0041}, abstract = {MOTIVATION: Network motif identification (MI) problem aims to find topological patterns in biological networks. Identifying disjoint motifs is a computationally challenging problem using classical computers. Quantum computers enable solving high complexity problems which do not scale using classical computers. In this article, we develop the first quantum solution, called QOMIC (Quantum Optimization for Motif IdentifiCation), to the MI problem. QOMIC transforms the MI problem using a integer model, which serves as the foundation to develop our quantum solution. We develop and implement the quantum circuit to find motif locations in the given network using this model.<br><br>RESULTS: Our experiments demonstrate that QOMIC outperforms the existing solutions developed for the classical computer, in term of motif counts. We also observe that QOMIC can efficiently find motifs in human regulatory networks associated with five neurodegenerative diseases: Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, and Motor Neurone Disease.<br><br>Our implementation can be found in https://github.com/ngominhhoang/Quantum-Motif-Identification.git.}, }
@article {pmid39801516, year = {2024}, author = {Kamiyama, D and Nishida, Y and Kamiyama, R and Sego, A and Vining, G and Bui, K and Fitch, M and Do, H and Avraham, O and Chihara, T}, title = {The VAPB Axis Precisely Coordinates the Timing of Motoneuron Dendritogenesis in Neural Map Development.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39801516}, issn = {2693-5015}, support = {P40 OD018537/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; }, abstract = {In Drosophila motoneurons, spatiotemporal dendritic patterns are established in the ventral nerve cord. While many guidance cues have been identified, the mechanisms of temporal regulation remain unknown. Previously, we identified the actin modulator Cdc42 GTPase as a key factor in this process. In this report, we further identify the upstream factors that activate Cdc42. Using single-cell genetics, FRET-based imaging, and biochemical techniques, we demonstrate that the guanine nucleotide exchange factor Vav is anchored to the plasma membrane via the Eph receptor tyrosine kinase, enabling Cdc42 activation. VAMP-associated protein 33 (Vap33), an Eph ligand supplied non-cell-autonomously, may induce Eph autophosphorylation, initiating downstream signaling. Traditionally known as an ER-resident protein, Vap33 is secreted extracellularly at the onset of Cdc42 activation, acting as a temporal cue. In humans, VAPB-the ortholog of Vap33-is similarly secreted in the spinal cord, and its dysregulation leads to amyotrophic lateral sclerosis type 8 (ALS8) and spinal muscular atrophy (SMA). Our findings provide a framework linking VAPB signaling to motor circuitry formation in both health and disease.}, }
@article {pmid39801319, year = {2025}, author = {Oliveira Santos, M and Domingues, S and Simão, S and Gromicho, M and Alves, I and de Carvalho, M}, title = {The Role of Gastrostomy and Noninvasive Ventilation in Primary Lateral Sclerosis.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {3}, pages = {450-456}, doi = {10.1002/mus.28346}, pmid = {39801319}, issn = {1097-4598}, mesh = {Humans ; *Gastrostomy ; Female ; Male ; *Noninvasive Ventilation/methods ; Middle Aged ; Retrospective Studies ; *Deglutition Disorders/etiology/therapy ; Aged ; *Respiratory Insufficiency/etiology/therapy ; Adult ; }, abstract = {INTRODUCTION/AIMS: Literature on the role of gastrostomy and noninvasive ventilation (NIV) in primary lateral sclerosis (PLS) is limited. We aim to investigate whether PLS patients develop dysphagia requiring feeding tubes or respiratory failure necessitating NIV.<br><br>METHODS: We conducted a retrospective study of PLS patients with a definite diagnosis followed at our center (1994-2024). Patients with marked dysphagia (score <&#x2009;3 on Question 3 of the ALSFRS-R) received a recommendation for gastrostomy and were divided into two groups: G1/G2 (accepted/declined gastrostomy). We investigated NIV indications due to respiratory failure and compared these patients (G3) to those without respiratory impairment (G4). Demographic, clinical, and neurophysiological data were collected and compared.<br><br>RESULTS: Forty-eight patients had a definite diagnosis of PLS. Gastrostomy was recommended to 18 (37.5%), yet only 7 patients (38.9%-G1) consented. The median time to gastrostomy was 77&#x2009;months. Total survival and survival post-gastrostomy recommendation were not different between G1 and G2. Six PLS patients (12.5%-G3) developed respiratory failure and initiated NIV (median of 63&#x2009;months). At 63&#x2009;months, G3 had significantly lower median forced vital capacity (65% vs. 99%; p&#x2009;<&#x2009;0.001) and phrenic nerve amplitude (0.43 vs. 0.75&#x2009;mV; p&#x2009;=&#x2009;0.039), but a greater ALSFRS-R slope (0.34 vs. 0.14; p&#x2009;=&#x2009;0.046) and shorter survival (35 vs. 94.9&#x2009;months; p&#x2009;=&#x2009;0.009) compared to G4.<br><br>DISCUSSION: Dysphagia requiring gastrostomy was common in our PLS cohort, but survival after gastrostomy recommendation did not differ between groups. Patients who developed respiratory impairment may represent a distinct group with faster disease progression and shorter survival. Our findings may contribute to a deeper understanding and improved management of PLS.}, }
@article {pmid39799559, year = {2025}, author = {Üremiş, N and Üremiş, MM}, title = {Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {1}, pages = {e70133}, pmid = {39799559}, issn = {1099-0461}, support = {//This research was supported by the T&#xfc;rkiye Bilimsel ve Teknolojik Ara&#x15f;t&#x131;rma Kurumu (grant number: TUB1)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Apoptosis ; *Oxidative Stress ; *Nitrosative Stress ; *Oxidation-Reduction ; Animals ; *Signal Transduction ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases are significant health concerns that have a profound impact on the quality and duration of life for millions of individuals. These diseases are characterized by pathological changes in various brain regions, specific genetic mutations associated with the disease, deposits of abnormal proteins, and the degeneration of neurological cells. As neurodegenerative disorders vary in their epidemiological characteristics and vulnerability of neurons, treatment of these diseases is usually aimed at slowing disease progression. The heterogeneity of genetic and environmental factors involved in the process of neurodegeneration makes current treatment methods inadequate. However, the existence of common molecular mechanisms in the pathogenesis of these diseases may allow the development of new targeted therapeutic strategies. Oxidative and nitrosative stress damages membrane components by accumulating ROS and RNS and disrupting redox balance. This process results in the induction of apoptosis, which is important in the pathogenesis of neurodegenerative diseases through oxidative stress. Studies conducted using postmortem human samples, animal models, and cell cultures have demonstrated that oxidative stress, nitrosative stress, and apoptosis are crucial factors in the development of diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. The excessive production of reactive oxygen and nitrogen species, elevated levels of free radicals, heightened mitochondrial stress, disturbances in energy metabolism, and the oxidation and nitrosylation of cellular macromolecules are recognized as triggers for neuronal cell death. Challenges in managing and treating neurodegenerative diseases require a better understanding of this field at the molecular level. Therefore, this review elaborates on the molecular mechanisms by which oxidative and nitrosative stress are involved in neuronal apoptosis.}, }
@article {pmid39799393, year = {2025}, author = {Valenzuela, V and Becerra, D and Astorga, JI and Fuentealba, M and Diaz, G and Bargsted, L and Chacón, C and Martinez, A and Gozalvo, R and Jackson, K and Morales, V and Heras, ML and Tamburini, G and Petrucelli, L and Sardi, SP and Plate, L and Hetz, C}, title = {Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {3}, pages = {1226-1245}, pmid = {39799393}, issn = {1525-0024}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy ; *Unfolded Protein Response ; Mice ; *Disease Models, Animal ; *Frontotemporal Dementia/genetics/metabolism ; *X-Box Binding Protein 1/metabolism/genetics ; *Endoplasmic Reticulum Stress ; *Dependovirus/genetics ; Humans ; Mice, Transgenic ; Genetic Vectors/administration &amp; dosage/genetics ; C9orf72 Protein/genetics/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here, we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAVs) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended lifespan of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.}, }
@article {pmid39799324, year = {2025}, author = {Freiha, J and Grand, E and Marshall, B and Arunchalam, R and Pinto, A and Osman, C}, title = {Amyotrophic lateral sclerosis in a patient with chronic lymphocytic leukaemia and drug related sarcoid-like reaction.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {16}, pmid = {39799324}, issn = {1471-2377}, mesh = {Humans ; Male ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/complications ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis ; *Sarcoidosis/diagnosis/complications ; Rituximab/therapeutic use/adverse effects ; Central Nervous System Diseases ; }, abstract = {Sarcoid-like reaction is an immunological reaction that can affect lymph nodes and organs but does not meet the diagnostic criteria for systemic sarcoidosis. Anti-CD20 auto-antibodies have been reported to be responsible for such reactions. There are several reported associations between Chronic lymphocytic leukaemia (CLL), Amyotrophic lateral sclerosis (ALS) and Sarcoid-like reactions (SLR). We report a case of ALS developing in a patient with treated CLL and drug related SLR one day after exposure to Venetoclax and Rituximab. A 60-year-old male presented with lower limb rash, left leg weakness followed by bulbar symptoms which progressed over 12-months. Workup demonstrated a Cerebrospinal fluid (CSF) pleocytosis and inguinal lymphadenopathy. Skin and inguinal lymph node biopsies showed non-necrotising granulomata. Electromyography met diagnostic criteria for ALS. He was treated for presumed neurosarcoidosis mimicking ALS. Despite prednisolone and infliximab treatment, the motor symptoms rapidly progressed; Hence, we made a clinical diagnosis of ALS. We discuss the diagnostic and treatment challenges of this case.}, }
@article {pmid39799044, year = {2025}, author = {Bracca, V and Premi, E and Cotelli, MS and Micheli, A and Altomare, D and Cantoni, V and Gasparotti, R and Borroni, B}, title = {Loss of Insight in Syndromes Associated with Frontotemporal Lobar Degeneration: Clinical and Imaging Features.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {33}, number = {4}, pages = {450-462}, doi = {10.1016/j.jagp.2024.12.005}, pmid = {39799044}, issn = {1545-7214}, mesh = {Humans ; Male ; Female ; Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/epidemiology ; *Magnetic Resonance Imaging ; Middle Aged ; Retrospective Studies ; Longitudinal Studies ; Atrophy/pathology ; Aphasia, Primary Progressive/diagnostic imaging/pathology ; Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/epidemiology ; Frontotemporal Dementia/diagnostic imaging/pathology ; Prevalence ; Brain/diagnostic imaging/pathology ; }, abstract = {OBJECTIVES: The present study aims to assess the prevalence, associated clinical symptoms, longitudinal changes, and imaging correlates of Loss of Insight (LOI), which is still unexplored in syndromes associated with Frontotemporal Lobar Degeneration (FTLD).<br><br>DESIGN: Retrospective longitudinal cohort study, from Oct 2009 to Feb 2023.<br><br>SETTING: Tertiary Frontotemporal Dementia research clinic.<br><br>PARTICIPANTS: A sample of 712 FTLD patients, 331 of whom had follow-up evaluation.<br><br>MEASUREMENTS: LOI was assessed by interview with the primary caregiver. Univariate and multiple logistic regression and linear mixed models were used to estimate predictors and longitudinal changes over time associated with LOI. Voxel-based morphometry and structural covariance analyses of brain structural MRI images were implemented in Statistical Parametric Mapping.<br><br>RESULTS: LOI was reported in 45% of patients (321/712, 95%CI = 41-49), with progressively increased prevalence from prodromal to severe dementia stages. LOI was more prevalent in the behavioural variant FTD, in the semantic variant of Primary Progressive Aphasia (svPPA) and FTD with Amyotrophic Lateral Sclerosis than in other phenotypes (all p-values<0.001). LOI severity increased over time only in patients with svPPA (&#x3b2; = +0.59, p <0.001) and clustered with other behavioral symptoms (all p-values <0.05). Finally, LOI was significantly associated with greater atrophy in the right medial orbital gyrus (p <0.001 uncorrected). Structural covariance analysis demonstrated loss of negative correlation between right medial orbital gyrus and regions belonging to the Default Mode Network (DMN), such as the left precuneus and the left angular gyrus (p &#x2264;0.05 family-wise error-corrected) in FTLD patients with LOI.<br><br>CONCLUSIONS: A better comprehension of LOI mechanisms could lead to more effective interventions and healthcare policies.}, }
@article {pmid39798947, year = {2025}, author = {Sorice, V and Ekumah, ND}, title = {Exploring the psychosocial dimensions and impacts of infertility in Africa: a commentary on Roomaney et al's scoping review of current evidence.}, journal = {Evidence-based nursing}, volume = {}, number = {}, pages = {}, doi = {10.1136/ebnurs-2024-104222}, pmid = {39798947}, issn = {1468-9618}, }
@article {pmid39798853, year = {2025}, author = {Guan, D and Liang, C and Zheng, D and Liu, S and Luo, J and Cai, Z and Zhang, H and Chen, J}, title = {The role of mitochondrial remodeling in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {183}, number = {}, pages = {105927}, doi = {10.1016/j.neuint.2024.105927}, pmid = {39798853}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Mitochondrial Dynamics/physiology ; Energy Metabolism/physiology ; }, abstract = {Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.}, }
@article {pmid39798254, year = {2025}, author = {Cao, S and Fu, X and Li, W and Wang, P and Li, C and Shang, H}, title = {Protective role of apolipoprotein A and B in Parkinson's disease: A prospective study from UK Biobank.}, journal = {Parkinsonism &amp; related disorders}, volume = {132}, number = {}, pages = {107266}, doi = {10.1016/j.parkreldis.2025.107266}, pmid = {39798254}, issn = {1873-5126}, mesh = {Humans ; Male ; *Parkinson Disease/blood ; Female ; Aged ; United Kingdom/epidemiology ; Middle Aged ; *Biological Specimen Banks ; Prospective Studies ; Apolipoproteins A/blood ; Apolipoproteins B/blood ; Protective Factors ; UK Biobank ; Apolipoprotein B-100 ; }, abstract = {INTRODUCTION: Evidence have indicated relation between apolipoproteins and neurodegenerative disorders (NDDs). However, previous studies have produced inconsistent results, and a comprehensive analysis of apolipoproteins in NDDs is currently lacking.<br><br>METHODS: Using Cox proportional hazards regression analysis based on data from UK Biobank, we examined the association between baseline serum levels of apolipoprotein A (ApoA) and apolipoprotein B (ApoB) and risk of Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis.<br><br>RESULTS: Elevated baseline levels of serum ApoA (HR&#xa0;=&#xa0;0.84, 95&#xa0;% CI: 0.71-0.99, P&#xa0;=&#xa0;0.047) and ApoB (HR&#xa0;=&#xa0;0.67, 95&#xa0;% CI: 0.57-0.78, P&#xa0;=&#xa0;3.18E-07) were associated with a reduced risk of incident PD. Subgroup analyses suggested the protective effect of serum ApoA was more significant for older participants and those with lower alcohol consumption, while higher serum ApoB was a more significant protective factor in males and those without stroke. No significant associations were found between apolipoproteins and other NDDs.<br><br>CONCLUSION: Increased baseline levels of serum ApoA and ApoB are linked to a lower risk of PD. These findings enhance understanding of the role of apolipoproteins in PD, and have implications for the development of therapeutic strategies in clinical trials.}, }
@article {pmid39797438, year = {2025}, author = {Zeng, Y and Liu, M and Qian, H and Zhao, H and Fang, Y and Yu, Q and Bai, L and Pan, L}, title = {Investigating non-target site resistance to pyroxsulam in a glyphosate-resistant Lolium rigidum population.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8636}, pmid = {39797438}, issn = {1526-4998}, support = {//the National Key RandD Program of China (no. 2023YFD1401100)/ ; //National Natural Science Foundation of China (32372568 and 32130091)/ ; //Young Elite Scientists Sponsorship Program by CAST (2021QNRC001)/ ; //Earmarked Fund for China Agriculture Research System (CARS-16-E19)/ ; //Postgraduate Scientific Research Innovation Project of Hunan Province (QL20230088)/ ; //Scientific Research Fund of Hunan Provincial Education Department (23B0225)/ ; //National Natural Science Foundation of China (U23A20174)/ ; //Australian Grains and Research Development and Corporation (GRDC)/ ; }, abstract = {BACKGROUND: Resistance to multiple herbicides is common in Lolium rigidum. Here, resistance to acetolactate synthase (ALS)- and susceptibility to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides was confirmed in a glyphosate-resistant L. rigidum population (NLR70) from Australia and the mechanisms of pyroxsulam resistance were examined.<br><br>RESULTS: No ALS target-site mutations nor gene overexpression were detected. Cytochrome P450 monooxygenase (P450) and glutathione S-transferase (GST) inhibitors (indicators of some certain P450s or GSTs) did not significantly affect the resistance to pyroxsulam. Nevertheless, HPLC analysis showed that plants of the NLR70 population metabolized pyroxsulam faster than plants of the herbicide-susceptible population (SVLR1). RNA sequencing analysis and RT-qPCR validation confirmed that four P450s (CYP709B2, CYP72A14, CYP89A2, CYP94B3), one GT (UGT79), and one ABC transporter (ABCG41) genes were constitutively upregulated in NLR70 plants.<br><br>CONCLUSION: This study demonstrates that the glyphosate-resistant L. rigidum population (NLR70) also exhibits resistance to pyroxsulam and identifies six candidate genes associated with non-target site resistance to pyroxsulam. &#xa9; 2025 Society of Chemical Industry.}, }
@article {pmid39796536, year = {2024}, author = {Cuffaro, F and Lamminpää, I and Niccolai, E and Amedei, A}, title = {Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.}, journal = {Nutrients}, volume = {17}, number = {1}, pages = {}, pmid = {39796536}, issn = {2072-6643}, support = {PNRR-MAD-2022-12375798//Ministero della Salute/ ; PE0000006//Ministry of University and Research (MUR)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Gastrointestinal Microbiome ; *Dysbiosis/therapy ; Probiotics/therapeutic use ; Brain-Gut Axis/physiology ; Fecal Microbiota Transplantation ; Fatty Acids, Omega-3 ; Prebiotics/administration &amp; dosage ; Oxidative Stress ; Nutritional Status ; Diet, Mediterranean ; Antioxidants ; }, abstract = {Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.}, }
@article {pmid39795334, year = {2024}, author = {Bhattacharya, S and Sen, MK and Hamouzová, K and Košnarová, P and Bharati, R and Menendez, J and Soukup, J}, title = {Pyroxsulam Resistance in Apera spica-venti: An Emerging Challenge in Crop Protection.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, pmid = {39795334}, issn = {2223-7747}, support = {QL24010167//National Agency for Agricultural Research (NAZV)/ ; }, abstract = {Apera spica-venti, a prevalent weed in Czech winter wheat fields, has developed resistance to ALS-inhibiting herbicides due to their frequent use. This study reports a biotype of A. spica-venti resistant to pyroxsulam, with cross and multiple resistance to iodosulfuron, propoxycarbazone, pinoxaden, and chlortoluron. Dose-response experiments revealed high resistance of both R1 and R2 biotypes to pyroxsulam, with resistance factors (RF) of 6.69 and 141.65, respectively. Pre-treatment with malathion reduced RF by 2.40× and 1.25× in R1 and R2, indicating the potential involvement of cytochrome P450 (CytP450). NBD-Cl pre-treatment decreased RF only in R2, suggesting possible GST involvement. Gene analysis revealed no mutations (at previously reported sites) or overexpression in the acetolactate synthase (ALS) gene. However, a significant difference in ALS enzyme activity between resistant and susceptible biotypes points to target-site resistance mechanisms. Studies with [14]C-labeled pyroxsulam showed that reduced absorption and translocation were not likely resistance mechanisms. In summary, herbicide resistance in A. spica-venti appears to result from multiple mechanisms. Possible causes include target-site resistance from an unidentified ALS mutation (within coding or regulatory regions). Enhanced herbicide metabolism via CytP450s and GSTs is also a contributing factor. Further experimental validation is needed to confirm these mechanisms and fully understand the resistance. This evolution underscores the adaptive capacity of weed populations under herbicide pressure, emphasizing the need for alternative control strategies.}, }
@article {pmid39794859, year = {2025}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Correction: Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {5}, pmid = {39794859}, issn = {2051-5960}, }
@article {pmid39794401, year = {2025}, author = {Cheng, J and Wu, BT and Liu, HP and Lin, WY}, title = {Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1564}, pmid = {39794401}, issn = {2045-2322}, support = {CMU110-MF-92//China Medical University, Taiwan/ ; CMU112-MF-62//China Medical University, Taiwan/ ; MOST 111-2314-B-039-017-MY3//National Science and Technology Council of Taiwan/ ; DMR-112-125//China Medical University Hospital, Taiwan/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Iron/metabolism ; Humans ; *Machine Learning ; *Lipid Metabolism ; *Endosomes/metabolism ; *Spinal Cord/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Although genes causing familial cases have been identified, those of sporadic ALS, which occupies the majority of patients, are still elusive. In this study, we adopted machine learning to build binary classifiers based on the New York Genome Center (NYGC) ALS Consortium's RNA-seq data of the postmortem spinal cord of ALS and non-neurological disease control. The accuracy of the classifiers was greater than 83% and 77% for the training set and the unseen test set, respectively. The classifiers contained 114 genes. Among them, 41 genes have been reported in previous ALS studies, and others are novel in this field. These genes are involved in mitochondrial respiration, lipid metabolism, endosomal trafficking, and iron metabolism, which may promote the progression of ALS pathology.}, }
@article {pmid39793633, year = {2025}, author = {Baker, RS and Wang, JT and Rouatbi, N and Lu, Y and Al-Adhami, T and Asker, D and Rahman, KM and Al-Chalabi, A and Forbes, B and Bansal, S and Al-Jamal, KT}, title = {Brain distribution study of [[14]C]-Riluzole following intranasal administration in mice.}, journal = {International journal of pharmaceutics}, volume = {670}, number = {}, pages = {125195}, doi = {10.1016/j.ijpharm.2025.125195}, pmid = {39793633}, issn = {1873-3476}, mesh = {Animals ; *Administration, Intranasal ; *Brain/metabolism ; Male ; Mice ; *Carbon Radioisotopes ; Tissue Distribution ; Biological Availability ; Tetrahydroisoquinolines/administration &amp; dosage/pharmacokinetics ; Blood-Brain Barrier/metabolism ; Administration, Oral ; Neuroprotective Agents/pharmacokinetics/administration &amp; dosage ; Acridines ; }, abstract = {Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [[14]C]-RLZ was synthesised using an optimised one-pot method. [[14]C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ([1]H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.}, }
@article {pmid39792652, year = {2025}, author = {Mercadante, S and Petronaci, P and Lo Cascio, A}, title = {Living Will and Advance Care Planning in Patients With Amyotrophic Lateral Sclerosis Admitted to Specialistic Home Palliative Care.}, journal = {The American journal of hospice &amp; palliative care}, volume = {}, number = {}, pages = {10499091241312906}, doi = {10.1177/10499091241312906}, pmid = {39792652}, issn = {1938-2715}, abstract = {Objectives: In Italy a recent law was approved for providing patients' wishes regarding end of life issues, commonly referred internationally to as "living wills", (Dichiarazione anticipata di trattamento, DAT). Regardless of this official document, advance care planning (ACP) is often used in a palliative care setting to share the treatments to start, to continue, to withdraw, thus preventing the stress on an acute decision. The aim of this study was to assess DAT and ACP in patients with amyotropic lateral sclerosis admitted to home palliative care. Methods: Patients consecutively admitted to speciliazed home palliative care were prospectively assessed. The presence of DAT or ACP was recorded. Results: Sixty-eight patients were enrolled in the period taken into consideration. No patient had drown up DAT, and only one patient provided his ACP prior to home palliative care admission. Along the course of home palliative care care assistance, 30.9% of patients provided their ACP. Discussion: In Italy DAT resulted scarcely widespread, despite an existing law, as no patient officially provided their indication on end of life issues. In addition, ACP was given only after starting specialized home palliative care in less than 1/3 of patients. Home palliative care seems to be a fundamental resource for improving communication and soliciting expression of patients' wishes regarding end of life issues.}, }
@article {pmid39792557, year = {2025}, author = {Dykstra, MM and Weskamp, K and Gómez, NB and Waksmacki, J and Tank, E and Glineburg, MR and Snyder, A and Pinarbasi, E and Bekier, M and Li, X and Miller, MR and Bai, J and Shahzad, S and Nedumaran, N and Wieland, C and Stewart, C and Willey, S and Grotewold, N and McBride, J and Moran, JJ and Suryakumar, AV and Lucas, M and Tessier, PM and Ward, M and Todd, PK and Barmada, SJ}, title = {TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.}, journal = {Cell reports}, volume = {44}, number = {1}, pages = {115113}, pmid = {39792557}, issn = {2211-1247}, support = {F31 NS115257/NS/NINDS NIH HHS/United States ; K08 NS072233/NS/NINDS NIH HHS/United States ; I01 BX004842/BX/BLRD VA/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; R01 NS099280/NS/NINDS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM136300/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Protein Isoforms/metabolism/genetics ; Homeostasis ; Nonsense Mediated mRNA Decay ; Transcription, Genetic ; Protein Processing, Post-Translational ; HEK293 Cells ; Animals ; HeLa Cells ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; }, abstract = {The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease.}, }
@article {pmid39792201, year = {2025}, author = {Fu, Z and Feng, B and Akogo, HY and Ma, J and Liu, Y and Quan, H and Zhang, X and Hou, Y and Zhang, X and Ma, J and Cui, H}, title = {Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6383-6396}, pmid = {39792201}, issn = {1559-1182}, support = {81801278//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Parkinson Disease/genetics/metabolism ; *Brain/metabolism/pathology ; *Gene Expression Profiling ; Gene Regulatory Networks ; Protein Interaction Maps/genetics ; Transcriptome/genetics ; MicroRNAs/genetics/metabolism ; Gene Ontology ; }, abstract = {This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.}, }
@article {pmid39791815, year = {2025}, author = {Rossi, A and Cuccioloni, M and Pellegrino, F and Giovannetti, R and Alladio, E}, title = {Discriminating Analysis of Metal Ions via Multivariate Curve Resolution-Alternating Least Squares Applied to Silver Nanoparticle Sensor.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {39791815}, issn = {2079-4991}, abstract = {Heavy metals are life-threatening pollutions because of their great toxicity, long-term persistence in nature and their bioaccumulation in living organisms. In this work, we performed multivariate curve resolution-alternating least squares analysis of UV-Vis raw spectra received by a colorimetric sensor constructed on mercaptoundecanoic acid functionalized silver nanoparticles (AgNPs@11MUA) to detect Cd[2+], Cu[2+], Mn[2+], Ni[2+], and Zn[2+] in water. This combined approach allowed the rapid identification and quantification of multiple heavy metals and showed adequate sensitivity and selectivity, thus representing a promising analytical and computational method for both laboratory and field applications such as environmental safety and public health monitoring.}, }
@article {pmid39791748, year = {2025}, author = {Moss, KR and Saxena, S}, title = {Schwann Cells in Neuromuscular Disorders: A Spotlight on Amyotrophic Lateral Sclerosis.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, pmid = {39791748}, issn = {2073-4409}, support = {K22 NS125057/NS/NINDS NIH HHS/United States ; }, mesh = {*Schwann Cells/pathology/metabolism ; *Amyotrophic Lateral Sclerosis/pathology ; Humans ; Animals ; Neuromuscular Diseases/pathology ; Motor Neurons/pathology/metabolism ; Charcot-Marie-Tooth Disease/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease primarily affecting motor neurons, leading to progressive muscle atrophy and paralysis. This review explores the role of Schwann cells in ALS pathogenesis, highlighting their influence on disease progression through mechanisms involving demyelination, neuroinflammation, and impaired synaptic function. While Schwann cells have been traditionally viewed as peripheral supportive cells, especially in motor neuron disease, recent evidence indicates that they play a significant role in ALS by impacting motor neuron survival and plasticity, influencing inflammatory responses, and altering myelination processes. Furthermore, advancements in understanding Schwann cell pathology in ALS combined with lessons learned from studying Charcot-Marie-Tooth disease Type 1 (CMT1) suggest potential therapeutic strategies targeting these cells may support nerve repair and slow disease progression. Overall, this review aims to provide comprehensive insights into Schwann cell classification, physiology, and function, underscoring the critical pathological contributions of Schwann cells in ALS and suggests new avenues for targeted therapeutic interventions aimed at modulating Schwann cell function in ALS.}, }
@article {pmid39791705, year = {2024}, author = {Sun, D and Amiri, M and Meng, Q and Unnithan, RR and French, C}, title = {Calcium Signalling in Neurological Disorders, with Insights from Miniature Fluorescence Microscopy.}, journal = {Cells}, volume = {14}, number = {1}, pages = {}, pmid = {39791705}, issn = {2073-4409}, support = {DP170100363//Australian Research Council under Discovery Project/ ; }, mesh = {*Calcium Signaling ; Humans ; *Nervous System Diseases/metabolism/pathology ; Animals ; *Microscopy, Fluorescence/methods ; Calcium/metabolism ; Neurons/metabolism ; }, abstract = {Neurological disorders (NDs), such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia, represent a complex and multifaceted health challenge that affects millions of people around the world. Growing evidence suggests that disrupted neuronal calcium signalling contributes to the pathophysiology of NDs. Additionally, calcium functions as a ubiquitous second messenger involved in diverse cellular processes, from synaptic activity to intercellular communication, making it a potential therapeutic target. Recently, the development of the miniature fluorescence microscope (miniscope) enabled simultaneous recording of the spatiotemporal calcium activity from large neuronal ensembles in unrestrained animals, providing a novel method for studying NDs. In this review, we discuss the abnormalities observed in calcium signalling and its potential as a therapeutic target for NDs. Additionally, we highlight recent studies that utilise miniscope technology to investigate the alterations in calcium dynamics associated with NDs.}, }
@article {pmid39791335, year = {2025}, author = {Dogan, EO and Simonini, SR and Bouley, J and Weiss, A and Brown, RH and Henninger, N}, title = {Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1[G93A] Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.27174}, pmid = {39791335}, issn = {1531-8249}, support = {NS131756/NS/NINDS NIH HHS/United States ; //Moloney Fellowship/ ; //Angel Fund for ALS Research/ ; }, abstract = {OBJECTIVE: Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.<br><br>METHODS: We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1[G93A] mouse ALS model, and whether loss of the primary regulator of axonal degeneration sterile alpha and TIR motif containing 1 (Sarm1) mitigates the histological and behavioral pathophysiology. We subjected wild-type (n&#x2009;=&#x2009;23), Sarm1 knockout (KO; n&#x2009;=&#x2009;17), SOD1[G93A] (n&#x2009;=&#x2009;19), and SOD1[G93A]xSarm1[KO] (n&#x2009;=&#x2009;26) mice of both sexes to rTBI or sham surgery at age 64&#x2009;days (62-68&#x2009;days). Body weight and ALS-deficit score were serially assessed up to 17&#x2009;weeks after surgery and histopathology assessed in layer V of the primary motor cortex at the study end point.<br><br>RESULTS: In sham injured SOD1[G93A] mice, genetic ablation of Sarm1 did not attenuate axonal loss, improve neurological deficits, or survival. The rTBI accelerated onset of G93A-SOD1 ALS, as indicated by accentuated body weight loss, earlier onset of hindlimb tremor, and shortened survival. The rTBI also triggered TDP-43 mislocalization, enhanced axonal and neuronal loss, microgliosis, and astrocytosis. Loss of Sarm1 significantly diminished the impact of rTBI on disease progression and rescued rTBI-associated neuropathology.<br><br>INTERPRETATION: SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1[G93A] mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025.}, }
@article {pmid39789167, year = {2025}, author = {Kassubek, J and Roselli, F and Witzel, S and Dorst, J and Ludolph, AC and Rasche, V and Vernikouskaya, I and Müller, HP}, title = {Hypothalamic atrophy in primary lateral sclerosis, assessed by convolutional neural network-based automatic segmentation.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1551}, pmid = {39789167}, issn = {2045-2322}, mesh = {Humans ; Female ; Male ; *Hypothalamus/pathology/diagnostic imaging ; Middle Aged ; *Neural Networks, Computer ; *Magnetic Resonance Imaging/methods ; *Atrophy/pathology ; Aged ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Adult ; Motor Neuron Disease/pathology/diagnostic imaging ; Image Processing, Computer-Assisted/methods ; Case-Control Studies ; }, abstract = {Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm[3]) when compared to controls (852 ± 77 mm[3]); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm[3]), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.}, }
@article {pmid39788313, year = {2025}, author = {Cassina, P and Miquel, E and Martínez-Palma, L and Cassina, A}, title = {Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury.}, journal = {Neuroscience}, volume = {567}, number = {}, pages = {227-234}, doi = {10.1016/j.neuroscience.2024.12.058}, pmid = {39788313}, issn = {1873-7544}, mesh = {Animals ; Humans ; *Astrocytes/metabolism/pathology ; *Mitochondria/metabolism ; *Neurons/metabolism/pathology ; }, abstract = {In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.}, }
@article {pmid39786806, year = {2025}, author = {Yang, S and Song, J and Deng, M and Cheng, S}, title = {Identification of Drug-Targetable Genes for Eczema and Dermatitis Using Integrated Genomic and Proteomic Approaches.}, journal = {Dermatitis : contact, atopic, occupational, drug}, volume = {}, number = {}, pages = {}, doi = {10.1089/derm.2024.0429}, pmid = {39786806}, issn = {2162-5220}, abstract = {Background: Eczema and dermatitis are common inflammatory skin conditions with significant morbidity. Identifying drug-targetable genes can facilitate the development of effective treatments. Methods: This study analyzed data obtained by meta-analysis of 2 genome-wide association studies on eczema/dermatitis (57,311 cases and 896,779 controls, European ancestry). We identified drug-targetable genes from the Drug-Gene Interaction Database and Finan et al's findings. Cis-expression quantitative trait loci (eQTL) data from human blood and skin tissues were used for Mendelian randomization (MR) analysis. Bayesian colocalization, proteomic MR, and meta-analysis validated the causal relationships. Finally, protein-protein interactions (PPIs) and correlation analysis of potential drug targets and cytokines were performed. Results: We identified 2532 drug-targetable genes; 3378 Single Nucleotide Polymorphism (SNPs) were associated with 1531 genes in blood cis-eQTLs, 664 SNPs with 667 genes in sun-exposed skin eQTLs, and 572 SNPs with 574 genes in nonsun-exposed skin eQTLs. Five genes (SLC22A5, NOTCH4, AGER, HLA-DRB5, and EHMT2) showed causal relationships with eczema/dermatitis across multiple datasets. Single-variable and multi-variable Mendelian randomization (SMR) and multi-SNP SMR analysis identified 8 genes (PIK3R4, DHODH, CXCR2, Interleukin (IL)18, LGALS9, RPS6KB2, SLC22A5, and AGER) across all tissues. Functional Summary Information for Variants in the Online Network (FUSION) analysis confirmed associations for SLC22A5 and AGER. Bayesian colocalization indicated AGER (PPH4: 0.95) as a shared causal variant. Proteomic MR and meta-analysis showed that increased AGER protein levels were associated with a lower risk of eczema or dermatitis (odds ratio: 0.995, 95% confidence interval: 0.997-0.993, P = 0.0002). A PPI network revealed interactions of AGER with NOTCH4 and multiple cytokines, whereas SLC22A5 showed no cytokine interactions. Conclusions: This study identified potential drug-targetable genes, with AGER showing strong potential as a target for reducing eczema/dermatitis risk. These findings provide a basis for developing targeted therapies.}, }
@article {pmid39786727, year = {2025}, author = {Midgley, SD and Bariami, S and Habgood, M and Mackey, M}, title = {Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations.}, journal = {Journal of chemical information and modeling}, volume = {65}, number = {2}, pages = {512-516}, pmid = {39786727}, issn = {1549-960X}, mesh = {*Thermodynamics ; Ligands ; Proteins/chemistry/metabolism ; Protein Binding ; Computer Simulation ; }, abstract = {Recent increases in the availability of computational power have improved the accessibility of ligand-protein relative binding free energy (RBFE) calculations; however, these calculations remain resource-intensive, which can limit their practical application. RBFE calculations typically use a set of thermodynamic intermediates mediated by the transformation coordinate λ. Optimizing λ offers a way to tune the computational efforts required for a given RBFE calculation. Here, we present Adaptive Lambda Scheduling (ALS), a streamlined approach for on-the-fly bespoke λ scheduling. We show it can achieve substantial reductions in computational cost while retaining predictive performance.}, }
@article {pmid39786321, year = {2025}, author = {Kim, K and Kim, S and Katana, M and Terentyev, D and Radwański, PB and Munger, MA}, title = {Riluzole is associated with reduced risk of heart failure.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70033}, pmid = {39786321}, issn = {1468-1331}, support = {R01HL14488/HL/NHLBI NIH HHS/United States ; R01 NS121234/NS/NINDS NIH HHS/United States ; R01 HL166604/HL/NHLBI NIH HHS/United States ; R01HL166604/HL/NHLBI NIH HHS/United States ; R01HL155378/HL/NHLBI NIH HHS/United States ; }, mesh = {*Riluzole/therapeutic use ; Humans ; *Heart Failure/epidemiology/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Amyotrophic Lateral Sclerosis/epidemiology/drug therapy ; Aged, 80 and over ; Cohort Studies ; United States/epidemiology ; }, abstract = {BACKGROUND: Reduction of intracellular Na[+] accumulation through late Na[+] current inhibition has been recognized as a target for cardiac Ca[2+] handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na[+] channel blocker with enhancement of Ca[2+]-activated K[+] channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca[2+] leak and therefore may improve cardiac function.<br><br>OBJECTIVES: The study aim was to investigate whether riluzole lowers HF incidence.<br><br>METHODS: Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts.<br><br>RESULTS: The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p&#x2009;<&#x2009;0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3&#x2009;months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99].<br><br>CONCLUSIONS: Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.}, }
@article {pmid39786151, year = {2025}, author = {Harrison, J and Bhardwaj, A and Houck, O and Sather, K and Sekiya, A and Knack, S and Saarunya Clarke, G and Puskarich, MA and Tignanelli, C and Rogers, L and Marmor, S and Beilman, G}, title = {Emergency medical services level of training is associated with mortality in trauma patients: A combined prehospital and in hospital database analysis.}, journal = {The journal of trauma and acute care surgery}, volume = {98}, number = {3}, pages = {402-409}, pmid = {39786151}, issn = {2163-0763}, mesh = {Humans ; Male ; Middle Aged ; Female ; *Wounds and Injuries/mortality/therapy ; Adult ; *Emergency Medical Services/statistics &amp; numerical data ; Aged ; Trauma Centers/statistics &amp; numerical data ; Propensity Score ; Databases, Factual ; Young Adult ; Retrospective Studies ; Adolescent ; Aged, 80 and over ; Emergency Medical Technicians/education/statistics &amp; numerical data ; }, abstract = {BACKGROUND: There is conflicting evidence regarding emergency medical service (EMS) provider level of training and outcomes in trauma. We hypothesized that advanced life support (ALS) provider transport is associated with lower mortality compared with basic life support transport.<br><br>METHODS: We performed secondary analysis of a combined prehospital and in-hospital database of trauma patients utilizing ESO electronic medical records from 2018 to 2022. We included encounters with patients aged 15 years to 100 years transported by ground to a Level I or II trauma center with trauma-specific ICD-10-CM codes. Patients dead upon EMS arrival and transfers were excluded. We matched patients using 1:1 nearest neighbor propensity scores based on demographic, injury, and EMS characteristics, prehospital vitals, and trauma center designation. The exposure variable was EMS level of training and outcome was mortality. We conducted subgroup analyses on predefined cohorts (age > 50 years, mechanism of injury, prehospital EMS time > 30 minutes).<br><br>RESULTS: We identified 30,735 ALS and 1,758 basic life support encounters, representing 1,154 pairs following propensity matching. Mortality was lower among patients transported by ALS providers (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.18-0.88; p = 0.023). Mortality was also lower in the subgroups of patients aged > 50 years (OR, 0.35; 95% CI, 0.13-0.98; p = 0.046), and in patients with mechanisms of injury excluding falls (OR, 0.35; 95% CI, 0.13-0.98; p = 0.047). In those with prolonged prehospital time, the association approached significance (OR, 0.30; 95% CI, 0.08-1.08; p = 0.067). In those with mechanisms of injury of fall, the association was not significant.<br><br>CONCLUSION: In this retrospective, propensity matched cohort study using a national sample of trauma patients, attendance by ALS providers was associated with reduced mortality. This was observed in the entire cohort, in those aged > 50 years, and those with a higher-risk mechanism of injury. It approached significance in those with prolonged prehospital time.<br><br>LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.}, }
@article {pmid39783196, year = {2025}, author = {Lee, I and Mitsumoto, H and Lee, S and Kasarskis, E and Rosenbaum, M and Factor-Litvak, P and Nieves, JW}, title = {Interaction between riluzole treatment and dietary glycemic index in the disease progression of amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {3}, pages = {491-498}, pmid = {39783196}, issn = {2328-9503}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; K23NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Riluzole/pharmacology/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; Male ; Female ; Middle Aged ; *Disease Progression ; *Glycemic Index/drug effects/physiology ; Aged ; *Neuroprotective Agents/pharmacology/administration &amp; dosage ; Cohort Studies ; Adult ; }, abstract = {OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n&#x2009;=&#x2009;304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates.<br><br>RESULTS: Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [&#x3b2;&#x2009;=&#x2009;-1.9, 95% CI (-4.1, -0.2), p&#x2009;=&#x2009;0.07], third [&#x3b2;&#x2009;=&#x2009;-3.0, 95% CI (-5.1, -0.8), p&#x2009;<&#x2009;0.01] and fourth [&#x3b2;&#x2009;=&#x2009;-2.2, 95% CI (-4.3, -0.01), p&#x2009;<&#x2009;0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI&#x2009;<&#x2009;47.2) among the RTG. Similarly, GL fourth quartile group (GL&#x2009;>&#x2009;109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [&#x3b2;&#x2009;=&#x2009;-2.6, 95% CI (-4.7, -0.5), p&#x2009;<&#x2009;0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups.<br><br>INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.}, }
@article {pmid39783194, year = {2025}, author = {Smith, SE and McCoy-Gross, K and Malcolm, A and Oranski, J and Markway, JW and Miller, TM and Bucelli, RC}, title = {Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting.}, journal = {Annals of clinical and translational neurology}, volume = {12}, number = {2}, pages = {311-319}, pmid = {39783194}, issn = {2328-9503}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/physiopathology ; Male ; Female ; *Superoxide Dismutase-1/genetics ; Middle Aged ; Aged ; *Neurofilament Proteins/blood ; Disease Progression ; Muscle Strength/drug effects/physiology ; Adult ; }, abstract = {OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.<br><br>METHODS: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.<br><br>RESULTS: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: -57.9%; mean change CSF pNFH: -67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD&#x2009;=&#x2009;0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD&#x2009;=&#x2009;3.85).<br><br>INTERPRETATION: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.}, }
@article {pmid39779800, year = {2025}, author = {Regondi, S and Donvito, G and Frontoni, E and Kostovic, M and Minazzi, F and Bratières, S and Filosto, M and Pugliese, R}, title = {Artificial intelligence empowered voice generation for amyotrophic lateral sclerosis patients.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1361}, pmid = {39779800}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/therapy/complications/psychology ; Humans ; *Artificial Intelligence ; *Voice ; Female ; Male ; Middle Aged ; *Quality of Life ; Aged ; Communication Aids for Disabled ; Speech/physiology ; Adult ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that can result in a progressive loss of speech due to bulbar dysfunction, which can have significant negative impact on the patient's mental well-being. Alternative Augmentative Communication (AAC) strategies based on synthetic voices have been shown to assist patients in maintaining communication and improving their Quality of Life (QoL). However, such synthetic voices are often perceived as impersonal and fail to capture the unique voice and identity of the patient. To tackle this issue, combining voice banking (VB) and artificial intelligence (AI) has emerged as a more natural communication strategy, enabling individuals to preserve their voice for use with AAC devices as needed. This involves recording speech samples to generate a synthetic voice closely resembling the individual's own. Despite the increasing interest in VB, there's a lack of clear strategies for its effective implementation in rapidly progressing diseases like ALS. Additionally, the perceptual quality of VB on patients with preserved speech, especially when offered early in the disease, remains poorly understood. In light of these challenges, this study aims to assess the effectiveness and the perceptual impact of AI-generated voices on ALS patients with preserved speech, utilizing a personalized voice synthesis system based on machine learning. The AI-generated patient-specific voice is achieved through voice recording, followed by fine-tuning using a Generative Adversarial Network for Efficient and High Fidelity Speech Synthesis (HiFi-GAN), resulting in a model capable of producing speech highly similar to the patient's own voice, with exceptional expressive and audio quality. By addressing these aspects, this study intends to offer valuable insights into the potential benefits and challenges of combining VB with AI voices to enhance communication support for ALS patients.}, }
@article {pmid39779704, year = {2025}, author = {Kempthorne, L and Vaizoglu, D and Cammack, AJ and Carcolé, M and Roberts, MJ and Mikheenko, A and Fisher, A and Suklai, P and Muralidharan, B and Kroll, F and Moens, TG and Yshii, L and Verschoren, S and Hölbling, BV and Moreira, FC and Katona, E and Coneys, R and de Oliveira, P and Zhang, YJ and Jansen, K and Daughrity, LM and McGown, A and Ramesh, TM and Van Den Bosch, L and Lignani, G and Rahim, AA and Coyne, AN and Petrucelli, L and Rihel, J and Isaacs, AM}, title = {Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {459}, pmid = {39779704}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; 217150/Z/19/Z//Wellcome Trust (Wellcome)/ ; 648716 - C9ND//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/therapy ; Humans ; *Frontotemporal Dementia/genetics/metabolism ; Animals ; *CRISPR-Cas Systems ; *RNA, Antisense/genetics ; Mice ; HEK293 Cells ; *Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Neurons/metabolism ; Genetic Therapy/methods ; }, abstract = {The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G4C2 repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.}, }
@article {pmid39779681, year = {2025}, author = {McCallister, TX and Lim, CKW and Singh, M and Zhang, S and Ahsan, NS and Terpstra, WM and Xiong, AY and Zeballos C, MA and Powell, JE and Drnevich, J and Kang, Y and Gaj, T}, title = {A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {460}, pmid = {39779681}, issn = {2041-1723}, support = {1R01NS123556-01A1//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 1U01NS122102-01A1//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; 5R01GM141296//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; MDA602798//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 GM141296/GM/NIGMS NIH HHS/United States ; 20-IIP-516//Amyotrophic Lateral Sclerosis Association (ALS Association)/ ; T32 EB019944/EB/NIBIB NIH HHS/United States ; U01 NS122102/NS/NINDS NIH HHS/United States ; R01 NS123556/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *CRISPR-Cas Systems ; Humans ; Animals ; DNA Repeat Expansion/genetics ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Mice ; }, abstract = {An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.}, }
@article {pmid39779313, year = {2025}, author = {Xiao, Y and Tan, Y and Li, C and Wei, Q and Jiang, Q and Wang, S and Yang, T and Lin, J and Zhang, L and Shang, H}, title = {Genetic and clinical analysis of OPTN in amyotrophic lateral sclerosis.}, journal = {Journal of medical genetics}, volume = {62}, number = {4}, pages = {242-248}, doi = {10.1136/jmg-2024-109978}, pmid = {39779313}, issn = {1468-6244}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Cell Cycle Proteins/genetics ; *Membrane Transport Proteins/genetics ; *Transcription Factor TFIIIA/genetics ; Male ; Female ; Middle Aged ; Mutation ; Phenotype ; Aged ; Genetic Association Studies/methods ; Adult ; Genetic Predisposition to Disease ; Asian People/genetics ; Genotype ; }, abstract = {BACKGROUND: Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation between OPTN genotypes and phenotypes.<br><br>METHODS: OPTN gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of OPTN mutations and explore the relationship between the genotype and phenotype of patients with ALS with OPTN.<br><br>RESULTS: A total of 33 unrelated patients with ALS with 24 rare OPTN variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of OPTN variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.<br><br>CONCLUSION: Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying OPTN variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.}, }
@article {pmid39778888, year = {2025}, author = {Etxebeste-Mitxeltorena, M and Flores-Romero, H and Ramos-Inza, S and Masiá, E and Nenchova, M and Montesinos, J and Martinez-Gonzalez, L and Porras, G and Orzáez, M and Vicent, MJ and Gil, C and Area-Gomez, E and Garcia-Saez, AJ and Martinez, A}, title = {Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {2}, pages = {1179-1194}, pmid = {39778888}, issn = {1520-4804}, support = {/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; *Endoplasmic Reticulum/metabolism/drug effects ; *Mitochondria/metabolism/drug effects ; *Lipid Metabolism/drug effects ; *Small Molecule Libraries/pharmacology/chemistry ; Cholesterol/metabolism ; HCT116 Cells ; Mitochondria Associated Membranes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.}, }
@article {pmid39778605, year = {2025}, author = {Urano, Y and Iwagaki, A and Takeishi, A and Uchiyama, N and Noguchi, N}, title = {Downregulation of the SREBP pathways and disruption of redox status by 25-hydroxycholesterol predispose cells to ferroptosis.}, journal = {Free radical biology &amp; medicine}, volume = {228}, number = {}, pages = {319-328}, doi = {10.1016/j.freeradbiomed.2025.01.010}, pmid = {39778605}, issn = {1873-4596}, mesh = {*Hydroxycholesterols/metabolism ; *Ferroptosis/drug effects/genetics ; Animals ; Mice ; *Oxidation-Reduction ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; Signal Transduction ; Schwann Cells/metabolism/drug effects/pathology ; Down-Regulation ; Sterol Regulatory Element Binding Protein 1/metabolism/genetics ; Sterol Regulatory Element Binding Protein 2/metabolism/genetics ; Cell Line ; Cell Survival/drug effects ; Humans ; Steroid Hydroxylases ; }, abstract = {Enzymatically formed side-chain oxysterols function as signaling molecules regulating cholesterol homeostasis and act as intermediates in the biosynthesis of bile acids. In addition to these physiological functions, an imbalance in oxysterol homeostasis has been implicated in pathophysiology. Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25-OHC), also formed by autoxidation, are associated with amyotrophic lateral sclerosis. However, the effects of 25-OHC on cell viability in glial cells remain unclear. This study demonstrates that 25-OHC induces ferroptosis, an iron-dependent programmed cell death, in mouse Schwann IMS32 cells. Mechanistically, 25-OHC suppressed the expression of selenoprotein glutathione peroxidase 4 (GPX4) at both the transcriptional and translational levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs). In addition, 25-OHC upregulated the expression of NADH-cytochrome b5 reductase 1 (CYB5R1) and NADPH-cytochrome P450 reductase (POR), enzymes that promote lipid peroxidation. We further found that 25-OHC increases the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) and decreases glutathione levels. Importantly, non-cytotoxic concentrations of 25-OHC enhanced cellular sensitivity to ferroptosis inducers by downregulating GPX4 expression. These findings reveal a multifaceted approach whereby 25-OHC induces ferroptosis through SREBP pathway suppression and redox imbalance in mouse Schwann IMS32 cells.}, }
@article {pmid39778593, year = {2025}, author = {Chen, Q and Chen, G and Wang, Q}, title = {Application of Network Pharmacology in the Treatment of Neurodegenerative Diseases with Traditional Chinese Medicine.}, journal = {Planta medica}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2512-8928}, pmid = {39778593}, issn = {1439-0221}, support = {2023AFB677//the Natural Science Foundation of Hubei Province/ ; 2024AFB578//the Natural Science Foundation of Hubei Province/ ; 2023LYYYGZRP0003//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; 2023LYYYSZRP0001//the Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology/ ; }, abstract = {In recent years, the incidence of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, has exhibited a steadily rising trend, which has posed a major challenge to the global public health. Traditional Chinese medicine, with its multicomponent and multitarget characteristics, offers a promising approach to treating neurodegenerative diseases. However, comprehensively elucidating the complex mechanisms underlying traditional Chinese medicine formulations remains challenging. As an emerging systems biology method, network pharmacology has provided a vital tool for revealing the multitarget mechanisms of traditional Chinese medicine through high-throughput technologies, molecular docking, and network analysis. This paper reviews the advancements in the application of network pharmacology in treating neurodegenerative diseases using traditional Chinese medicine, analyzes the current status of relevant databases and technological methods, discusses the limitations, and proposes future directions to promote the modernization of traditional Chinese medicine and the development of precision medicine.}, }
@article {pmid39778572, year = {2025}, author = {Je, Y and Park, YE and Shin, YB}, title = {Differentiating Inclusion Body Myositis From Amyotrophic Lateral Sclerosis Based on the Features of Dysphagia: Insights From a Patient With Rapidly Progressive Dysphagia.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {1}, pages = {83-85}, pmid = {39778572}, issn = {1738-6586}, support = {/PNUH/Pusan National University Hospital/Korea ; }, }
@article {pmid39777244, year = {2025}, author = {Moura, FA and Siqueira, AIAN}, title = {Gut-liver axis in sepsis-associated liver injury: Epidemiology, challenges and clinical practice.}, journal = {World journal of gastroenterology}, volume = {31}, number = {1}, pages = {99987}, pmid = {39777244}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Sepsis/complications/epidemiology ; *Dysbiosis ; *Liver/metabolism/pathology ; Animals ; *Oxidative Stress ; Bacterial Translocation ; Liver Diseases/epidemiology/microbiology ; Critical Illness ; Intensive Care Units/statistics &amp; numerical data ; Anti-Bacterial Agents/therapeutic use ; }, abstract = {Although the liver has a remarkable regenerative capacity, sepsis-associated liver injury (SLI) is a complication often seen in intensive care units. Due to its role in immune and inflammatory regulation, the liver is particularly vulnerable during severe infections. Understanding the global prevalence, causes, and management of SLI is essential to improve outcomes and reduce healthcare costs. This paper aims to explore these factors, with an emphasis on identifying effective strategies for clinical management. Zhang et al's bibliometric analysis of 787 publications (745 original articles and 42 reviews, mostly in animal models) from 2000 to 2023 highlights the growing interest in SLI, focusing on oxidative stress, gut microbiota, and inflammatory processes. Key components such as nuclear factor-kappa B and the NOD-like receptor thermal protein domain associated protein 3 inflammasome pathway, along with their links to gut microbiota imbalance and oxidative stress, are crucial for understanding SLI pathogenesis. The gut-liver axis, particularly the role of intestinal permeability and bacterial translocation in liver inflammation, is emphasized. In this context, bacterial translocation is especially relevant for critically ill patients, as it can exacerbate liver inflammation. The findings underscore the need for integrated care in intensive care units, prioritizing gut health and careful antibiotic use to prevent dysbiosis. Despite extensive research, there remains a lack of clinical trials to validate therapeutic approaches. The abundance of experimental studies highlights potential therapeutic targets, stressing the need for high-quality randomized clinical trials to translate these findings into clinical practice.}, }
@article {pmid39776752, year = {2024}, author = {Schwamburger, J and Brock, K and Cooper, R}, title = {The effect of GV-58, a calcium channel modifier, on synaptic transmission at the larval Drosophila and crayfish neuromuscular junctions.}, journal = {microPublication biology}, volume = {2024}, number = {}, pages = {}, pmid = {39776752}, issn = {2578-9430}, abstract = {GV-58 is known to increase the opening time of the mammalian P-type calcium channel in presynaptic motor nerve terminals. GV-58 is suggested as a therapeutic agent for dampening the symptoms of amyotrophic lateral sclerosis. To further understand the mechanisms of GV-58 actions, the Drosophila and crayfish neuromuscular junctions were used as models. Their presynaptic calcium channels are a P-type based on pharmacology profiles. However, exposure of GV-58 (1mM) did not produce any consistent alteration in synaptic transmission in these two preparations. It is possible that the molecular structure of the P-type channels is different in the Drosophila and crayfish.}, }
@article {pmid39776251, year = {2025}, author = {Öijerstedt, L and Foucher, J and Lovik, A and Yazdani, S and Juto, A and Kläppe, U and Fang, F and Ingre, C}, title = {Correction: Repeated cognitive assessments show stable function over time in patients with ALS.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {104}, doi = {10.1007/s00415-024-12833-z}, pmid = {39776251}, issn = {1432-1459}, }
@article {pmid39775908, year = {2025}, author = {de Vries, E and Hagbohm, C and Ouellette, R and Granberg, T}, title = {Clinical 7 Tesla magnetic resonance imaging: Impact and patient value in neurological disorders.}, journal = {Journal of internal medicine}, volume = {297}, number = {3}, pages = {244-261}, pmid = {39775908}, issn = {1365-2796}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Nervous System Diseases/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnostics and treatment monitoring, particularly for diseases of the central nervous system. Although 1.5- and 3 Tesla (T) field strengths remain the clinical standard, the advent of 7 T MRI represents a transformative step forward, offering superior spatial resolution, contrast, and sensitivity for visualizing neuroanatomy, metabolism, and function. Recent innovations, including parallel transmission and deep learning-based reconstruction, have resolved many prior technical challenges of 7 T MRI, enabling its routine clinical use. This review examines the diagnostic impact, patient value, and practical considerations of 7 T MRI, emphasizing its role in facilitating earlier diagnoses and improving care in conditions, such as amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis (MS), dementia, parkinsonism, tumors, and vascular diseases. Based on insights from over 1200 clinical scans with a second-generation 7 T system, the review highlights disease-specific biomarkers such as the motor band sign in ALS and the new diagnostic markers in MS, the central vein sign, and paramagnetic rim lesions. The unparalleled ability of 7 T MRI to study neurological diseases ex vivo at ultra-high resolution is also explored, offering new opportunities to understand pathophysiology and identify novel treatment targets. Additionally, the review provides a clinical perspective on patient handling and safety considerations, addressing challenges and practicalities associated with clinical 7 T MRI. By bridging research and clinical practice, 7 T MRI has the potential to redefine neuroimaging and advance the understanding and management of complex neurological disorders.}, }
@article {pmid39775401, year = {2025}, author = {Grassi, M and Tarantino, B}, title = {SEMdag: Fast learning of Directed Acyclic Graphs via node or layer ordering.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0317283}, pmid = {39775401}, issn = {1932-6203}, mesh = {Humans ; *Algorithms ; *COVID-19 ; SARS-CoV-2 ; Breast Neoplasms ; Software ; }, abstract = {A Directed Acyclic Graph (DAG) offers an easy approach to define causal structures among gathered nodes: causal linkages are represented by arrows between the variables, leading from cause to effect. Recently, industry and academics have paid close attention to DAG structure learning from observable data, and many techniques have been put out to address the problem. We provide a two-step approach, named SEMdag(), that can be used to quickly learn high-dimensional linear SEMs. It is included in the R package SEMgraph and employs a two-stage order-based search using previous knowledge (Knowledge-based, KB) or data-driven method (Bottom-up, BU), under the premise that a linear SEM with equal variance error terms is assumed. We evaluated our framework's for finding plausible DAGs against six well-known causal discovery techniques (ARGES, GES, PC, LiNGAM, CAM, NOTEARS). We conducted a series of experiments using observed expression (or RNA-seq) data, taking into account a pair of training and testing datasets for four distinct diseases: Amyotrophic Lateral Sclerosis (ALS), Breast cancer (BRCA), Coronavirus disease (COVID-19) and ST-elevation myocardial infarction (STEMI). The results show that the SEMdag() procedure can recover a graph structure with good disease prediction performance evaluated by a conventional supervised learning algorithm (RF): in the scenario where the initial graph is sparse, the BU approach may be a better choice than the KB one; in the case where the graph is denser, both BU an KB report high performance, with highest score for KB approach based on topological layers. Besides its superior disease predictive performance compared to previous research, SEMdag() offers the user the flexibility to define distinct structure learning algorithms and can handle high dimensional issues with less computing load. SEMdag() function is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph.}, }
@article {pmid39774976, year = {2025}, author = {Naito, H and Nakamori, M and Toko, M and Hayashi, Y and Tazuma, T and Watanabe, T and Ishihara, K and Tachiyama, K and Yamazaki, Y and Maruyama, H}, title = {A single-center, single-arm, prospective, open-label, and comparative trial to evaluate the safety and tolerability profile of a 90-day oral L-arginine hydrochloride intervention for patients with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {1120}, pmid = {39774976}, issn = {2045-2322}, support = {23K16642//Japan Society for the Promotion of Science/ ; NA//ALS Foundation, Japan ALS Association/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Administration, Oral ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Arginine/administration &amp; dosage/adverse effects/therapeutic use ; Nutritional Status ; Prospective Studies ; Treatment Outcome ; }, abstract = {Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were - 0.37 kg, -1.1 kg/m[2], and - 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug.Trial Registration number: Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.}, }
@article {pmid39772789, year = {2025}, author = {Stolwyk, K and Lee, I}, title = {Rapid progression of amyotrophic lateral sclerosis after initiation of GLP-1 agonist: a case report.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/21678421.2024.2446847}, pmid = {39772789}, issn = {2167-9223}, }
@article {pmid39771101, year = {2024}, author = {Chetverikova, D and Bakaeva, M and Starikov, S and Kendjieva, A and Chetverikov, S}, title = {The Influence of Plant Growth-Stimulating Bacteria on the Glutathione-S-Transferase Activity and the Toxic Effect of the Herbicide Metsulfuron-Methyl in Wheat and Canola Plants.}, journal = {Toxics}, volume = {12}, number = {12}, pages = {}, pmid = {39771101}, issn = {2305-6304}, support = {23-26-00097//Russian Science Foundation/ ; }, abstract = {The ability of some rhizosphere bacteria to mitigate herbicidal stress in cultivated plants may be useful in agriculture and bioremediation. There is poor understanding of how bacteria directly or through herbicide degradation affect the biochemical processes in plants exposed to sulfonylurea herbicides. In this study, treatment with a combination of herbicide metsulfuron-methyl (MSM) and bacteria (Pseudomonas protegens DA1.2 or P. chlororaphis 4CH) of wheat (Triticum aestivum L.) and canola (Brassica napus L.) plants was carried out. Activity of glutathione-S-transferase (GST), an important enzyme for the herbicide detoxification, and acetolactate synthase (ALS), a target for MSM in plants, was measured by spectrophotometric assays. MSM residues were analyzed using the HPLC-MS. Then, 24 h after bacterial treatment, GST activity increased by 75-91% in wheat and by 38-94% in canola. On the 30th day, a decrease in MSM in the soil associated with bacterial treatment was 54.6-79.7%. An increase in GST activity and acceleration of MSM degradation were accompanied by a decrease in inhibition of the ALS enzyme in plants, which indicated a mitigation of the toxic effect. The results obtained are evidence that rhizospheric bacteria can have beneficial effects on plants exposed to MSM due to the combination of abilities to directly affect detoxification enzymes in plants and degrade MSM in the soil.}, }
@article {pmid39770989, year = {2024}, author = {Pekdemir, B and Raposo, A and Saraiva, A and Lima, MJ and Alsharari, ZD and BinMowyna, MN and Karav, S}, title = {Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, pmid = {39770989}, issn = {2072-6643}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; Brain/drug effects/metabolism ; Animals ; Flavonoids/pharmacology/therapeutic use ; Apoptosis/drug effects ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.}, }
@article {pmid39770252, year = {2024}, author = {Guo, H and Yao, J and Chen, S and Qian, C and Pan, X and Yin, K and Zhu, H and Gao, X and Wang, S and Sun, L}, title = {Enhancing Resistive Switching in AlN-Based Memristors Through Oxidative Al2O3 Layer Formation: A Study on Preparation Techniques and Performance Impact.}, journal = {Micromachines}, volume = {15}, number = {12}, pages = {}, pmid = {39770252}, issn = {2072-666X}, support = {11874105//National Natural Science Foundation of China/ ; }, abstract = {Aluminum nitride (AlN) with a wide band gap (approximately 6.2 eV) has attractive characteristics, including high thermal conductivity, a high dielectric constant, and good insulating properties, which are suitable for the field of resistive random access memory. AlN thin films were deposited on ITO substrate using the radio-frequency magnetron sputtering technique. Al's and Au's top electrodes were deposited on AlN thin films to make a Au/Al/AlN/ITO sandwich structure memristor. The effects of the Al2O3 film on the on/off window and voltage characteristics of the device were investigated. The deposition time and nitrogen content in the sputtering atmosphere were changed to adjust the thickness and composition of AlN films, respectively. The possible mechanism of resistive switching was examined via analyses of the electrical resistive switching characteristics, forming voltage, and switching ratio.}, }
@article {pmid39769215, year = {2024}, author = {Wei, Z and Iyer, MR and Zhao, B and Deng, J and Mitchell, CS}, title = {Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769215}, issn = {1422-0067}, support = {1944247//National Science Foundation/ ; R35GM152245/NH/NIH HHS/United States ; U19-AG056169/NH/NIH HHS/United States ; 253558//Chan Zuckerberg Initiative/ ; }, mesh = {Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/physiopathology ; *Alzheimer Disease/metabolism/genetics/physiopathology/pathology ; *Artificial Intelligence ; Algorithms ; }, abstract = {The overlapping molecular pathophysiology of Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research.}, }
@article {pmid39769213, year = {2024}, author = {Gu, A and Zhang, Y and He, J and Zhao, M and Ding, L and Liu, W and Xiao, J and Huang, J and Liu, M and Liu, X}, title = {Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769213}, issn = {1422-0067}, support = {2016YFC0905100//National Key Research and Development Program of China/ ; 2021JJ30801//Natural Science Foundation of Hunan Province, China/ ; kq2202077//Natural Science Foundation of Changsha, China/ ; 1053320222758//Fundamental Research Funds for the Central Universities of Central South University/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; *Oxidative Stress ; *Motor Neurons/metabolism/pathology ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Stress Granules/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Autophagy ; Cell Cycle Proteins/metabolism/genetics ; Nerve Degeneration/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Sodium Compounds/pharmacology ; }, abstract = {The pathogenesis of neurodegenerative diseases results from the interplay between genetic and environmental factors. Aging and chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation and protects against oxidative stress. In ALS neurons harboring UBQLN2 mutations, oxidative stress accelerates pathological changes, yet the precise mechanisms remain unclear. Using induced motor neurons (iMNs) derived from UBQLN2 P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, and reduced viability. Sodium arsenite (SA)-induced oxidative stress triggered stress granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX and bosutinib treatments reduced ubiquitinated protein accumulation and alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize the role of chronic oxidative stress and stress granule formation in UBQLN2 ALS, offering insights into novel therapeutic targets.}, }
@article {pmid39769209, year = {2024}, author = {Xing, C and Chen, H and Bi, W and Lei, T and Hang, Z and Du, H}, title = {Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769209}, issn = {1422-0067}, support = {32300682//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Serotonin/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Alzheimer Disease/metabolism/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Parkinson Disease/metabolism/drug therapy ; Receptors, Serotonin/metabolism ; }, abstract = {There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application.}, }
@article {pmid39769187, year = {2024}, author = {O'Day, DH}, title = {The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {24}, pages = {}, pmid = {39769187}, issn = {1422-0067}, mesh = {Animals ; Humans ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Calmodulin/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; Parkinson Disease/metabolism/pathology/therapy ; Protein Glutamine gamma Glutamyltransferase 2 ; RNA-Binding Protein FUS/metabolism/genetics ; tau Proteins/metabolism ; Transglutaminases/metabolism ; }, abstract = {The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.}, }
@article {pmid39768371, year = {2024}, author = {Orlova, A and Malygin, Y and Gofman, A and Sotulenko, S and Gandalian, V and Kartashov, I and Brylev, L and Bolevich, S and Nikolic Turnic, T and Jakovljevic, V}, title = {Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {39768371}, issn = {2075-1729}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients.<br><br>METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus.<br><br>RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation.<br><br>CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.}, }
@article {pmid39768167, year = {2024}, author = {Chen, X and Lv, S and Liu, J and Guan, Y and Xu, C and Ma, X and Li, M and Bai, X and Liu, K and Zhang, H and Yan, Q and Zhou, F and Chen, Y}, title = {Exploring the Role of Axons in ALS from Multiple Perspectives.}, journal = {Cells}, volume = {13}, number = {24}, pages = {}, pmid = {39768167}, issn = {2073-4409}, support = {82271483//The National Natural Science Foundation of China/ ; ZR2024MH112; ZR2024QH628//Shandong Province Natural Science Foundation of China/ ; 2023YX036; 2022YX043//Weifang Science and Technology Development Plan Project/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology ; *Axons/pathology/metabolism ; Animals ; Axonal Transport ; Motor Neurons/pathology ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as motor neuron disease, is a neurodegenerative disorder characterized by the progressive degeneration of both upper and lower motor neurons. This pathological process results in muscle weakness and can culminate in paralysis. To date, the precise etiology of ALS remains unclear. However, a burgeoning body of research indicates that axonal dysfunction is a pivotal element in the pathogenesis of ALS and significantly influences the progression of disease. Dysfunction of axons in ALS can result in impediments to nerve impulse transmission, leading to motor impairment, muscle atrophy, and other associated complications that severely compromise patients' quality of life and survival prognosis. In this review, we concentrate on several key areas: the ultrastructure of axons, the mechanisms of axonal degeneration in ALS, the impact of impaired axonal transport on disease progression in ALS, and the potential for axonal regeneration within the central nervous system (CNS). Our objective is to achieve a more holistic and profound understanding of the multifaceted role that axons play in ALS, thereby offering a more intricate and refined perspective on targeted axonal therapeutic interventions.}, }
@article {pmid39767639, year = {2024}, author = {Wan, M and Zhang, L and Huo, J and Fu, Y and Huang, T and Fan, D}, title = {Genetic Variation in Targets of Antidiabetic Drugs and Amyotrophic Lateral Sclerosis Risk.}, journal = {Biomedicines}, volume = {12}, number = {12}, pages = {}, pmid = {39767639}, issn = {2227-9059}, support = {82101490, and 82071426//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS.<br><br>METHODS: Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles.<br><br>RESULTS: Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05).<br><br>CONCLUSIONS: The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.}, }
@article {pmid39766833, year = {2024}, author = {Bisogni, G and Conte, A and Costantino, U and Lattante, S and Bernardo, D and Lucioli, G and Patanella, AK and Cimbolli, P and Del Giudice, E and Vettor, F and Marangi, G and Doronzio, PN and Zollino, M and Sabatelli, M}, title = {Exploring the Role of CCNF Variants in Italian ALS Patients.}, journal = {Genes}, volume = {15}, number = {12}, pages = {}, pmid = {39766833}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Italy ; Middle Aged ; Aged ; Mutation, Missense ; Cyclins/genetics ; Frontotemporal Dementia/genetics/pathology ; Genetic Association Studies ; High-Throughput Nucleotide Sequencing ; Phenotype ; Adult ; Genetic Predisposition to Disease ; }, abstract = {Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients.}, }
@article {pmid39766450, year = {2024}, author = {Donaghy, R and Pioro, EP}, title = {Neurophysiologic Innovations in ALS: Enhancing Diagnosis, Monitoring, and Treatment Evaluation.}, journal = {Brain sciences}, volume = {14}, number = {12}, pages = {}, pmid = {39766450}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive disease of both upper motor neurons (UMNs) and lower motor neurons (LMNs) leading invariably to decline in motor function. The clinical exam is foundational to the diagnosis of the disease, and ordinal severity scales are used to track its progression. However, the lack of objective biomarkers of disease classification and progression delay clinical trial enrollment, muddle inclusion criteria, and limit accurate assessment of drug efficacy. Ultimately, biomarker evidence of therapeutic target engagement will support, and perhaps supplant, more traditional clinical trial outcome measures. Electrophysiology tools including nerve conduction study and electromyography (EMG) have already been established as diagnostic biomarkers of LMN degeneration in ALS. Additional understanding of the motor manifestations of disease is provided by motor unit number estimation, electrical impedance myography, and single-fiber EMG techniques. Dysfunction of UMN and non-motor brain areas is being increasingly assessed with transcranial magnetic stimulation, high-density electroencephalography, and magnetoencephalography; less common autonomic and sensory nervous system dysfunction in ALS can also be characterized. Although most of these techniques are used to explore the underlying disease mechanisms of ALS in research settings, they have the potential on a broader scale to noninvasively identify disease subtypes, predict progression rates, and assess physiologic engagement of experimental therapies.}, }
@article {pmid39766276, year = {2024}, author = {Wysoczański, B and Świątek, M and Wójcik-Gładysz, A}, title = {Organ-on-a-Chip Models-New Possibilities in Experimental Science and Disease Modeling.}, journal = {Biomolecules}, volume = {14}, number = {12}, pages = {}, pmid = {39766276}, issn = {2218-273X}, mesh = {*Lab-On-A-Chip Devices ; Humans ; Animals ; Models, Biological ; Liver/metabolism/cytology ; Cell Culture Techniques/methods ; Microphysiological Systems ; }, abstract = {'Organ-on-a-chip' technology is a promising and rapidly evolving model in biological research. This innovative microfluidic cell culture device was created using a microchip with continuously perfused chambers, populated by living cells arranged to replicate physiological processes at the tissue and organ levels. By consolidating multicellular structures, tissue-tissue interfaces, and physicochemical microenvironments, these microchips can replicate key organ functions. They also enable the high-resolution, real-time imaging and analysis of the biochemical, genetic, and metabolic activities of living cells in the functional tissue and organ contexts. This technology can accelerate research into tissue development, organ physiology and disease etiology, therapeutic approaches, and drug testing. It enables the replication of entire organ functions (e.g., liver-on-a-chip, hypothalamus-pituitary-on-a-chip) or the creation of disease models (e.g., amyotrophic lateral sclerosis-on-a-chip, Parkinson's disease-on-a-chip) using specialized microchips and combining them into an integrated functional system. This technology allows for a significant reduction in the number of animals used in experiments, high reproducibility of results, and the possibility of simultaneous use of multiple cell types in a single model. However, its application requires specialized equipment, advanced expertise, and currently incurs high costs. Additionally, achieving the level of standardization needed for commercialization remains a challenge at this stage of development.}, }
@article {pmid39765493, year = {2024}, author = {Zhang, T and Xu, Q and Zhou, B and Xiao, J and Zheng, S and Li, J and Lv, Q and Zhang, Y and Wang, R and Su, R and Wang, Z}, title = {Development and Validation of a 5K Liquid Chip for Identifying Cashmere Goat Populations in Inner Mongolia Autonomous Region.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {24}, pages = {}, pmid = {39765493}, issn = {2076-2615}, support = {2022YFE0113300&#xff0c;2022YFD1300201,2022YFD1300204//National Key Research and Development Program/ ; BR220112//Project for Enhancing Young Teacher's Research Ability/ ; NJYT22038//Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region/ ; 2023ZD0405102//Project for 2030 Science and Technology Innovation Major/ ; NMGIRT2322//Program for Inner Mongolia Autonomous Region Higher Education Innovation Team Development/ ; }, abstract = {(1) Background: Cashmere goats, as one of the characteristic species, are rich in genetic resources. Protecting and rationally utilizing these genetic resources is of great significance for the genetic improvement of cashmere goats. (2) Methods: In this study, tissue samples were collected from Inner Mongolia white cashmere goats, which included the Arbas type (ARBS); Erlangshan type (ELS); Alashan type (ALS), Hanshan white cashmere goats (HS), and Ujimqin white cashmere goats (WZMQ). Genomic DNA was extracted and subjected to high-depth genome resequencing. GenoBait technology was used for probe design and site optimization, followed by the synthesis of a low-density liquid phase chip. Finally, a total of 281 individuals from five cashmere goat populations in the Inner Mongolia Autonomous Region were randomly selected to verify the chip. (3) Results: The results showed that a total of 5002 SNP sites were finally screened and retained for the synthesis of the low-density liquid chip for identifying cashmere goats in Inner Mongolia Autonomous Region. Principal component analysis and phylogenetic tree construction indicated that the ARBS, ELS, and ALS populations were clustered into one category. (4) Conclusions: This chip can accurately identify the three breeds: Inner Mongolia white cashmere goats, Hanshan white cashmere goats, and Ujimqin white cashmere goats.}, }
@article {pmid39764140, year = {2024}, author = {Akif, A and My Nguyen, TT and Liu, L and Xu, X and Kulkarni, A and Jiang, J and Zhang, Y and Hao, J}, title = {Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39764140}, issn = {2693-5015}, support = {R01 NS105787/NS/NINDS NIH HHS/United States ; R21 NS133895/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.<br><br>METHODS: In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50[th] day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1&#x3b2;), Tumor Necrosis Factor-alpha (TNF-&#x3b1;) and Interleukin-4 (IL-4) in the blood were measured using ELISA.<br><br>RESULTS: AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-&#x3b1; and IL-1&#x3b2; levels, while increasing the anti-inflammatory IL-4 level in the blood.<br><br>CONCLUSIONS: The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.}, }
@article {pmid39763885, year = {2024}, author = {Shelest, O and Tindel, I and Lauzon, M and Dawson, A and Ho, R}, title = {Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39763885}, issn = {2692-8205}, support = {R00 AG056678/AG/NIA NIH HHS/United States ; }, abstract = {The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.}, }
@article {pmid39762986, year = {2025}, author = {Berlowitz, DJ and Rowe, D and Howard, ME and Piper, A and Graco, M and Braat, S and Singh, B and Souza, TV and Lannin, N and McLean, A and Sawyer, A and Carey, KA and Ahamed, Y and , }, title = {Polysomnographic titration of non-invasive ventilation in motor neurone disease (3TLA): study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {26}, number = {1}, pages = {10}, pmid = {39762986}, issn = {1745-6215}, mesh = {Humans ; *Noninvasive Ventilation/methods/adverse effects/instrumentation ; *Motor Neuron Disease/therapy/physiopathology ; *Polysomnography ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; Australia ; Multicenter Studies as Topic ; Time Factors ; Sleep ; Respiratory Insufficiency/therapy/physiopathology ; Quality of Life ; }, abstract = {BACKGROUND: Non-invasive ventilation (NIV) uses positive pressure to assist people with respiratory muscle weakness or severe respiratory compromise to breathe. Most people use this treatment during sleep when breathing is most susceptible to instability. The benefits of using NIV in motor neurone disease (MND) are well-established. However, uptake and usage are low (~ 19%) and there is no consensus on how to best implement NIV in MND in Australia. Consequently, clinical practice models are highly variable. Our team has recently provided evidence that specific and individualised NIV titration using a sleep study (polysomnography; PSG) leads to better outcomes in people with MND. However, for this clinical practice model to result in sustained benefits, evidence of effectiveness across multiple sites, as well as culture and practice change, must occur.<br><br>METHODS: A two-arm, assessor-blinded, individual participant randomised controlled trial in MND care centres across Australia will be undertaken. Two-hundred and forty-four participants will be randomised (1:1) to either the intervention group (PSG-assisted commencement of NIV settings; PSG) or a control group (sham PSG). Participants will be asked to use their NIV device for 7&#xa0;weeks and will then return for follow-up assessments. Respiratory, sleep and patient-reported outcome measures will be collected at baseline and follow-up. The primary aim is to determine if the proportion of participants using NIV for&#x2009;>&#x2009;4&#xa0;h/day during the intervention period is higher in the PSG than the control group. A process evaluation, health economic evaluation and 12-month cohort follow-up will be undertaken and reported separately.<br><br>DISCUSSION: The results of this trial will demonstrate the effects of PSG-assisted titration of NIV on usage of NIV in people with MND. We hypothesise that the PSG intervention will improve synchrony between the user and the machine, which will lead to greater NIV usage compared to the control group.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.}, }
@article {pmid39762711, year = {2025}, author = {Apostolo, D and Ferreira, LL and D'Onghia, D and Vincenzi, F and Vercellino, N and Perazzi, M and Pirisi, M and Cantello, R and Minisini, R and Mazzini, L and Bellan, M and De Marchi, F}, title = {Lower Circulating Gas6 Levels Are Associated with Bulbar Phenotype and Faster Disease Progression in Amyotrophic Lateral Sclerosis Patients.}, journal = {Molecular neurobiology}, volume = {62}, number = {5}, pages = {6273-6282}, pmid = {39762711}, issn = {1559-1182}, support = {2021-1541//Fondazione Cariplo/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/pathology ; Female ; Male ; *Disease Progression ; Middle Aged ; *Intercellular Signaling Peptides and Proteins/blood ; *Phenotype ; Aged ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects the motor neurons in the brain and spinal cord. While the exact cause of ALS is not fully understood, a combination of genetic and environmental factors is believed to contribute to its development. Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been recognized to enhance oligodendrocytes and neurons' survival and is associated with different kinds of (neuro)inflammatory conditions. Therefore, we aimed to determine a possible implication of Gas6 in ALS phenotype and progression by evaluating the value of circulating Gas6 and its soluble receptors (sAxl, sMer, sTyro-3) in ALS patients. We conducted a prospective observational study including 65 ALS patients and measured the circulating serum levels of Gas6, sAxl, sMer, soluble Tyro-3 (sTyro-3), and neurofilaments (NfLs). In our ALS cohort, lower serum levels of Gas6 and concomitantly higher levels of NfLs were associated with a more aggressive disease, expressed with bulbar phenotype (p-value for Gas6 = 0.03) and faster progression (p-value for Gas6 = 0.03). Also, serum Gas6 was able to distinguish (area under the curve, cut-off 13.70 ng/mL, sensitivity 69.57%, specificity 72.72%) between fast and slow progressors. Due to its neuroprotective properties, our data suggest that Gas6 could be an intriguing biomarker in ALS patients.}, }
@article {pmid39761853, year = {2025}, author = {Weeks, AT and Bird, AJ}, title = {Regulation of sod1 mRNA and protein abundance by zinc in fission yeast is dependent on the CCR4-NOT complex.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {2}, pages = {108156}, pmid = {39761853}, issn = {1083-351X}, support = {R01 GM105695/GM/NIGMS NIH HHS/United States ; }, mesh = {*Schizosaccharomyces/metabolism/genetics ; *Zinc/metabolism ; *Schizosaccharomyces pombe Proteins/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Gene Expression Regulation, Fungal/drug effects ; *Superoxide Dismutase/metabolism/genetics ; Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Zinc is an essential micronutrient that serves as a cofactor in a wide variety of enzymes, including Cu-Zn Superoxide Dismutase 1 (Sod1). We have discovered in Schizosaccharomyces pombe that Sod1 mRNA and protein levels are regulated in response to cellular zinc availability. We demonstrate that lower levels of sod1 mRNA and protein accumulate under low zinc conditions and that this regulation does not require the sod1 promoter or known factors that regulate the transcription of sod1 in response to zinc and other environmental stresses. Further analyses using yeast deletion strains and an inactive allele of Caf1 revealed that the reduced accumulation of sod1 mRNA and protein under low zinc conditions depends on the Caf1 and Ccr4 deadenylases of the CCR4-NOT complex. We also found that Caf1 and Ccr4 are both required for growth under zinc-limiting conditions. To gain additional mechanistic insight we used immunoblot analysis to map the regions required for the regulation of the Sod1 protein by zinc. We found that the sod1 ORF and 3'UTR are both necessary and sufficient for the zinc-dependent changes in Sod1 protein abundance. Our studies reveal a novel mechanism of altering mRNA and protein abundance in response to zinc status, which depends on the CCR4-NOT complex.}, }
@article {pmid39759580, year = {2025}, author = {Chourpiliadis, C and Lovik, A and Seitz, C and Hu, Y and Wu, J and Ljungman, P and Press, R and Samuelsson, K and Ingre, C and Fang, F}, title = {Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study.}, journal = {The Lancet regional health. Europe}, volume = {49}, number = {}, pages = {101173}, pmid = {39759580}, issn = {2666-7762}, abstract = {BACKGROUND: The evidence on the link between cardiometabolic diseases (CMDs) and motor neuron diseases (MNDs) remains inconsistent. We aimed to determine whether there is an association of CMDs, namely, any cardiovascular disease, cardiac arrhythmia, heart failure, thromboembolic disease, hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus type 2, and hypercholesterolemia with the risk and progression of MNDs.<br><br>METHODS: We included 1463 MND patients (amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive spinal muscular atrophy (PSMA), and unspecified MND) diagnosed from January 1, 2015, to July 1, 2023, in Sweden according to the Swedish Motor Neuron Disease Quality Registry (i.e., cases), up to 5 MND-free population controls per case (N&#xa0;=&#xa0;7311) who were individually matched to the cases on age and sex, and the full siblings (N&#xa0;=&#xa0;2002) and spouses (N&#xa0;=&#xa0;1220) of MND patients (i.e., relative controls). Conditional logistic regression models were used to estimate the risk of MND diagnosis in relation to previous CMDs, through comparing MND patients to population controls or relative controls. MND patients were followed from diagnosis to assess the role of pre-diagnostic CMDs on disease progression. A joint longitudinal-survival model was used to estimate risk of mortality (or use of invasive ventilation) in relation to CMDs after taking into account the longitudinal changes of ALS functional rating scale-revised (ALSFRS-R) in the time-to-event analysis. Hierarchical clustering with the Ward's linkage and a dissimilarity matrix created by Gower's method was used to identify clusters of MND patients with distinct phenotypes.<br><br>FINDINGS: Among the CMDs studied, a history of diabetes mellitus type 2 (OR 0.75; 95% CI 0.62, 0.93) or hypercholesterolemia (OR 0.82; 95% CI 0.71, 0.94) more than one year before diagnosis was associated with a lower risk for MNDs. The associations persisted for more than five years before MND diagnosis. MND patients with a history of any cardiovascular disease (HR 1.43; 95% CI 1.13, 1.81), arrhythmia (HR 1.42; 95% CI 1.04, 1.93), heart failure (HR&#xa0;1.79; 95% CI 1.02, 3.14), hypertension (HR 1.41; 95% CI 1.12, 1.77), or hypercholesterolemia (HR 1.28; 95% CI 1.01, 1.62) had an increased mortality risk, compared to others, after taking into consideration the longitudinal changes in ALSFRS-R. Cluster analysis identified two clusters of MND patients, where one cluster demonstrated higher age, worse functional status, and higher prevalence of CMDs at the time of diagnosis as well as a higher mortality and faster functional decline during follow-up, compared to the ones included in the other cluster.<br><br>INTERPRETATION: Diabetes mellitus type 2 and hypercholesterolemia were associated with a lower future risk of MND. On the other hand, most of the CMDs were indicative of a poor disease progression after an MND diagnosis.<br><br>FUNDING: European Research Council, US Center for Disease Control and Prevention, Swedish Research Council.}, }
@article {pmid39759457, year = {2024}, author = {Ahmad, SR and Zeyaullah, M and Khan, MS and AlShahrani, AM and Altijani, AAG and Ali, H and Dawria, A and Mohieldin, A and Alam, MS and Mohamed, AOA}, title = {Pharmacogenomics for neurodegenerative disorders - a focused review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1478964}, pmid = {39759457}, issn = {1663-9812}, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive degeneration of neuronal structure and function, leading to severe cognitive and motor impairments. These conditions present significant challenges to healthcare systems, and traditional treatments often fail to account for genetic variability among patients, resulting in inconsistent therapeutic outcomes. Pharmacogenomics aims to tailor medical treatments based on an individual's genetic profile, thereby improving therapeutic efficacy and reducing adverse effects. This focused review explores the genetic factors influencing drug responses in neurodegenerative diseases and the potential of pharmacogenomics to revolutionize their treatment. Key genetic markers, such as the APOE ε4 allele in AD and the CYP2D6 polymorphisms in PD, are highlighted for their roles in modulating drug efficacy. Additionally, advancements in pharmacogenomic tools, including genome-wide association studies (GWAS), next-generation sequencing (NGS), and CRISPR-Cas9, are discussed for their contributions to personalized medicine. The application of pharmacogenomics in clinical practice and its prospects, including ethical and data integration challenges, are also examined.}, }
@article {pmid39757610, year = {2024}, author = {Mojgani, N and Dadar, M and Shahali, Y and Simal-Gandara, J and Kumar, P and Ashique, S and Bhowmick, M and Kumar, H}, title = {Antioxidant Nutraceuticals: Their Adjunct Role in the Management of COVID-19 Infections and Post-COVID Syndrome.}, journal = {Infectious disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715265320091241017161919}, pmid = {39757610}, issn = {2212-3989}, abstract = {The COVID-19 epidemic in recent years has been produced by various coronavirus strains that nearly destroyed world health policies and economics. Emerging viral strains exac-erbated the pandemic. Huge investments have been made in preventative vaccines to combat the disease, but the genetic instability of these viruses has hampered their usefulness. However, in addition to traditional therapeutic approaches, nutraceuticals have been considered effica-cious in preventing and or treating COVID-19 and post-COVID syndrome. In this context, nutraceuticals such as vitamins or dietary supplements including multiple vitamins and miner-als and propolis have been widely studied for their significant impact on viral respiratory dis-eases like SARS-CoV-2 and COVID-19. Some of these nutraceuticals having antioxidant, anti-inflammatory, and immune-modulatory properties have been highly recommended for use as an adjunct option to moderate the adverse effects associated with the COVID-19 pandemic. In this review, we intend to present the recent understanding and converse scientific implications for the use of nutraceutical antioxidants such as vitamins, minerals, probiotics, and polyphenols like bee propolis, in the management of viral respiratory diseases and post-COVID-19 syn-drome. Future challenges and limitations regarding the use and bioavailability of these ingre-dients, and dose-response studies are further emphasized.}, }
@article {pmid39756374, year = {2025}, author = {Loap, P and Kirova, Y}, title = {Initial Characterization and Outcome Assessment of Anal Lymphomas in a Large-Size Contemporary Cohort: A Population-Based SEER Database Study (2000-2022).}, journal = {Acta haematologica}, volume = {}, number = {}, pages = {1-7}, doi = {10.1159/000541595}, pmid = {39756374}, issn = {1421-9662}, abstract = {INTRODUCTION: Anal lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aimed to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.<br><br>METHODS: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL cases were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.<br><br>RESULTS: The majority of AL cases were diffuse large B-cell lymphoma (70.9%). Other notable subtypes included anaplastic T-cell lymphoma, marginal zone lymphoma, B-cell non-Hodgkin lymphoma, Burkitt lymphoma/leukemia (each accounting for 6.3%), followed by follicular lymphoma and mantle-cell lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0%, respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.<br><br>CONCLUSION: This research corresponds to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.}, }
@article {pmid39756021, year = {2025}, author = {Akaree, N and Secco, V and Levy-Adam, F and Younis, A and Carra, S and Shalgi, R}, title = {Regulation of physiological and pathological condensates by molecular chaperones.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.17390}, pmid = {39756021}, issn = {1742-4658}, support = {//AriSLA/ ; //Giovanni Armenise Harvard Foundation/ ; HT94252310319//Congressionally Directed Medical Research Programs/ ; AHA-MCA 2022//AriAlzh/ ; //Rappaport Family Institute for Research in Medical Sciences/ ; //Prince Center for Neurodegenerative Disorders of the Brain/ ; }, abstract = {Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type of physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the cellular stress response and various diseases. SGs, composed of several hundred RNA-binding proteins, form transiently in response to stress to protect mRNAs from translation and disassemble when the stress subsides. Interestingly, SGs contain several aggregation-prone proteins, such as TDP-43, FUS, hnRNPA1, and others, which are typically found in pathological inclusions seen in autopsy tissues from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Moreover, mutations in these genes lead to the familial form of ALS and FTD. This has led researchers to propose that pathological aggregation is seeded by aberrant SGs: SGs that fail to properly disassemble, lose their dynamic properties, and become pathological condensates which finally 'mature' into aggregates. Here, we discuss the evidence supporting this model for various ALS/FTD-associated proteins. We further continue to focus on molecular chaperone-mediated regulation of ALS/FTD-associated physiological condensates on one hand, and pathological condensates on the other. In addition to SGs, we review ALS/FTD-relevant nuclear condensates, namely paraspeckles, anisosomes, and nucleolar amyloid bodies, and discuss their emerging regulation by chaperones. As the majority of chaperoning mechanisms regulate physiological condensate disassembly, we highlight parallel themes of physiological and pathological condensation regulation across different chaperone families, underscoring the potential for early disease intervention.}, }
@article {pmid39755715, year = {2025}, author = {Liu, Q and Sun, Y and He, B and Chen, H and Wang, L and Wang, G and Zhang, K and Zhao, X and Zhang, X and Shen, D and Zhang, X and Cui, L}, title = {Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {2}, pmid = {39755715}, issn = {2051-5960}, support = {2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2021-I2M-1-034//the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; 2022YFC2703904//National Key Research and Development Program/ ; 2022YFC2703900//National Key Research and Development Program/ ; 2022-PUMCH-B-017//National High Level Hospital Clinical Research Funding/ ; 81971293//National Natural Science Foundation of China/ ; 82201562//National Natural Science Foundation of China/ ; XDB39040000//Strategic Priority Research Program (Pilot study) "Biological basis of aging and therapeutic strategies" of the Chinese Academy of Sciences/ ; }, mesh = {Animals ; *Autophagy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mice ; Humans ; Male ; *Gain of Function Mutation ; Neuroinflammatory Diseases/pathology/genetics/metabolism ; Female ; Annexins/genetics/metabolism ; Mice, Transgenic ; Protein Aggregation, Pathological/genetics/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Middle Aged ; Age of Onset ; Protein Aggregates ; RNA-Binding Proteins/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction.}, }
@article {pmid39753993, year = {2025}, author = {Cheng, L and Liu, Z and Shen, C and Xiong, Y and Shin, SY and Hwang, Y and Yang, SB and Chen, Z and Zhang, X}, title = {A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {31}, number = {1}, pages = {e70208}, pmid = {39753993}, issn = {1755-5949}, support = {20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; GJJ211812//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; GJJ211813//Science and Technology Project Funded by the Education Department of Jiangxi Province/ ; 202131084//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; 202211982//Jiangxi Provincial Health Commission Science and Technology Plan Project/ ; RZYB202201//Research project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province/ ; 20224BAB206040//Provincial Natural Science Foundation of Jiangxi Province/ ; 202411843024//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; S202411843050//Foundation of Students' Platform for Innovation and Entrepreneurship Training Program/ ; 2022B1010//Administration of Traditional Chinese Medicine of Jiangxi Province/ ; }, mesh = {*Adenosine Deaminase/genetics/metabolism ; Humans ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Central Nervous System Diseases/genetics/metabolism/therapy ; RNA Editing ; }, abstract = {BACKGROUND: Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases.<br><br>RESULTS: In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases.<br><br>CONCLUSIONS: Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGouti&#xe8;res syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.}, }
@article {pmid39753665, year = {2025}, author = {Quintanilla, CA and Fitzgerald, Z and Kashow, O and Radojicic, MS and Ulupinar, E and Bitlis, D and Genc, B and Andjus, P and van Drongelen, W and Ozdinler, PH}, title = {High-density multielectrode arrays bring cellular resolution to neuronal activity and network analyses of corticospinal motor neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {732}, pmid = {39753665}, issn = {2045-2322}, support = {778405 "AUTOIGG"//EU H2020 MSCA RISE/ ; R01 AG061708/AG/NIA NIH HHS/United States ; 4242 "NIMOCHIP"//Science Fund of the Republic of Serbia/ ; R01AG061708-03/NH/NIH HHS/United States ; 5T32NS041234-18/NH/NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/physiology ; Mice ; *Microelectrodes ; Motor Cortex/physiology ; Pyramidal Tracts/physiology ; Nerve Net/physiology ; Mice, Transgenic ; }, abstract = {Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.}, }
@article {pmid39753643, year = {2025}, author = {Mravinacová, S and Bergström, S and Olofsson, J and de San José, NG and Anderl-Straub, S and Diehl-Schmid, J and Fassbender, K and Fliessbach, K and Jahn, H and Kornhuber, J and Landwehrmeyer, GB and Lauer, M and Levin, J and Ludolph, AC and Prudlo, J and Schneider, A and Schroeter, ML and Wiltfang, J and Steinacker, P and ,  and Otto, M and Nilsson, P and Månberg, A}, title = {Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {668}, pmid = {39753643}, issn = {2045-2322}, mesh = {Humans ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; Middle Aged ; Brain/metabolism/pathology ; Alzheimer Disease/cerebrospinal fluid/diagnosis ; Cerebrospinal Fluid Proteins/analysis ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; }, abstract = {Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer's disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins-neurofilament medium and myelin basic protein-showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.}, }
@article {pmid39753538, year = {2025}, author = {Larrea, D and Tamucci, KA and Kabra, K and Velasco, KR and Yun, TD and Pera, M and Montesinos, J and Agrawal, RR and Paradas, C and Smerdon, JW and Lowry, ER and Stepanova, A and Yoval-Sanchez, B and Galkin, A and Wichterle, H and Area-Gomez, E}, title = {Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS).}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {379}, pmid = {39753538}, issn = {2041-1723}, support = {R21 NS125466/NS/NINDS NIH HHS/United States ; R01 NS131322/NS/NINDS NIH HHS/United States ; R01 AG056387/AG/NIA NIH HHS/United States ; F31 NS095571/NS/NINDS NIH HHS/United States ; T32 DK007647/DK/NIDDK NIH HHS/United States ; R01 NS112381/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Animals ; Spinal Cord/metabolism ; Mice ; Glucose/metabolism ; Fatty Acids/metabolism ; Male ; Energy Metabolism ; Pyruvic Acid/metabolism ; Intracellular Membranes/metabolism ; Electron Transport Complex I/metabolism/genetics ; Brain/metabolism ; Mitochondria Associated Membranes ; }, abstract = {Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.}, }
@article {pmid39753182, year = {2025}, author = {Swarup, G and Medchalmi, S and Ramachandran, G and Sayyad, Z}, title = {Molecular aspects of cytoprotection by Optineurin during stress and disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {3}, pages = {119895}, doi = {10.1016/j.bbamcr.2024.119895}, pmid = {39753182}, issn = {1879-2596}, mesh = {Humans ; *Cell Cycle Proteins/genetics/metabolism ; *Membrane Transport Proteins/genetics/metabolism ; *Transcription Factor TFIIIA/genetics/metabolism ; Signal Transduction ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Oxidative Stress ; Cytoprotection/genetics ; Animals ; Glaucoma/genetics/metabolism/pathology ; Neurodegenerative Diseases/genetics/metabolism ; Endoplasmic Reticulum Stress/genetics ; Mutation ; Autophagy/genetics ; }, abstract = {Optineurin/OPTN is an adapter protein that plays a crucial role in mediating many cellular functions, including autophagy, vesicle trafficking, and various signalling pathways. Mutations of OPTN are linked with neurodegenerative disorders, glaucoma, and amyotrophic lateral sclerosis (ALS). Recent work has shown that OPTN provides cytoprotection from many types of stress, including oxidative stress, endoplasmic reticulum stress, protein homeostasis stress, tumour necrosis factor α, and microbial infection. Here, we discuss the mechanisms involved in cytoprotective functions of OPTN, which possibly depend on its ability to modulate various stress-induced signalling pathways. ALS- and glaucoma-causing mutants of OPTN are altered in this regulation, which may affect cell survival, particularly under various stress conditions. We suggest that OPTN deficiency created by mutations may cooperate with stress-induced signalling to enhance or cause neurodegeneration. Other functions of OPTN, such as neurotrophin secretion and vesicle trafficking, may also contribute to cytoprotection.}, }
@article {pmid39752797, year = {2025}, author = {Ju, W and Min, YG and Kim, JS and Ryu, S and Ahn, SW and Hong, YH and Choi, SJ and Sung, JJ}, title = {Clinical features of FOSMN syndrome in Korea: A comparative analysis with bulbar-onset amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {469}, number = {}, pages = {123372}, doi = {10.1016/j.jns.2024.123372}, pmid = {39752797}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Male ; Female ; Middle Aged ; Republic of Korea/epidemiology ; Aged ; Adult ; Age of Onset ; Motor Neuron Disease/epidemiology/diagnosis ; Cohort Studies ; Disease Progression ; }, abstract = {Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare neurodegenerative disorder initially characterized by facial sensory deficits, which later progress to motor deficits in a rostral-caudal distribution. This study investigated the prevalence, clinical features, and prognosis of FOSMN syndrome and compared these aspects with those of bulbar-onset amyotrophic lateral sclerosis (ALS) within a single institutional cohort of motor neuron diseases. We identified four patients with FOSMN syndrome who had been misclassified as having bulbar-onset ALS, representing approximately 2 % of such ALS cases. The median age of onset for FOSMN syndrome was similar to that of bulbar-onset ALS. However, patients with FOSMN syndrome were often diagnosed at more advanced stages and had lower ALS Functional Rating Scale-revised (ALSFRS-R) scores. Despite the slower progression of FOSMN syndrome, therapeutic interventions such as gastrostomy or non-invasive ventilation were frequently required. In conclusion, this study provides detailed clinical profiles of patients with FOSMN syndrome and deepens our understanding of a heterogeneous group of neurodegenerative disorders.}, }
@article {pmid39751824, year = {2025}, author = {Sghaier, I and Kacem, I and Ratti, A and Takout, K and Abida, Y and Peverelli, S and Ticozzi, N and Gargouri-Berrachid, A and Silani, V and Gouider, R}, title = {Impact of APOE and MAPT genetic profile on the cognitive functions among Amyotrophic Lateral Sclerosis Tunisian patients.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {4}, pages = {609-618}, pmid = {39751824}, issn = {1435-1463}, mesh = {Humans ; *tau Proteins/genetics ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Tunisia/epidemiology ; Middle Aged ; Aged ; *Apolipoproteins E/genetics ; Cognitive Dysfunction/genetics/epidemiology ; Adult ; Genotype ; }, abstract = {Amyotrophic Lateral Sclerosis(ALS) has traditionally been managed as a neuromuscular disorder. However, recent evidence suggests involvement of non-motor domains. This study aims to evaluate the impact of APOE and MAPT genotypes on the cognitive features of ALS. We included confirmed ALS cases from the Neurology department at Razi University Hospital, Tunisia. APOE and MAPT screening were conducted with Sanger sequencing validation, and preliminary screening for four main ALS genes was performed. Clinical phenotypes and genotypes were analyzed using appropriate tests, with healthy controls (HC) representing the Tunisian population. Two-hundred-seventy ALS patients were included, stratified as 213 spinal cases,49 with bulbar onset and 8 patients with generalized form with 140 HC. Regarding APOE, we reported high frequency of ALS cases carrier of APOE-ε4 isoform compared to controls(p < 0.0001).We found a significant association between APOE-ɛ4 and ALS onset site (p = 0.05,r = 0.33),with higher frequencies in bulbar onset patients. Cognitive signs were more frequent in ɛ4 carriers (r = 0.43,p < 0.01),and a significant link was observed between dysexecutive functions and the APOE risk allele (p = 0.0495).Concerning the MAPT haplotypes, we reported high frequency of ALS cases carrier of MAPT H1-haplotype HC (94.45% and 72.14% respectively, p < 0.001).Among ALS cases,MAPT-H1 showed a stronger positive correlation with the presence of oculomotor signs(p = 0.05,r = 0.28).As well as significant positive association between cognitive impairments(p = 0.039,r = 0.59). Our findings emphasize the correlation between APOE and MAPT genotypes and the cognitive features in our ALS patients. We also observed other interesting, though weak, significant correlations (with coefficients not exceeding 0.20),which require further validation in a larger cohort to confirm our results.}, }
@article {pmid39749679, year = {2025}, author = {Young, CA and Chaouch, A and Mcdermott, CJ and Al-Chalabi, A and Chhetri, SK and Bidder, C and Edmonds, E and Ellis, C and Annadale, J and Wilde, L and Sharrack, B and Malaspina, A and Leach, O and Mills, R and Tennant, A}, title = {Determinants and progression of stigma in amyotrophic lateral sclerosis/motor neuron disease.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/21678421.2024.2435969}, pmid = {39749679}, issn = {2167-9223}, abstract = {Objective: Stigma in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) may be felt or enacted; felt stigma covers feeling devalued by the illness, whereas enacted stigma refers to being treated differently because of it. Stigma in ALS/MND has been shown to increase social withdrawal, worsen quality of life, and reduce use of assistive devices, so we explored prevalence and factors influencing stigma. Methods: Participants in the Trajectories of Outcome in Neurological Conditions-ALS study completed scales measuring stigma, fatigue, spasticity, functioning, mood, worry, self-esteem, and perceived health, as well as demographic information and symptoms like head drop or emotional lability. Following transformation to interval-scale estimates, data were analyzed by regression, structural equation modeling, and trajectory models. Results: Stigma was experienced by 83.5% of 1059 respondents. Worry, disease severity (King's stage ≥ 3), emotional lability, fatigue, spasticity, and bulbar onset increase stigma. In contrast, increasing age, living with spouse/partner, and greater self-esteem were associated with reduced stigma. Trajectory analysis over 30 months (N = 1049) showed three groups, the largest (70.2%) had high levels of stigma which significantly increased during follow-up. In a recently diagnosed subset of 347 participants, stigma was experienced early in the disease course (<7 months after diagnosis), and for 77.2% stigma significantly increased over time. Conclusions: Both felt and enacted stigma are frequently perceived by people living with ALS/MND. Younger people and those with bulbar onset, emotional lability, worry, fatigue, and spasticity, or at more advanced clinical stages, are at greater risk.}, }
@article {pmid39749674, year = {2025}, author = {Tankéré, P and Cascarano, E and Saint Raymond, C and Mallaret, M and Toribio Ruiz, C and Herquelot, E and Denis, H and Cals Maurette, M and Tamisier, R and Pépin, JL}, title = {Care trajectories and adherence to respiratory management recommendations in persons living with amyotrophic lateral sclerosis: a ten-year cohort study in a French tertiary university centre.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2447911}, pmid = {39749674}, issn = {2167-9223}, abstract = {Objective: This study determined real-life care trajectories before and after initiation of noninvasive ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS). Caregiver adherence to respiratory management recommendations and the associated survival rate of people with ALS were also assessed. Methods: Data were obtained from a tertiary center prospective ALS database that included 10 years of follow-up data for people with ALS. Results are presented numerically and with graphical time sequence analysis through K clustering (TAK) representation. Kaplan Meier and Cox models were used to determine survival and associated prognostic factors. Results: 109 patients with ALS patients were included; median [interquartile range] follow-up was 25.0 months [15.3-43.3]. During study timeframe patients had a median of 4.0 [2.0-6.0] clinical visits; death occurred in 54.1%. Median time between clinical visits was 3.9 [2.8-6.5] months, between arterial blood gases was 4.3 months [3.0-6.6], between spirometry testing was 5.8 months [4.1-8.2], and between nocturnal oximetry was 4.4 months [3.0-7.8]. Visualization of care trajectories TAK show marked heterogeneity in survival, time to NIV initiation, and time from NIV initiation to death. Mortality was correlated with NIV initiation and arterial carbon dioxide pressure increase. Conclusions: The current framework in ALS guidelines should be adapted to the ALS disease stage and individual patient characteristics. Understanding how subgroups of patients with ALS use healthcare services over time could help to highlight fragility areas and priorities in the allocation of care resources and implementation of best practices.}, }
@article {pmid39749668, year = {2025}, author = {Mehta, P and Raymond, J and Nair, T and Han, M and Berry, J and Punjani, R and Larson, T and Mohidul, S and Horton, DK}, title = {Amyotrophic lateral sclerosis estimated prevalence cases from 2022 to 2030, data from the national ALS Registry.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/21678421.2024.2447919}, pmid = {39749668}, issn = {2167-9223}, abstract = {Objective: To estimate the projected number of ALS cases in the United States from 2022 to 2030. Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no known cure. Because ALS is not a notifiable disease in the United States, the accurate ascertainment of prevalent ALS cases continues to be a challenge. To overcome this, the National ALS Registry (Registry) uses novel methods to estimate newly diagnosed and existing cases in the United States. Methods: We estimated ALS prevalence retrospectively from 2022 to 2024 and prospectively from 2025 to 2030 using prevalence obtained through previous CRC analyses on 2018 Registry data (the most current data available) to generate projected observed, missing, and total cases. Projected prevalent cases were then stratified by age, race, and sex. Results: The number of estimated ALS cases in 2022 was 32,893. By 2030, projected cases increase more than 10%, to 36,308. The largest increase occurs for the population ages 66 years and older, with a 25% increase (from 16,349 cases in 2022 to 20,438 cases in 2030). The projected number of cases classified as "other race" will increase by 15% (from 2,473 cases in 2022 to 2,854 cases in 2030). Conclusions: These estimates of projected ALS cases reflect anticipated changes in the underlying demographics of the United States. Our projections are likely an underestimation because emerging therapeutics and improved healthcare will improve survivability in this vulnerable population. These results should inform policy to more efficiently allocate resources for ALS patients and programs.}, }
@article {pmid39749172, year = {2024}, author = {Chauhan, A and Begum, J and Lavanya, KM and Gupta, A and Ghosh, S and Kulkarni, S}, title = {Experiential Learning of Active Learning Strategies in Mentor Learner Web-based Discussions: A Perceptions Study.}, journal = {International journal of applied &amp; basic medical research}, volume = {14}, number = {4}, pages = {258-265}, pmid = {39749172}, issn = {2229-516X}, abstract = {BACKGROUND: Active learning strategies (ALSs) in medical education are valued for their effectiveness but face adoption challenges among educators, underscoring the need for a deeper understanding of their implementation and impact.<br><br>AIM: The aim of the study was to investigate the perceptions of medical educators regarding the effectiveness and challenges of ALS through mentor-learner (ML) web-based discussions.<br><br>SETTINGS AND DESIGN: The retrospective cross-sectional study analyzed data from 32 medical educators enrolled in the Foundation for Advancement of International Medical Education Research course at Christian Medical College, Ludhiana. It utilized a mixed-method approach, gathering both quantitative and qualitative data through ML web discussions.<br><br>MATERIALS AND METHODS: The study used a "dual-method" approach, combining traditional online discussions with a "role-reversal" method on an ML web platform, promoting experiential learning. Participant responses on ALS implementation tasks were collected and analyzed within these discussions.<br><br>RESULTS: Participants shared various ALS for collaborative learning (20), classroom engagement (26), assessing prior knowledge (12), and note-taking during lectures (10). Further, among the 11 ALS examined, the ease of implementation varied significantly among participants (P < 0.0001). Challenges in ALS implementation included inadequate faculty training (91%), motivation (84%), resource constraints (81%), student (75%), and administrative resistance (69%). Four themes emerged as recommendations for effective ALS implementation: empowering educators, engaging students, streamlining support systems, and monitoring impact.<br><br>CONCLUSION: The study highlights a mixed perspective of medical educators on ALS. Although ALS was perceived as effective in fostering critical thinking and developing collaborative learning among students, various challenges, such as a lack of skilled faculty and resources, necessitated robust faculty development initiatives.}, }
@article {pmid39748876, year = {2025}, author = {Salter, S and Salter, E and Kim, AJ and Liu, AK}, title = {Rising Voltage-Gated Potassium Channel Antibody Level as a Possible Disease Progression Marker for Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e76760}, pmid = {39748876}, issn = {2168-8184}, abstract = {A subset of amyotrophic lateral sclerosis (ALS) patients tests positive for antibodies commonly associated with autoimmune neurological diseases, including voltage-gated potassium channel (VGKC)-complex antibodies. Although an autoimmune basis for ALS remains speculative, and immunomodulatory therapies have shown minimal benefit as of yet, isolated cases suggest that VGKC-complex antibodies may be relevant to disease type and progression. In this report, we present a case of ALS in which increasing VGKC-complex antibody levels correlated with clinical decline, raising the question of whether such antibodies could serve as biomarkers of progression in VGKC-complex antibody-positive ALS patients. To date, no published studies have systematically evaluated changes in VGKC-complex antibody levels in ALS patients over time. Our findings suggest that tracking VGKC-complex antibodies in ALS may offer insights into disease progression and prompt further investigation into their potential role as prognostic biomarkers, especially in certain subtypes of the disease.}, }
@article {pmid39748816, year = {2024}, author = {Li, Z and Liu, X and Zhang, H and Li, P and Yao, F}, title = {Improving resistance to lepidopteran pests and herbicide using Sanming dominant genic male sterile rice (Oryza sativa L.).}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1525620}, pmid = {39748816}, issn = {1664-462X}, abstract = {In order to improve both resistance to lepidopteran pests and resistance to the herbicide imazethapyr in mainstay japonica varieties of the Huang-Huai rice region, Sanming dominant genic male sterile (S-DGMS) rice was used as a platform to facilitate the pyramiding of functional genes and the replacement of the genomic background. Twelve novel lines were developed, each carrying a crystal toxin gene conferring resistance to lepidopteran pests and the ALS[627N] allele conferring resistance to herbicide imazethapyr in the background of a mainstay japonica variety. The genomic background of the 12 novel lines was examined using 48 specified molecular markers, and each line carried less than two polymorphic markers relative to the corresponding mainstay variety. All 12 lines displayed high resistance to lepidopteran pests and the herbicide imazethapyr. The major agronomic traits of the 12 lines showed no difference relative to the responding mainstay variety when sprayed with pesticide. The popularization of the 12 japonica lines could reduce the use of pesticides and provide highly efficient control of weeds and weedy rice in the future, thus promoting the development of japonica rice production. Therefore, S-DGMS rice could be a powerful tool for the genetic improvement of target traits in rice.}, }
@article {pmid39748214, year = {2025}, author = {Brown, G and Jesus, S and Leboffe, E and Esch, A and Newport, K}, title = {Advance Care Planning Billing Codes Associated With Decreased Healthcare Utilization in Neurological Disease.}, journal = {Journal of healthcare management / American College of Healthcare Executives}, volume = {70}, number = {1}, pages = {58-73}, pmid = {39748214}, issn = {1096-9012}, mesh = {Humans ; Aged ; Male ; Female ; *Advance Care Planning/statistics &amp; numerical data ; United States ; *Nervous System Diseases/therapy ; Aged, 80 and over ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; Cohort Studies ; }, abstract = {GOALS: Advance care planning (ACP) procedure codes have been established to reimburse meaningful care goal discussions; however, the utilization frequency of these codes in neurological disease is unknown. The objective of this study is to identify the association between ACP codes and healthcare utilization in chronic neurodegenerative diseases.<br><br>METHODS: This is a multicenter cohort study using real-world electronic health data. Using the TriNetX database, we collected electronic health data from 92 institutions in the United States. We included patients aged 65 and older who had been diagnosed with one of four neurological diseases: Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis (ALS). Patients with congestive heart failure were included as a reference. From the 64,683,009 total patients in the database, 877,138 had Alzheimer's disease, 544,610 had Parkinson's disease, 208,341 had multiple sclerosis, 9,944 had amyotrophic lateral sclerosis, and 1,500,186 had congestive heart failure. For each disease, we compared hospitalizations and emergency department (ED) visits over a two-year period between patients with and without ACP codes documented. Then, in patients with ACP, we investigated the rates of hospitalizations and ED visits over the two&#xa0;years before ACP and two&#xa0;years after ACP to understand the impact of ACP on the healthcare utilization trend. All patients had records for at least two&#xa0;years after index.<br><br>PRINCIPAL FINDINGS: The rate of ACP code documentation ranged from 1.8% of multiple sclerosis patients to 3.6% of Alzheimer's disease patients. After matching for demographic and health variables, usage of ACP codes was associated with significantly fewer hospitalizations for Alzheimer's disease patients. Across all diseases, there was a 20% to 30% decrease in ED visits, which was significant. Furthermore, there was a significant change in the trend of hospitalizations and ED visits for patients after ACP documentation. Patients went from increasing utilization before ACP documentation to decreasing utilization after documentation.<br><br>PRACTICAL APPLICATIONS: ACP billing codes are used infrequently in neurological disease, which may indicate that reimbursement alone is not sufficient to drive code usage. Usage of ACP billing codes was associated with decreased healthcare utilization, particularly in terms of ED visits. Beyond the primary objective of providing goal-concordant care, ACP may impact the economic burden of chronic neurodegenerative disease, which has high costs of care in our aging society. There may be particular benefits with Alzheimer's disease, which had an impact on both hospitalizations and ED visits and is the most prevalent neurodegenerative disease. Future work is needed to better understand the best implementation strategy for ACP in a multifaceted approach that emphasizes patient care preferences for their illness.}, }
@article {pmid39747792, year = {2025}, author = {Lee, J and Kouznetsova, VL and Kesari, S and Tsigelny, I}, title = {Selective diagnostics of Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases with machine learning and miRNA.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {79}, pmid = {39747792}, issn = {1573-7365}, mesh = {*MicroRNAs/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/metabolism ; *Machine Learning ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Parkinson Disease/diagnosis/genetics/metabolism ; *Biomarkers ; }, abstract = {The diagnosis of neurological diseases can be expensive, invasive, and inaccurate, as it is often difficult to distinguish between different types of diseases with similar motor symptoms. However, the dysregulation of miRNAs can be used to create a robust machine-learning model for a reliable diagnosis of neurological diseases. We used miRNA sequence descriptors and gene target data to create machine-learning models that can be used as diagnostic tools. The top-performing machine-learning models, trained on filtered miRNA datasets for Amyotrophic Lateral Sclerosis, Alzheimer's and Parkinson's Diseases of this research yielded 94, 97, and 96, percent accuracies, respectively. Analysis of dysregulated miRNA in neurological diseases elucidated novel biomarkers that could be used to diagnose and distinguish between the diseases. Machine-learning models developed using sequence and gene target descriptors of miRNA biomarkers can achieve favorable accuracies for disease classification and attain a robust discerning capability of neurological diseases.}, }
@article {pmid39747573, year = {2025}, author = {Kim, KM and Girdhar, A and Cicardi, ME and Kankate, V and Hayashi, M and Yang, R and Carey, JL and Fare, CM and Shorter, J and Cingolani, G and Trotti, D and Guo, L}, title = {NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {2}, pmid = {39747573}, issn = {2399-3642}, support = {R35GM138109//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31 NS111870/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; 628389//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; R01 NS121143/NS/NINDS NIH HHS/United States ; F31NS111870//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35 GM140733/GM/NIGMS NIH HHS/United States ; R35GM140733//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; RF1NS121143//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21-NS090912//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128396//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01GM099836//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R21 NS090912/NS/NINDS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; T32GM008275//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 GM099836/GM/NIGMS NIH HHS/United States ; RF1 AG057882/AG/NIA NIH HHS/United States ; T32 GM008275/GM/NIGMS NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Frontotemporal Dementia/metabolism/genetics ; *Dipeptides/metabolism ; beta Karyopherins/metabolism/genetics ; RNA-Binding Protein FUS/metabolism/genetics ; Protein Binding ; HEK293 Cells ; }, abstract = {Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity. Here, we use FUS as a model RBP to investigate the mechanism of R-DPR-induced aberrant RBP phase transition. We find that this phase transition can be mitigated by Kapβ2. However, as a nuclear import receptor and phase modifier for PY-NLS-containing RBPs, the function of WT Kapβ2 could lead to undesired interaction with its native substrates when used as therapeutics for C9-ALS/FTD. To address this issue, it is crucial to devise effective strategies that allow Kapβ2 to selectively target its binding to the R-DPRs, instead of the RBPs. We show that NLS-binding deficient Kapβ2W460A:W730A can indeed selectively interact with R-DPRs in FUS assembly without affecting normal FUS phase separation. Importantly, Kapβ2W460A:W730A prevents enrichment of poly(GR) in stress granules and mitigates R-DPR neurotoxicity. Thus, NLS-binding deficient Kapβ2 may be implemented as a potential therapeutic for C9-ALS/FTD.}, }
@article {pmid39747563, year = {2025}, author = {Adim, H and Fahmideh, L and Fakheri, BA and Zarrini, HN and Sasanfar, H}, title = {iTRAQ-based quantitative proteomic analysis of herbicide stress in Avena ludoviciana Durieu.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {577}, pmid = {39747563}, issn = {2045-2322}, mesh = {*Herbicides/pharmacology/toxicity ; *Avena/drug effects/genetics/metabolism ; *Proteomics/methods ; *Herbicide Resistance/genetics ; *Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; Stress, Physiological/drug effects ; Acetyl-CoA Carboxylase/metabolism/genetics ; }, abstract = {Winter wild oat (Avena sterilis subsp. ludoviciana (Durieu) Gillet &amp; Magne) has been considered the most common and troublesome weed in wheat fields of Iran. The widespread and continuous use of herbicides has led to the emergence and development of resistant biotypes in A. ludoviciana, making it one of the most important herbicide-resistant weeds within field crops. Considering the importance of understanding the mechanisms underlying resistance to herbicides and identifying key proteins involved in the response to Acetyl-coenzyme A carboxylase (ACCase) and Acetolactate synthase (ALS) inhibitor herbicides in A. ludoviciana. This study aimed to identify the proteins involved in herbicide resistance in A. ludoviciana using the Isobaric Tags for Relative and Absolute Quantification (iTRAQ) technique. In this study, a total of 18,313 peptides were identified with ≤ 0.01 FDR, which could be classified into 484 protein groups. Additionally, 138 differentially expressed proteins (DEPs) were identified in the resistant biotype (R), while 93 DEPs were identified in the susceptible biotype (S). Gene Ontology (GO) analysis revealed that these DEPs mainly consisted of proteins related to photosynthesis, respiration, amino acid synthesis and translation, secondary metabolite biosynthesis, defense proteins, and detoxification. Furthermore, enrichment pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the most important pathways included metabolic pathways, carbohydrate metabolism, secondary metabolites, amino acid synthesis, and photosynthesis. The function of DEPs indicated that some proteins, such as cytochrome P450, play a direct role in herbicide detoxification. Overall, the results of this study demonstrated the complex response of the resistant biotype to herbicides and its ability to increase antioxidant capacity through up-regulated detoxification proteins, particularly cytochrome P450 (Q6YSB4), and defense proteins, particularly superoxide dismutase (Q0DRV6) and polyamine oxidase (Q7XR46). In the resistant A. ludoviciana populations, in addition to the activation of enzymatic and non-enzymatic defense systems, other strategies such as reduced photosynthesis and respiration, increased transcription and translation activity, enhanced lipid metabolism, regulation of cellular processes and homeostasis, and up-regulation of proteins associated with signaling and ion channels play a role in resistance to herbicide. Overall these findings provide new insights into the role of different proteins in resistance to herbicides and contribute to a comprehensive understanding of herbicide resistance in A. ludoviciana.}, }
@article {pmid39745174, year = {2025}, author = {Antonelli, S and Castañeda, FN and Olivieri, AC and Carabajal, MD and Pellegrino Vidal, RB}, title = {Novel Data Fusion Strategy for Second-Order Data: Multivariate Curve Resolution for the Determination of Pharmaceuticals by Means of Fluorimetric Measurements.}, journal = {Analytical chemistry}, volume = {97}, number = {1}, pages = {962-968}, doi = {10.1021/acs.analchem.4c05725}, pmid = {39745174}, issn = {1520-6882}, mesh = {Multivariate Analysis ; Least-Squares Analysis ; *Water Pollutants, Chemical/analysis ; Pharmaceutical Preparations/analysis/chemistry ; Fluorometry/methods ; }, abstract = {A new strategy is proposed for second-order data fusion based on the simultaneous modeling of two data sets using the multivariate curve resolution-alternating least-squares (MCR-ALS) model, applying a new constraint during the ALS stage, called "Proportionality of Scores". This approach allows for the fusion of data from different sources, without requiring common dimensionality, and enables the application of specific constraints to each data set. This strategy was applied to the determination of five pharmaceutical contaminants (naproxen, danofloxacin, ofloxacin, sarafloxacin, and enoxacin) in environmental water samples, by fusing two sets of excitation-emission fluorescence matrices, measured before and after photochemical derivatization. The predictive performance of the fused model was compared to individual PARAFAC models built for each fluorescence data set, showing that data fusion significantly increases precision and accuracy, as indicated by the elliptical joint confidence region test. Data fusion allowed improvement of relative errors of prediction, from 13-32% to 8-15% in validation samples and from 25-121% to 13-20% in real samples. The advantages of data fusion were evident in both cases, particularly in instances of substantial signal overlap between analytes or the presence of uncalibrated interferents with similar profiles, as demonstrated by the superior predictive capacity achieved through the proposed strategy.}, }
@article {pmid39744204, year = {2024}, author = {Morales-Galicia, AE and Ramírez-Mejía, MM and Ponciano-Rodriguez, G and Méndez-Sánchez, N}, title = {Revolutionizing the understanding of liver disease: Metabolism, function and future.}, journal = {World journal of hepatology}, volume = {16}, number = {12}, pages = {1365-1370}, pmid = {39744204}, issn = {1948-5182}, abstract = {The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.}, }
@article {pmid39743746, year = {2025}, author = {Wang, Z and Wang, X and Li, P and Xia, H and Yang, X}, title = {Genetic associations between immune-related plasma proteins and neurodegenerative diseases.}, journal = {Neurological research}, volume = {47}, number = {2}, pages = {129-138}, doi = {10.1080/01616412.2024.2448745}, pmid = {39743746}, issn = {1743-1328}, mesh = {Humans ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/immunology/blood ; *Blood Proteins/genetics/metabolism ; *Genetic Predisposition to Disease/genetics ; Alzheimer Disease/genetics/immunology/blood ; Amyotrophic Lateral Sclerosis/genetics/immunology/blood ; Parkinson Disease/genetics/immunology/blood ; Multiple Sclerosis/genetics/blood/immunology ; }, abstract = {BACKGROUND: Immune dysregulation is commonly associated with neurodegenerative diseases (NDs), yet the underlying causes and mechanisms still require further investigation.<br><br>OBJECTIVE: This study investigates the correlation between immune-related plasma proteins and the risk of NDs by integrating genome-wide association study (GWAS) data for Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with plasma proteome analysis.<br><br>METHODS: By analyzing GWAS data for 4907 immune-related plasma proteins, this research evaluates the direct impact of plasma proteins on the risk of four NDs: AD, PD, ALS, and MS. Additionally, the study conducts an analysis of protein expression levels using single-cell RNA sequencing data.<br><br>RESULTS: We have identified plasma proteins that are closely associated with the risk of NDs. Using stringent criteria, we identified 88 proteins associated with AD, 115 with PD, 100 with ALS, and 87 with MS. Additionally, single-cell sequencing analyzed the protein expression and its distribution within different cell types in the brain.<br><br>CONCLUSIONS: Our research has demonstrated that plasma proteins may contribute to the risk of NDs, and it has also provided concrete evidence linking genetic susceptibility for these diseases to immune mechanisms. Furthermore, we found that specific proteins influence genetic variations linked to NDs risk via plasma-mediated regulation, emphasizing the importance of interactions between the brain and circulatory system.}, }
@article {pmid39743546, year = {2025}, author = {Faller, KME and Chaytow, H and Gillingwater, TH}, title = {Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {86-102}, pmid = {39743546}, issn = {1759-4766}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; }, abstract = {The motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics.}, }
@article {pmid39743298, year = {2024}, author = {Wang, L and Liu, H and Li, L}, title = {Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.}, journal = {Journal of Zhejiang University. Science. B}, volume = {25}, number = {12}, pages = {1115-1119}, pmid = {39743298}, issn = {1862-1783}, support = {81970431//the National Natural Science Foundation of China/ ; 2023JJ50136//the Hunan Provincial Natural Science Foundation of China/ ; }, mesh = {*Autophagy ; Humans ; *Neurodegenerative Diseases/metabolism ; *Protein Aggregates ; Animals ; Organelles/metabolism ; Alzheimer Disease/metabolism ; Neurons/metabolism ; Huntington Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; }, abstract = {Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.}, }
@article {pmid39743215, year = {2024}, author = {Chiu, Y and Xia, S and Qiao, H and Zhao, Z}, title = {Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics.}, journal = {The American journal of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajpath.2024.11.006}, pmid = {39743215}, issn = {1525-2191}, abstract = {Neurodegenerative diseases, including Alzheimer disease, frontotemporal dementia, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis, are often casually linked to protein aggregation and inclusion. As the origins of those proteinopathies have been biochemically traced and genetically mapped, genetically engineered animal models carrying the specific mutations or variants are widely used for investigating the etiology of these diseases, as well as for testing potential therapeutics. This article focuses on the mouse models of Alzheimer disease and closely related frontotemporal dementia, particularly the ones that have provided most valuable knowledge, or are in a trajectory of doing so. More importantly, some of the major findings from these models are summarized, based on the recent single-cell transcriptomics, multiomics, and spatial transcriptomics studies. While no model is perfect, it is hoped that the new insights from these models and the practical use of these models will continue to help to establish a path forward.}, }
@article {pmid39743032, year = {2025}, author = {Li, Y and Zhang, W and Zhang, Q and Li, Y and Xin, C and Tu, R and Yan, H}, title = {Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110283}, doi = {10.1016/j.abb.2024.110283}, pmid = {39743032}, issn = {1096-0384}, mesh = {*Mitophagy ; Humans ; *Oxidative Stress/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Animals ; *Antioxidants/metabolism/therapeutic use ; Mitochondria/metabolism ; }, abstract = {Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.}, }
@article {pmid39742161, year = {2024}, author = {Mashimo, S and Matsuoka, A and Tanese, K and Kano, O and Ishiko, A}, title = {Idiopathic Multiple Localized Lipoatrophy Mimicking Amyotrophic Lateral Sclerosis.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e74887}, pmid = {39742161}, issn = {2168-8184}, abstract = {Localized lipoatrophy is a rare condition characterized by the localized loss of subcutaneous adipose tissue. It may occur idiopathically without specific triggers. The pathogenesis of idiopathic localized lipoatrophy remains largely unknown. We present the case of a 53-year-old Japanese woman with multiple localized lipoatrophy who exhibited upper motor neuron signs clinically and panniculitis histologically. She was initially suspected to have amyotrophic lateral sclerosis due to progressive left limb volume loss. Histologically, the lesions showed adipocyte destruction accompanied by predominant plasma infiltration.}, }
@article {pmid39741274, year = {2024}, author = {Mandeville, R and Sedghamiz, H and Mansfield, P and Sheean, G and Studer, C and Cordice, D and Ghanbari, G and Malhotra, A and Nemati, S and Koola, J}, title = {Deep learning enhanced transmembranous electromyography in the diagnosis of sleep apnea.}, journal = {BMC neuroscience}, volume = {25}, number = {1}, pages = {80}, pmid = {39741274}, issn = {1471-2202}, support = {R01 HL157985/HL/NHLBI NIH HHS/United States ; T15 LM011271/LM/NLM NIH HHS/United States ; R01 HL166485/HL/NHLBI NIH HHS/United States ; R01 AG063925/AG/NIA NIH HHS/United States ; R01 HL154926/HL/NHLBI NIH HHS/United States ; R01 HL148436/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Deep Learning ; *Electromyography/methods ; Male ; Middle Aged ; Female ; Adult ; Sleep Apnea, Obstructive/diagnosis/physiopathology ; Polysomnography/methods ; Aged ; Sleep Apnea Syndromes/diagnosis/physiopathology ; }, abstract = {Obstructive sleep apnea (OSA) is widespread, under-recognized, and under-treated, impacting the health and quality of life for millions. The current gold standard for sleep apnea testing is based on the in-lab sleep study, which is costly, cumbersome, not readily available and represents a well-known roadblock to managing this huge societal burden. Assessment of neuromuscular function involved in the upper airway using electromyography (EMG) has shown potential to characterize and diagnose sleep apnea, while the development of transmembranous electromyography (tmEMG), a painless surface probe, has made this opportunity practical and highly feasible. However, experience and ability to interpret electrical signals from the upper airway are scarce, and much of the pertinent information within the signal is likely difficult to detect visually. To overcome this issue, we explored the use of transformers, a deep learning (DL) model architecture with attention mechanisms, to model tmEMG data and distinguish between electromyographic signals from a cohort of control, neurogenic, and sleep apnea patients. Our approach involved three strategies to train a generalizable model on a relatively small dataset including, (1) transfer learning using an audio spectral transformer (AST), (2) the use of 6,000 simulated EMG recordings, converted to spectrograms and using standard backpropagation for fine-tuning, and (3) application of regularization to prevent overfitting and enhance generalizability. This DL approach was tested using 177 transoral EMG recordings from a prior study's database that included six healthy controls, five moderate to severe OSA patients, and five amyotrophic lateral sclerosis (ALS) patients with evidence of bulbar involvement (neurogenic injury). Sensitivity and specificity for classifying neurogenic cases from controls were 98% and 73%, respectively, while classifying OSA from controls were 88% and 64%, respectively. Notably, by averaging the predicted probabilities of each segment for individual patients, the model correctly classified up to 82% of control and OSA patients. These results not only suggest a potential to diagnose OSA patients accurately, but also to identify OSA endotypes that involve neuromuscular pathology, which has major implications for clinical management, patient outcomes, and research.}, }
@article {pmid39741002, year = {2024}, author = {Lembo, A and Schiavetti, I and Serafino, M and Caputo, R and Nucci, P}, title = {Comparison of the performance of myopia control in European children and adolescents with defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL) spectacles.}, journal = {BMJ paediatrics open}, volume = {8}, number = {1}, pages = {}, pmid = {39741002}, issn = {2399-9772}, mesh = {Humans ; *Eyeglasses ; Adolescent ; Child ; Male ; Female ; Retrospective Studies ; *Myopia/therapy/epidemiology/physiopathology/prevention &amp; control ; *Refraction, Ocular/physiology ; Disease Progression ; Europe/epidemiology ; Equipment Design ; Visual Acuity/physiology ; }, abstract = {PURPOSE: A performance comparison of two myopia control spectacle lens designs, defocus incorporated multiple segments (DIMS) and highly aspherical lenslets (HAL), at slowing myopia progression in a European child/adolescent population. Previous research directly comparing these designs has been limited to Chinese participants and 1-year follow-up. The prevalence of myopia in European child/adolescent has been estimated at 22.60%.<br><br>METHODS: Retrospective cohort study of individuals (6-17 years) with myopia progression. Participants wore DIMS (Hoya MiyoSmart) or HAL (Essilor Stellest) spectacles for a minimum of 2 years. Axial length (AL) and cycloplegic autorefraction (spherical equivalent refraction (SER)) were measured at baseline and 1 and 2 years.<br><br>RESULTS: Mean 1-year SER changes for DIMS were -0.34D (&#xb1;0.46 SD) and HAL -0.30D (&#xb1;0.30); 2-year changes for DIMS were -0.50D (&#xb1;0.64 SD) and HAL -0.63D (&#xb1;0.56). Mean 1-year AL increases for DIMS were 0.19&#x2009;mm (&#xb1;0.56) and HAL 0.15&#x2009;mm (&#xb1;0.47); 2-year increases for DIMS were 0.29&#x2009;mm (&#xb1;0.63) and HAL 0.32&#x2009;mm (&#xb1;0.72). For equivalence margins of 0.25D and 0.50D for SER at 1 and 2&#x2009;years, respectively, and similarly 0.20&#x2009;mm and 0.30&#x2009;mm margins for AL, DIMS and HAL lenses were equivalent apart from AL at 1&#x2009;year where the 0.21&#x2009;mm 95%&#x2009;CI upper limit just exceeded 0.20&#x2009;mm. At both 1 and 2&#x2009;years, none of the differences in mean SERs or ALs between DIMS and HAL were clinically or statistically significant (p&#x2265;0.05 Mann-Whitney U test). Using linear mixed model analysis, the interaction between lens type and time did not significantly affect SER or AL at 1- or 2-year follow-up (p&#x2265;0.05). 38.4% of children/adolescents with DIMS had no SER progression at 2&#x2009;years, compared with 21.9% with HAL (p=0.047).<br><br>CONCLUSION: In a European population, DIMS and HAL lenses are essentially equivalent in their ability to reduce myopia progression and AL elongation over a 2-year follow-up period.}, }
@article {pmid39740768, year = {2025}, author = {Jiang, Y and Fan, W and Li, Y and Xue, H}, title = {Genetic Insights Into the Role of Cathepsins in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis: Evidence From Mendelian Randomization Study.}, journal = {Brain and behavior}, volume = {15}, number = {1}, pages = {e70207}, pmid = {39740768}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Mendelian Randomization Analysis ; *Alzheimer Disease/genetics ; *Parkinson Disease/genetics ; *Cathepsins/genetics ; *Genome-Wide Association Study ; Cathepsin B/genetics/metabolism ; Cathepsin H/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Previous studies have confirmed the significant role of cathepsins in the development of neurodegenerative diseases. We aimed to determine whether genetically predicted 10 cathepsins may have a causal effect on Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We conducted a two-sample bidirectional Mendelian randomization (MR) study using publicly available data from genome-wide association study (GWAS) to assess the causal associations between 10 cathepsins and three neurodegenerative diseases, including AD, PD, and ALS. We employed the following methods, including inverse variance weighting (IVW), MR-Egger, and weighted median (WM). The results were further validated using sensitivity analysis.<br><br>RESULTS: The forward MR analysis results indicate that elevated cathepsin H levels increase the risk of AD (p = 0.005, odds ratio [OR] = 1.040, 95% confidence interval [CI] = 1.011-1.069), elevated cathepsin B levels decrease the risk of PD (p < 0.001, OR = 0.890, 95% CI = 0.831-0.954), and no significant association was found between cathepsin levels and ALS. Reverse MR analysis suggests that there is no causal association between 10 cathepsins and three neurodegenerative diseases.<br><br>CONCLUSION: Our study provides new genetic insights into the role of cathepsin H in AD and cathepsin B in PD. However, our findings need to be further validated in a wider population, and future research should explore the potential mechanisms of cathepsins in these diseases in order to provide a basis for the development of new therapeutic strategies.}, }
@article {pmid39740575, year = {2025}, author = {Fortuna, A and Sorarù, G}, title = {Cervical lower motor neuron syndromes: A diagnostic challenge.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123357}, doi = {10.1016/j.jns.2024.123357}, pmid = {39740575}, issn = {1878-5883}, mesh = {Humans ; *Motor Neuron Disease/diagnosis/physiopathology/diagnostic imaging ; Magnetic Resonance Imaging/methods ; }, abstract = {Cervical lower motor neuron (LMN) syndromes, also known as brachial paresis, are characterized by muscle atrophy, weakness, and decreased reflexes in the upper limbs, devoid of sensory symptoms. These syndromes can stem from various factors, including degenerative conditions, immune-mediated diseases, infections, toxic exposures, metabolic disorders, and vascular anomalies.[1] Clinical presentations vary, with motor neuron involvement potentially limited to the cervical area or extending to other regions, affecting prognosis. Misdiagnosis is a significant issue, particularly in lower motor neuron presentations, with an error rate nearing 20 %.[2] This review proposes a classification system based on magnetic resonance imaging (MRI) findings, the onset timing of symptoms (acute, subacute, or chronic), the symmetry and distribution of atrophy, and the etiology (sporadic or hereditary). Acute conditions may include spinal ischemia,[3] whereas subacute or chronic forms can manifest as symmetric (e.g., cervical spondylogenic myelopathy)[4] or asymmetric (e.g., Hirayama disease)[5] presentations. Neurophysiological assessments and cervical MRI are crucial for accurate diagnosis, as they reveal patterns that provide lesion localization and additional clues to the underlying cause. A systematic diagnostic approach is essential for navigating the complexities of these syndromes.}, }
@article {pmid39739690, year = {2024}, author = {Tian, Y and Heinsinger, N and Hu, Y and Lim, UM and Wang, Y and Fernandis, AZ and Parmentier-Batteur, S and Klein, B and Uslaner, JM and Smith, SM}, title = {Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0308428}, pmid = {39739690}, issn = {1932-6203}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; *Ataxin-2/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Neurons/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Protein Binding ; }, abstract = {Ataxin-2 is a protein containing a polyQ extension and intermediate length of polyQ extensions increases the risk of Amyotrophic Lateral Sclerosis (ALS). Down-regulation of Ataxin-2 has been shown to mitigate TDP-43 proteinopathy in ALS models. To identify alternative therapeutic targets that can mitigate TDP-43 toxicity, we examined the interaction between Ataxin-2 and TDP-43. Co-immunoprecipitation demonstrated that Ataxin-2 and TDP-43 interact, that their interaction is mediated through the RNA recognition motif (RRM) of TDP-43, and knocking down Ataxin-2 or mutating the RRM domains rescued TDP-43 toxicity in an iPSC-derived neuronal model with TDP-43 overexpression. To decipher the Ataxin-2 and TDP-43 interactome, we used co-immunoprecipitation followed by mass spectrometry to identify proteins that interacted with Ataxin-2 and TDP-43 under conditions of endogenous or overexpressed TDP-43 in iPSC-derived neurons. Multiple interactome proteins were differentially regulated by TDP-43 overexpression and toxicity, including those involved in RNA regulation, cell survival, cytoskeleton reorganization, protein modification, and diseases. Interestingly, the RNA-binding protein (RBP), TAF15 which has been implicated in ALS was identified as a strong binder of Ataxin-2 in the condition of TDP-43 overexpression. Together, this study provides a comprehensive annotation of the Ataxin-2 and TDP-43 interactome and identifies potential therapeutic pathways and targets that could be modulated to alleviate Ataxin-2 and TDP-43 interaction-induced toxicity in ALS.}, }
@article {pmid39739500, year = {2025}, author = {Saiduzzaman, M and Roy, S and Bhattacharjee, M}, title = {Young Patient with Amyotrophic Lateral Sclerosis Following Suicidal Organophosphorus Compounds Poisoning: A Case Report.}, journal = {Mymensingh medical journal : MMJ}, volume = {34}, number = {1}, pages = {272-275}, pmid = {39739500}, issn = {2408-8757}, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/therapy/complications ; *Organophosphate Poisoning/complications/therapy/etiology ; Suicide, Attempted ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons. Its underlying etiology is not well established. But certain risk factors including genetic predilection and exposure to certain environmental toxins like Organophosphorus Compounds (OPC) have been postulated. Here we describe a young male patient presented with progressive weakness of all four limbs immediately following survival from OPC ingestion as a suicidal attempt. He also had slurred, indistinct speech without swallowing difficulty and sensory findings. Neurological examination findings are having mixed upper and lower motor neuron signs. EMG (Electromyography) shows features of denervation and reinnervation suggestive of ALS. ALS following single exposure to OPC is a relatively rare finding. Supportive treatments including physiotherapy and psychotherapy were given. This case may strengthen the etiological link between OPC and ALS.}, }
@article {pmid39739450, year = {2025}, author = {Aiello, EN and Poletti, B and Consonni, M and Iazzolino, B and Torre, S and Faltracco, V and Telesca, A and Palumbo, F and Curti, B and De Luca, G and Bella, ED and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Education moderates the association between motor involvement and executive status in ALS.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e70027}, pmid = {39739450}, issn = {1468-1331}, support = {//BIBLIOSAN/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; Female ; *Executive Function/physiology ; Middle Aged ; *Educational Status ; Aged ; *Cognitive Reserve/physiology ; Neuropsychological Tests ; Cohort Studies ; }, abstract = {BACKGROUND: This study aimed to determine whether educational attainment-a common proxy of cognitive reserve (CR)-influences the association between motor and cognitive/behavioural outcomes in a large cohort of ALS patients without dementia.<br><br>METHODS: N&#x2009;=&#x2009;726 ALS patients without FTD were assessed for motor (ALSFRS-R), cognitive (Edinburgh Cognitive and Behavioural ALS Screen, ECAS) and behavioural outcomes (ECAS-Carer Interview, ECAS-CI). CR was operationalized via educational attainment (in years). Moderation models were run on each subscale of the cognitive section of the ECAS and on the ECAS-CI by addressing ALSFRS-R as the predictor and education as the moderator.<br><br>RESULTS: Education was associated with both the ALSFRS-R and all the cognitive subscales of the ECAS, while not with the ECAS-CI. As to moderation models, a significant Education*ALSFRS-R interaction was detected solely with regard to the ECAS-Executive-with its simple slope-based decomposition revealing that higher ALSFRS-R scores were associated with higher scores on the ECAS-Executive for patients with low (p&#x2009;<&#x2009;0.001) and average (p&#x2009;=&#x2009;0.007), while not high, levels of education.<br><br>DISCUSSION: Education seems to moderate the association between motor involvement and executive status in ALS patients without dementia, thus possibly exerting a protective role towards both motor function and cognition in this population.}, }
@article {pmid39738171, year = {2024}, author = {Jeon, P and Ham, HJ and Choi, H and Park, S and Jang, JW and Park, SW and Cho, DH and Lee, HJ and Song, HK and Komatsu, M and Han, D and Jang, DJ and Lee, JA}, title = {NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10925}, pmid = {39738171}, issn = {2041-1723}, support = {2020M3E5D9079911//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; 2023R1A2C2008092//National Research Foundation of Korea (NRF)/ ; RS-2023-00218515//National Research Foundation of Korea (NRF)/ ; JP19H05706//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21H004771//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 23K20044//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 24H00060//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP22gm1410004h0003//Japan Agency for Medical Research and Development (AMED)/ ; }, mesh = {Humans ; *Ubiquitination ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Stress Granules/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Sequestosome-1 Protein/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Neurons/metabolism ; HEK293 Cells ; Oxidative Stress ; HeLa Cells ; Autophagy ; Viral Nonstructural Proteins/metabolism/genetics ; Protein Binding ; Cytoplasmic Granules/metabolism ; Apoptosis Regulatory Proteins ; }, abstract = {The NS1 binding protein, known for interacting with the influenza A virus protein, is involved in RNA processing, cancer, and nerve cell growth regulation. However, its role in stress response independent of viral infections remains unclear. This study investigates NS1 binding protein's function in regulating stress granules during oxidative stress through interactions with GABARAP subfamily proteins. We find that NS1 binding protein localizes to stress granules, interacting with core components, GABARAP proteins, and p62, a protein involved in autophagy. In cells lacking NS1 binding protein, stress granule dynamics are altered, and p62 ubiquitination is increased, suggesting impaired stress granule degradation. Overexpression of NS1 binding protein reduces p62 ubiquitination. In amyotrophic lateral sclerosis patient-derived neurons, reduced NS1 binding protein and p62 disrupt stress granule morphology. These findings identify NS1 binding protein as a negative regulator of p62 ubiquitination and a facilitator of GABARAP recruitment to stress granules, implicating it in stress granule regulation and amyotrophic lateral sclerosis pathogenesis.}, }
@article {pmid39737952, year = {2024}, author = {Alecki, C and Rizwan, J and Le, P and Jacob-Tomas, S and Comaduran, MF and Verbrugghe, M and Xu, JMS and Minotti, S and Lynch, J and Biswas, J and Wu, T and Durham, HD and Yeo, GW and Vera, M}, title = {Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10796}, pmid = {39737952}, issn = {2041-1723}, support = {RF1 MH126719/MH/NIMH NIH HHS/United States ; 300232//Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9; (Fonds de la recherche en sante du Quebec)/ ; MH126719//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; HG009889//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U24 HG009889/HG/NHGRI NIH HHS/United States ; R01 HG004659/HG/NHGRI NIH HHS/United States ; HG011864//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; PJT-186141//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Sant&#xe9; du Canada)/ ; HG004659//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; Hudson Translational Team Grant//ALS Society of Canada (ALS Canada)/ ; R01 HG011864/HG/NHGRI NIH HHS/United States ; R01 NS103172/NS/NINDS NIH HHS/United States ; 2022-ALS Discovery Grant//ALS Society of Canada (ALS Canada)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; U41 HG009889/HG/NHGRI NIH HHS/United States ; }, mesh = {*Dendrites/metabolism ; *Proteostasis ; Animals ; Humans ; Mice ; *RNA-Binding Protein FUS/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Motor Neurons/metabolism ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Hippocampus/metabolism/cytology ; Spinal Cord/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Protein Biosynthesis ; Molecular Chaperones/metabolism/genetics ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Microtubules/metabolism ; }, abstract = {Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.}, }
@article {pmid39737769, year = {2025}, author = {Akyuz, E and Aslan, FS and Hekimoglu, A and Yilmaz, BN}, title = {Insights Into Retinal Pathologies in Neurological Disorders: A Focus on Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease.}, journal = {Journal of neuroscience research}, volume = {103}, number = {1}, pages = {e70006}, doi = {10.1002/jnr.70006}, pmid = {39737769}, issn = {1097-4547}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; *Parkinson Disease/diagnosis/diagnostic imaging/pathology ; *Multiple Sclerosis/pathology/diagnosis/diagnostic imaging ; *Alzheimer Disease/pathology/diagnosis ; *Retina/pathology/diagnostic imaging ; Tomography, Optical Coherence/methods ; Retinal Diseases/diagnosis/pathology/etiology ; Animals ; }, abstract = {Neurological diseases are central nervous system (CNS) disorders affecting the whole body. Early diagnosis of the diseases is difficult due to the lack of disease-specific tests. Adding new biomarkers external to the CNS facilitates the diagnosis of neurological diseases. In this respect, the retina has a common embryologic origin with the CNS. Retinal imaging technologies including optical coherence tomography (OCT) can be used in the understanding and processual monitoring of neurological diseases. Retinal imaging has been recently recognized as a potential source of biomarkers for neurological diseases, increasing the number of studies in this direction. In this review, the association of retinal abnormalities with Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) is explained. Structural and functional abnormalities in retina as a predictive marker may facilitate early diagnosis of diseases. Although not all retinal abnormalities are predictive of neurologic diseases, changes in the retinal layers including retinal pigment epithelium and plexiform layers should suggest the risk of PD, MS, ALS, and AD.}, }
@article {pmid39737526, year = {2024}, author = {Nakaya, T}, title = {Release of FUS into the extracellular space is regulated by its amino-terminal prion-like domain.}, journal = {FEBS letters}, volume = {}, number = {}, pages = {}, doi = {10.1002/1873-3468.15086}, pmid = {39737526}, issn = {1873-3468}, support = {22K07374//Japan Society for the Promotion of Science/ ; }, abstract = {Fused in sarcoma (FUS) is a causative factor of amyotrophic lateral sclerosis (ALS) and is believed to propagate pathologically by transmission from cell to cell. However, the mechanism underlying FUS release from cells, which is a critical step for the propagation system, remains poorly understood. This study conducted an analysis of the release of human and mouse FUS from neurons, revealing that human FUS is significantly released into the media compared to its mouse counterpart. Further study using chimeric FUS proteins identified the amino-terminal region of human FUS as essential for its release. These findings indicate that human FUS is released directly from neurons and underscore the novel functional role of its amino-terminal region in this process.}, }
@article {pmid39736981, year = {2024}, author = {Zhang, Y and Li, N and Ge, Z and Li, F}, title = {Blood component therapy for dry eye disease: a systematic review and network meta-analysis.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1500160}, pmid = {39736981}, issn = {2296-858X}, abstract = {OBJECTIVE: Blood component therapy has shown promising potential as an emerging treatment for dry eye disease; however, it remains unclear which specific blood component is the most effective. This study aims to compare the efficacy of different blood components in the treatment of dry eye disease through a network meta-analysis, with the goal of providing the latest and most reliable evidence for clinical practice.<br><br>METHODS: We conducted a systematic search of the PubMed, Web of Science, Cochrane, Embase, and Scopus databases, with the search concluding on June 1, 2024. Two independent researchers performed literature screening, data extraction, and quality assessment.<br><br>RESULTS: A total of 16 randomized controlled trials (RCTs) involving 898 patients with dry eye disease were included. Six different blood components were utilized in treating dry eye disease, with platelet-rich plasma (PRP) being the most widely used. The results of the network meta-analysis indicated that platelet-rich plasma eye drops (PRPD) significantly outperformed artificial tears (AT) in improving the corneal fluorescein staining score (CFSS), while autologous serum (ALS) and umbilical cord serum (UCS) also demonstrated significantly better effects than AT in enhancing tear break-up time (TBUT). Additionally, ALS, PRP injection (PRPI), and PRPD showed significantly superior outcomes compared to AT in improving the ocular surface disease index (OSDI). However, no statistically significant differences were found among the various treatment modalities regarding their effects on Schirmer's I value, CFSS, TBUT, and OSDI. SUCRA analysis predicted that UCS was the most effective in improving Schirmer's I value and TBUT, while PRP excelled in enhancing CFSS and OSDI. Limitations such as publication bias and issues related to randomization, allocation concealment, and blinding may affect the reliability of the current findings.<br><br>CONCLUSION: Blood component therapy can significantly improve the pathological damage and ocular surface health in patients with dry eye disease. For those with aqueous-deficient dry eye, UCS may represent the optimal treatment option. In contrast, for patients with more severe corneal epithelial damage, PRP may offer a more effective therapeutic approach.<br><br>https://www.crd.york.ac.uk/PROSPERO/, CRD42024534091.}, }
@article {pmid39736783, year = {2024}, author = {Zeng, J and Luo, C and Jiang, Y and Hu, T and Lin, B and Xie, Y and Lan, J and Miao, J}, title = {Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {205}, pmid = {39736783}, issn = {2051-5960}, support = {YNXM2024062//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; YNXM2024015//High-quality development project of public hospitals in Baoan District, Shenzhen/ ; }, mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; Animals ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43's crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43's involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein's propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington's disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein's central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.}, }
@article {pmid39735276, year = {2024}, author = {Moyana, TN}, title = {Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.}, journal = {World journal of gastroenterology}, volume = {30}, number = {48}, pages = {5198-5204}, pmid = {39735276}, issn = {2219-2840}, mesh = {Humans ; *Small Cell Lung Carcinoma/therapy/secondary/pathology/diagnostic imaging ; *Stomach Neoplasms/pathology/therapy/diagnostic imaging ; *Lung Neoplasms/secondary/therapy/pathology/diagnostic imaging ; Prognosis ; Biomarkers, Tumor/analysis/metabolism ; Positron Emission Tomography Computed Tomography/methods ; Immune Checkpoint Inhibitors/therapeutic use ; Immunohistochemistry ; }, abstract = {Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.}, }
@article {pmid39735081, year = {2024}, author = {Dost, W and Rasully, MQ and Zaman, MN and Dost, W and Ali, W and Ayobi, SA and Dost, R and Niazi, J and Bakht, K and Iqbal, A and Bokhari, SFH}, title = {Predictive Biomarkers for the Early Detection of Anastomotic Leaks in Colorectal Surgeries: A Systematic Review.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74616}, pmid = {39735081}, issn = {2168-8184}, abstract = {Anastomotic leaks (ALs) remain a serious postoperative complication in colorectal surgery, often resulting in significant morbidity, prolonged hospitalization, and increased mortality risk. This systematic review aims to evaluate the role of predictive biomarkers in the early detection of ALs, focusing on their diagnostic accuracy and clinical utility. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across MEDLINE, Scopus, CENTRAL, and Web of Science, identifying studies that examined biomarkers such as C-reactive protein (CRP), procalcitonin (PCT), and white blood cell (WBC) count in the context of AL. A total of 20 studies met the inclusion criteria, with sample sizes ranging from 59 to 2,655 patients undergoing colorectal surgeries with primary anastomosis. CRP emerged as the most widely studied and reliable biomarker, with studies suggesting that elevated CRP levels, particularly on postoperative days 3-4, can effectively indicate AL risk, showing high negative predictive value. PCT has also shown promise as a complementary biomarker, offering enhanced specificity for infectious complications. Although WBC count alone was a limited predictor, it may add diagnostic value when used with other markers. In addition, innovative biomarkers, such as inflammatory indices in peritoneal fluid, demonstrated potential for further improving AL detection accuracy.}, }
@article {pmid39731449, year = {2024}, author = {Fabbrizio, P and Baindoor, S and Margotta, C and Su, J and Morrissey, EP and Woods, I and Hogg, MC and Vianello, S and Venø, MT and Kjems, J and Sorarù, G and Bendotti, C and Prehn, JHM and Nardo, G}, title = {Protective role of Angiogenin in muscle regeneration in amyotrophic lateral sclerosis: Diagnostic and therapeutic implications.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {}, number = {}, pages = {e13328}, doi = {10.1111/bpa.13328}, pmid = {39731449}, issn = {1750-3639}, support = {CUP E48I20000000007//Regione Lombardia/ ; 17/JPND/3455/SFI_/Science Foundation Ireland/Ireland ; 20/SP/8953/SFI_/Science Foundation Ireland/Ireland ; 21/RC/10294_P2/SFI_/Science Foundation Ireland/Ireland ; //EU Joint Programme-Neurodegenerative Disease Research/ ; SG-2018-12366226//Ministero della Salute, Italy/ ; MUSALS-AChR//Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica/ ; 18/CRT/6214//Science Foundation Ireland CRT in Genomics Data Science/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease with no effective treatments, in part caused by variations in progression and the absence of biomarkers. Mice carrying the SOD1G93A transgene with different genetic backgrounds show variable disease rates, reflecting the diversity of patients. While extensive research has been done on the involvement of the central nervous system, the role of skeletal muscle remains underexplored. We examined the impact of angiogenin, including its RNase activity, in skeletal muscles of ALS mouse models and in biopsies from ALS patients. Elevated levels of angiogenin were found in slowly progressing mice but not in rapidly progressing mice, correlating with increased muscle regeneration and vascularisation. In patients, higher levels of angiogenin in skeletal muscles correlated with milder disease. Mechanistically, angiogenin promotes muscle regeneration and vascularisation through satellite cell-endothelial interactions during myogenesis and angiogenesis. Furthermore, specific angiogenin-derived tiRNAs were upregulated in slowly progressing mice, suggesting their role in mediating the effects of angiogenin. These findings highlight angiogenin and its tiRNAs as potential prognostic markers and therapeutic targets for ALS, offering avenues for patient stratification and interventions to mitigate disease progression by promoting muscle regeneration.}, }
@article {pmid39731185, year = {2024}, author = {Itou, T and Fujita, K and Okuzono, Y and Warude, D and Miyakawa, S and Mihara, Y and Matsui, N and Morino, H and Kikukawa, Y and Izumi, Y}, title = {Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis: a case control study.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {331}, pmid = {39731185}, issn = {1742-2094}, support = {NA//Takeda Pharmaceutical Company/ ; JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/pathology ; Humans ; *Disease Progression ; Female ; *CD8-Positive T-Lymphocytes/immunology ; Middle Aged ; Male ; *Th17 Cells/immunology/metabolism ; Case-Control Studies ; Aged ; Adult ; }, abstract = {The immune system has garnered attention due to its association with disease progression in amyotrophic lateral sclerosis (ALS). However, the role of peripheral immune cells in this context remains controversial. Here, we conducted single-cell RNA-sequencing of peripheral blood mononuclear cells to comprehensively profile immune cells concerning the rate of disease progression in patients with ALS. Our analysis revealed increased frequencies of T helper 17 cells (Th17) relative to regulatory T cells, effector CD8 T cells relative to naïve CD8 T cells, and CD16[high]CD56[low] mature natural killer cells relative to CD16[low]CD56[high] naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.}, }
@article {pmid39730482, year = {2024}, author = {Mitsi, E and Votsi, C and Koutsou, P and Georghiou, A and Christodoulou, CC and Kleopa, K and Zamba-Papanicolaou, E and Christodoulou, K and Nicolaou, P}, title = {Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30781}, pmid = {39730482}, issn = {2045-2322}, support = {73234//Telethon Cyprus/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Male ; Cyprus/epidemiology ; Female ; Middle Aged ; Aged ; *C9orf72 Protein/genetics ; Superoxide Dismutase-1/genetics ; Genetic Predisposition to Disease ; Molecular Epidemiology ; DNA-Binding Proteins/genetics ; Adult ; RNA-Binding Protein FUS/genetics ; High-Throughput Nucleotide Sequencing ; Mutation ; Cohort Studies ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. More than fifty genes carrying causative or disease-modifying variants have been identified since the 1990s, when the first ALS-associated variant in the gene SOD1 was discovered. The most commonly mutated ALS genes in the European populations include the C9orf72, SOD1, TARDBP and FUS. Understanding the genetic causes of ALS within a population is becoming more significant, especially in light of the possible development of personalized medicine. Here, we provide clinical and genetic data on familial and sporadic ALS patients in a Greek-Cypriot population-based cohort. Eighty-nine ALS patients, including 21 familial ALS (fALS) (23.6%) and 68 sporadic ALS (sALS) (76.4%), provided the cohort for variant screening of the most common ALS-associated genes. Moreover, next-generation sequencing (NGS) was also performed to identify rare ALS variants, and in silico prediction tools were applied to predict the downstream effect of the variants detected in our study. The pathogenic hexanucleotide G4C2 repeat expansion in C9orf72 was the predominant genetic cause (22.47%) of ALS in our population, while variants in six additional ALS-associated genes were identified, including ALS2, TARDBP, FIG4, TBK1, GLT8D1, and BICD2.}, }
@article {pmid39729643, year = {2024}, author = {Meiling, JB and Caress, JB and Cartwright, MS}, title = {Ultra High-Frequency Ultrasound of Median Nerve Fascicles at the Wrist in Amyotrophic Lateral Sclerosis: An Exploratory Study.}, journal = {Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNP.0000000000001136}, pmid = {39729643}, issn = {1537-1603}, abstract = {PURPOSE: High-frequency ultrasound (HFUS) of muscle and nerve has the potential to be a reliable, responsive, and informative biomarker of disease progression for individuals with amyotrophic lateral sclerosis (ALS). High-frequency ultrasound is not able to visualize median nerve fascicles to the same extent as ultra-high-frequency ultrasound (UHFUS). Evaluating the number and size of fascicles within a nerve may facilitate a better understanding of nerve diseases. This exploratory study aims to image median nerve fascicles at the wrist in individuals with ALS using UHFUS and compare these findings with those from previously observed controls.<br><br>METHODS: Fifteen individuals with ALS underwent sonographic examination of the median nerves on each upper limb using UHFUS with a 48-MHz linear array transducer. Fascicle count and density in each examined nerve were determined by a single rater. Demographic and sonographic data from 20 previously studied controls were compared.<br><br>RESULTS: In individuals with ALS, the average fascicle number was 22.4 (SD 5.2) and average fascicle density 1.7 (SD 0.5). There was no significant difference in fascicle counts between individuals with ALS and controls.<br><br>CONCLUSIONS: Fascicular quantification using UHFUS is possible in individuals with ALS. Given the lack of appreciable difference between fascicle counts in individuals with ALS and controls, UHFUS of the median nerve at the wrist may not be a responsive biomarker for ALS disease progression.}, }
@article {pmid39728809, year = {2024}, author = {Al Haffar, M and Fajloun, Z and Azar, S and Sabatier, JM and Abi Khattar, Z}, title = {Lesser-Known Cyanotoxins: A Comprehensive Review of Their Health and Environmental Impacts.}, journal = {Toxins}, volume = {16}, number = {12}, pages = {}, pmid = {39728809}, issn = {2072-6651}, mesh = {Humans ; *Cyanobacteria/metabolism ; *Bacterial Toxins/toxicity ; Animals ; Harmful Algal Bloom ; Cyanobacteria Toxins ; Microcystins/toxicity ; }, abstract = {Cyanobacteria, also known as blue-green algae, are a diverse phylum of photosynthetic, Gram-negative bacteria and one of the largest microbial taxa. These organisms produce cyanotoxins, which are secondary metabolites that can have significant impacts on both human health and the environment. While toxins like Microcystins and Cylindrospermopsins are well-documented and have been extensively studied, other cyanotoxins, including those produced by Lyngbya and Nostoc, remain underexplored. These lesser-known toxins can cause various health issues in humans, including neurotoxicity, hepatotoxicity, and dermatotoxicity, each through distinct mechanisms. Moreover, recent studies have shown that cyanobacteria can be aerosolized and transmitted through the air over long distances, providing an additional route for human exposure to their harmful effects. However, it remains an area that requires much more investigation to accurately assess the health risks and develop appropriate public health guidelines. In addition to direct exposure to toxins, cyanobacteria can lead to harmful algal blooms, which pose further risks to human and wildlife health, and are a global concern. There is limited knowledge about these lesser-known cyanotoxins, highlighting the need for further research to understand their clinical manifestations and improve society's preparedness for the associated health risks. This work aims to review the existing literature on these underexplored cyanotoxins, which are associated with human intoxication, elucidate their clinical relevance, address significant challenges in cyanobacterial research, and provide guidance on mitigating their adverse effects.}, }
@article {pmid39728753, year = {2024}, author = {Boziki, M and Theotokis, P and Kesidou, E and Nella, M and Bakirtzis, C and Karafoulidou, E and Tzitiridou-Chatzopoulou, M and Doulberis, M and Kazakos, E and Deretzi, G and Grigoriadis, N and Kountouras, J}, title = {Impact of Mast Cell Activation on Neurodegeneration: A Potential Role for Gut-Brain Axis and Helicobacter pylori Infection.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1750-1778}, pmid = {39728753}, issn = {2035-8385}, abstract = {BACKGROUND: The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise "primary cerebrovascular and neurodegenerative" disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction.<br><br>METHODS: This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis.<br><br>RESULTS: In view of recent evidence that the gut-brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut-brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut-brain axis homeostasis towards local and systemic pro-inflammatory responses.<br><br>CONCLUSION: As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field.}, }
@article {pmid39728018, year = {2024}, author = {Jeyarajan, S and Ranjith, S and Veerapandian, R and Natarajaseenivasan, K and Chidambaram, P and Kumarasamy, A}, title = {Antibiofilm Activity of Epinecidin-1 and Its Variants Against Drug-Resistant Candida krusei and Candida tropicalis Isolates from Vaginal Candidiasis Patients.}, journal = {Infectious disease reports}, volume = {16}, number = {6}, pages = {1214-1229}, pmid = {39728018}, issn = {2036-7430}, support = {BT/PR2071/BBE/117/241/2016//Department of Biotechnology, India/ ; 311/RUSA(2.0)/2018//RUSA 2.0 Biological Sciences/ ; 01706/P6/2021//Tamil Nadu State Council for Higher Education (TANSCHE)/ ; ICMR-NET- 61754/2010//Indian Council of Medical Research/ ; }, abstract = {Background/Objective: Indwelling intrauterine contraceptive devices (IUDs) have surfaces that facilitate the attachment of Candida spp., creating a suitable environment for biofilm formation. Due to this, vulvovaginal candidiasis (VVC) is frequently linked to IUD usage, necessitating the prompt removal of these devices for effective treatment. In this study, we evaluated the susceptibility of antimicrobial peptides in vitro against biofilm forming, Amphotericin B (MIC50 > 2 mg L[-1]) resistant Candida krusei and Candida tropicalis isolated from IUD users who had signs of vaginal candidiasis (hemorrhage, pelvic pain, inflammation, itching, and vaginal discharge). Three antimicrobial peptides, namely, epinecidin-1 (epi-1) and its two variants, namely, variant-1 (Var-1) and variant-2 (Var-2), which were reported to have enhanced antibacterial activity were tested against IUD isolates (C. krusei and C. tropicalis) with pathogenic form of Candida albicans as control. Variants of epi-1, namely, Var-1 and Var-2 were created by substituting lysine in the place of histidine and alanine. Methods: The antimicrobial activity was measured using the microbroth dilution method to determine the minimum inhibitory concentration (MIC) of peptides against C. albicans, C. krusei and C. tropicalis. The MIC of each peptide was used for biofilm assay by Crystal violet staining, Scanning Electron Microscopy, and Reactive Oxygen Species (ROS) assay. To find the possible mechanism of anti-biofilm activity by the peptides, their ability to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2 were determined through PatchDock. Results: The MIC values of peptides: epi-1, var-1 and var-2 against C. albicans are 128 μg mL[-1], 64 μg mL[-1] and 32 μg mL[-1], C. tropicalis are 256 μg mL[-1], 64 μg mL[-1,] and 32 μg mL[-1] and C. krusei are 128 µg mL[-1], 128 µg mL[-1] and 64 µg mL[-1], respectively. Both the variants outperformed epi-1. Specifically for tested Candida spp., var-1 showed two- to four-fold enhancements and var-2 showed two- to eight-fold enhancements compared to epi-1. Electron microscopy confirmed that the mechanism of action involves pore formation thus inducing reactive oxygen species in Candida spp. cell membrane. Computational analysis showed that the peptides have a high tendency to interact with Candida spp. cell membrane proteins such as Exo-β-(1,3)-Glucanase, Secreted Aspartic Proteinase (Sap) 1, and N-terminal Domain Adhesin: Als 9-2, thereby preventing biofilm formation. Conclusions: The in vitro evidence supports the potential use of epi-1 and its variants to be used as an anti-biofilm agent to coat IUDs in the future for therapeutic purposes.}, }
@article {pmid39727843, year = {2024}, author = {An, J and Gopalakrishnan, L and Ortega, V and Saul, J and Kadali, R and Bowser, R}, title = {Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids.}, journal = {Biosensors}, volume = {14}, number = {12}, pages = {}, pmid = {39727843}, issn = {2079-6374}, support = {Development of TDP-43 Immunoassays//Target ALS/ ; }, mesh = {Humans ; Immunoassay ; *DNA-Binding Proteins/metabolism ; Amyotrophic Lateral Sclerosis/diagnosis ; Luminescent Measurements ; Biomarkers/blood ; Reproducibility of Results ; Electrochemical Techniques ; Biosensing Techniques ; Limit of Detection ; }, abstract = {Transactive response DNA-binding protein of 43 kDa (TDP-43) is a major component of pathological inclusions in various neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The detection of TDP-43 in biofluids is crucial for the development of diagnostic and prognostic indicators of disease and therapeutic development for TDP-43-related proteinopathies. Despite its potential as a biomarker for numerous neurological disorders, the lack of a sensitive and reproducible TDP-43 assay hinders progress in TDP-43-based therapy development, underscoring the need for an effective and standardized method for accurate quantification. Addressing the limitations of sensitivity and reproducibility in existing assays, in this study, we developed and validated a highly sensitive electrochemiluminescence immunoassay on the Meso Scale Discovery platform. The assay demonstrated the detection of full-length TDP-43 in human biofluids with a limit of detection of 4pg/mL, a working range of 4-20,000 pg/mL, and a total assay time of 16 h. In this study, we developed and validated a sensitive immunoassay for the detection of full-length TDP-43 in human biofluids using the Meso Scale Discovery platform. We used this immunoassay to quantify TDP-43 levels in the plasma and serum of healthy controls and ALS patients. Our results indicate a reduction in full-length TDP-43 in the blood of ALS patients compared to healthy controls.}, }
@article {pmid39726289, year = {2025}, author = {Kollstrøm, AM and Christiansen, N and Sandvig, A and Sandvig, I}, title = {Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons.}, journal = {American journal of physiology. Cell physiology}, volume = {328}, number = {3}, pages = {C1029-C1044}, doi = {10.1152/ajpcell.00725.2024}, pmid = {39726289}, issn = {1522-1563}, support = {//Alf Harborgs fund/ ; //Olav Thon Stiftelsen (Olav Thon Foundation)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Humans ; *Motor Neurons/metabolism/pathology ; *Synapses/metabolism/pathology/genetics ; *C9orf72 Protein/genetics/metabolism ; Nerve Net/metabolism/pathology/physiopathology ; Mutation ; Neuronal Outgrowth/genetics ; Action Potentials ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper and lower motor neurons. Several studies have identified structural and functional alterations in the motor neurons before the manifestation of symptoms, yet the underlying cause of such alterations and how they contribute to the progressive degeneration of affected motor neuron networks remain unclear. Importantly, the short- and long-term spatiotemporal dynamics of neuronal network activity make it challenging to discern how ALS-related network reconfigurations emerge and evolve. To address this, we systematically monitored the structural and functional dynamics of motor neuron networks with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived motor neurons display time-dependent neural network dysfunction, specifically reduced firing rate and spike amplitude, impaired bursting, but higher overall synchrony in network activity. These changes coincided with altered neurite outgrowth and branching within the networks. Moreover, transcriptional analyses revealed dysregulation of molecular pathways involved in synaptic development and maintenance, neurite outgrowth, and cell adhesion, suggesting impaired synaptic stabilization. This study identifies early synaptic dysfunction as a contributing mechanism resulting in network-wide structural and functional compensation, which may over time render the networks vulnerable to neurodegeneration.NEW &amp; NOTEWORTHY RNA-sequencing of ALS patient-derived motor neurons revealed altered expression of genes involved in cell adhesion, neurite outgrowth, synaptic development and maintenance, and synaptic plasticity. These alterations were accompanied by time-dependent structural impairments and disrupted neuronal activity, suggesting that early synaptic changes and network-wide structural and functional compensations contribute to motor neuron vulnerability in ALS.}, }
@article {pmid39725771, year = {2024}, author = {Pagliari, E and Taiana, M and Manzini, P and Sali, L and Quetti, L and Bertolasi, L and Oldoni, S and Melzi, V and Comi, G and Corti, S and Nizzardo, M and Rizzo, F}, title = {Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {82}, number = {1}, pages = {29}, pmid = {39725771}, issn = {1420-9071}, support = {Craiplo Grant 2020-3623//Fondazione Cariplo/ ; 22739//SMA Europe Grant/ ; }, mesh = {Animals ; *Stathmin/metabolism/genetics ; *Muscular Atrophy, Spinal/therapy/genetics/pathology/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Neuromuscular Junction/metabolism/pathology ; Neuroprotection ; Dependovirus/genetics ; Genetic Therapy/methods ; }, abstract = {The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment.}, }
@article {pmid39724103, year = {2024}, author = {Garcia-Toscano, L and Currey, HN and Hincks, JC and Stair, JG and Lehrbach, NJ and Liachko, NF}, title = {Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.}, journal = {PLoS genetics}, volume = {20}, number = {12}, pages = {e1011518}, pmid = {39724103}, issn = {1553-7404}, support = {P40 OD010440/OD/NIH HHS/United States ; R01 AG066729/AG/NIA NIH HHS/United States ; I01 BX005762/BX/BLRD VA/United States ; I01 BX004044/BX/BLRD VA/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *HSP90 Heat-Shock Proteins/metabolism/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Humans ; Phosphorylation ; Mutation ; Heat-Shock Response/genetics ; TDP-43 Proteinopathies/genetics/metabolism ; }, abstract = {Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell. The heat shock responsive chaperone Hsp90 has been shown to interact with TDP-43 and stabilize its normal conformation; however, it is not known whether this interaction contributes to neurotoxicity in vivo. Using a C. elegans model of fALS mutant TDP-43 proteinopathy, we find that loss of function of HSP-90 protects against TDP-43 neurotoxicity and subsequent neurodegeneration in adult animals. This protection is accompanied by a decrease in both total and phosphorylated TDP-43 protein. We also find that hsp-90 mutation or inhibition upregulates key stress responsive heat shock pathway gene expression, including hsp-70 and hsp-16.1, and we demonstrate that normal levels of hsp-16.1 are required for hsp-90 mutation effects on TDP-43. We also observe that the neuroprotective effect due to HSP-90 dysfunction does not involve direct regulation of proteasome activity in C. elegans. Our data demonstrate for the first time that Hsp90 chaperone activity contributes to adverse outcomes in TDP-43 proteinopathies in vivo using a whole animal model of ALS.}, }
@article {pmid39722698, year = {2024}, author = {Jiao, L and Yang, J and Wang, W and Liu, X and Fu, Y and Fan, D}, title = {sTREM2 cerebrospinal fluid levels are a potential biomarker in amyotrophic lateral sclerosis and associate with UMN burden.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1515252}, pmid = {39722698}, issn = {1664-2295}, abstract = {OBJECTIVES: The aims of this study were to investigate whether CSF sTREM2 may be a potential marker of disease monitoring for amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We investigated whether CSF sTREM2 levels are altered in ALS patients and are correlated with upper motor neuron (UMN) burden and disease progression.<br><br>RESULTS: CSF sTREM2 was greater in the ALS patients than in the controls (p&#x202f;=&#x202f;0.002). Elevated CSF sTREM2 was associated with the UMN score (r&#x202f;=&#x202f;0.38, p&#x202f;=&#x202f;0.009), &#x394;FS (r&#x202f;=&#x202f;0.30, p&#x202f;=&#x202f;0.04) and serum NFL (lg) (r&#x202f;=&#x202f;0.35, p&#x202f;=&#x202f;0.015). As the motor band sign (MBS) score increased, the CSF sTREM2 level increased (p-trend&#x202f;=&#x202f;0.014). Furthermore, the correlations became stronger (UMN score (r&#x202f;=&#x202f;0.50, p&#x202f;=&#x202f;0.01) &#x394;FRS (r&#x202f;=&#x202f;0.52, p&#x202f;=&#x202f;0.008) and serum NFL (lg) (r&#x202f;=&#x202f;0.55, p&#x202f;=&#x202f;0.004) when estimated only among patients with a disease duration >12&#x202f;months.<br><br>CONCLUSION: We found that CSF sTREM2 is elevated in ALS patients and may be a novel marker, probably reflecting upper motor unit severity and prognosis.}, }
@article {pmid39722495, year = {2024}, author = {García-Ramírez, Y and Cayuela-Fuentes, JM and Mira-Escolano, MP and Maceda-Roldán, LA and Mikulasova, E and Oliva-López, C and Sánchez-Escámez, A and Ciller-Montoya, P and Palomar-Rodríguez, JA}, title = {Characterization, epidemiology, and factors associated with evolution and survival in patients with amyotrophic lateral sclerosis in southeastern Spain, 2008-2021: a population-based study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/21678421.2024.2439454}, pmid = {39722495}, issn = {2167-9223}, abstract = {OBJECTIVE: To describe the epidemiology, characteristics, and factors associated with the evolution and survival in patients with amyotrophic lateral sclerosis (ALS) in a region of southeastern Spain.<br><br>METHODS: An observational study was carried out in people with a diagnosis of ALS in the period 2008-2021 who were registered in the Information System of Rare Diseases of the Region of Murcia (SIER). We calculated crude and standardized incidence rate (SIR) using European Standard Population of 2013 and point prevalence. The Kaplan-Meier method and the log-rank test were used to estimate and compare survival curves.<br><br>RESULTS: We identified 374 cases. The mean age at diagnosis was 66.5&#x2009;&#xb1;&#x2009;11.7 and 50.3% persons were spinal onset. Mean time from the onset of symptoms to diagnosis was 0.9&#x2009;&#xb1;&#x2009;1.0 years. The global SIR was 1.95/100,000 person-years (95%CI: 1.77-2.12), which was higher in men (ratio 1.34), and the point prevalence in 2021 was 4.57 per 100,000 (95% CI: 4.46-4.68). There were 297 deaths with a mean age of 69.8&#x2009;&#xb1;&#x2009;10.8. The median survival from clinical onset was 2 years (95%CI: 1.0-3.0). Factors associated with lower survival were bulbar onset (p&#x2009;<&#x2009;0.001), older age at the onset of symptoms (p&#x2009;<&#x2009;0.001), and the absence of riluzole treatment (p&#x2009;=&#x2009;0.003).<br><br>CONCLUSIONS: This study is one of few to evaluate the epidemiological, characteristics, and prognostic factors of ALS in Spain, with findings similar to previous population studies. The use of population-based registries offers reliable information on the magnitude, or evolution in these patients.}, }
@article {pmid39722149, year = {2024}, author = {Simão, S and Naumann, LL and de Carvalho, M and Santos, MO and Martins, IP}, title = {Adaptation and Validation of Version B of the Edinburgh Cognitive and Behavioural ALS Screen for the Portuguese Population.}, journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists}, volume = {}, number = {}, pages = {}, doi = {10.1093/arclin/acae118}, pmid = {39722149}, issn = {1873-5843}, support = {GA101017598//European Union's Horizon 2020/ ; }, abstract = {OBJECTIVE: This study aims to adapt and provide psychometric support for the validation of version B of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for the Portuguese population, addressing the need for consistent cognitive evaluations in amyotrophic lateral sclerosis (ALS). A second culturally adapted ECAS screen facilitates the accurate characterization of ALS progression, mitigates learning effects, and supports tailored care management.<br><br>METHODS: The adaptation process included forward-backward translation, cultural adaptation, and cognitive debriefing on a prospective sample of 193 ALS patients and 106 controls. A multiple regression analysis identified predictors relevant for establishing ECAS cut-off scores. Psychometric evaluations, including reliability assessments and tests of convergent, construct, and criterion validity, were conducted. Additionally, version A's psychometric properties were reevaluated with complementary analyses and a larger sample.<br><br>RESULTS: Version B demonstrated good internal consistency with Cronbach's alpha of 0.802, comparable to the previously established version A. Moderate inter-item correlations further supported reliability, reflecting internal coherence. Equivalence testing between the Portuguese versions supported convergent validity, confirming version B's alignment with version A's theoretical framework. Exploratory factor analysis provided preliminary support for construct validity, and receiver operating characteristic analyses established cut-off values for both versions, revealing moderate sensitivity with a tendency toward false negatives, and higher specificity.<br><br>CONCLUSIONS: This study provided evidence for the cultural suitability, reliability, and validity of the Portuguese ECAS B. As evidence supports the equivalence of the Portuguese ECAS versions, they can be used for flexible screenings and applied with the calculated cut-off values to enhance diagnostic accuracy.}, }
@article {pmid39722074, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {203}, pmid = {39722074}, issn = {2051-5960}, support = {R35 NS132179/NS/NINDS NIH HHS/United States ; R01 5R35NS132179/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *C9orf72 Protein/genetics ; *Disease Models, Animal ; *DNA-Binding Proteins/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Mice ; *Mice, Transgenic ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Dependovirus/genetics ; Humans ; Male ; Behavior, Animal/physiology ; Mice, Inbred C57BL ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, }
@article {pmid39721808, year = {2024}, author = {Almukhlifi, Y and Crowfoot, G and Hutton, A}, title = {Barriers and Facilitators Toward Disaster Knowledge, Skills, and Preparedness among Emergency Medical Services in Saudi Arabia.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {6}, pages = {395-401}, doi = {10.1017/S1049023X24000670}, pmid = {39721808}, issn = {1945-1938}, mesh = {Humans ; Saudi Arabia ; Male ; Female ; Adult ; *Disaster Planning ; Emergency Medical Services/organization &amp; administration ; Interviews as Topic ; Qualitative Research ; Health Knowledge, Attitudes, Practice ; Emergency Medical Technicians ; Middle Aged ; }, abstract = {INTRODUCTION: Disasters pose significant challenges globally, affecting millions of people annually. In Saudi Arabia, floods constitute a prevalent natural disaster, underscoring the necessity for effective disaster preparedness among Emergency Medical Services (EMS) workers. Despite their critical role in disaster response, research on disaster preparedness among EMS workers in Saudi Arabia is limited.<br><br>STUDY OBJECTIVE/METHODS: The study aimed to explore the disaster preparedness among EMS workers in Saudi Arabia. This study applied an explanatory sequential mixed-methods design to explore disaster preparedness among EMS workers in Saudi Arabia, focusing on the qualitative phase. Semi-structured interviews were conducted with 15 EMS workers from National Guard Health Affairs (NGHA) and Ministry of Health (MOH) facilities in Riyadh, Dammam, and Jeddah. Thematic analysis was conducted following Braun and Clarke's six-step process, ensuring data rigor through Schwandt, et al's criteria for trustworthiness.<br><br>FINDINGS: The demographic characteristics of participants revealed a predominantly young, male workforce with varying levels of experience and educational backgrounds. Thematic analysis identified three key themes: (1) Newly/developed profession, highlighting the challenges faced by young EMS workers in acquiring disaster preparedness; (2) Access to opportunities and workplace resources (government versus military), indicating discrepancies in disaster preparedness support between government and military hospitals; and (3) Workplace policies and procedures, highlighting the need for clearer disaster policies, training opportunities, and role clarity among EMS workers.<br><br>CONCLUSION: The study underscores the importance of addressing the unique challenges faced by EMS workers in Saudi Arabia to enhance disaster preparedness. Recommendations include targeted support for young EMS professionals, standardization of disaster training across health care facilities, and improved communication of disaster policies and procedures. These findings have implications for policy and practice in disaster management and EMS training in Saudi Arabia.}, }
@article {pmid39720511, year = {2024}, author = {Terao, SI and Nosaki, Y and Murao, A and Torii, R and Ogawa, N and Miura, N and Sasaki, Y and Sobue, G}, title = {Onset of age, site and respiratory symptoms are strongly associated with respiratory decline in sporadic amyotrophic lateral sclerosis: a long-term longitudinal study.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000829}, pmid = {39720511}, issn = {2632-6140}, abstract = {OBJECTIVE: The objective of this study is to identify factors influencing progression of respiratory decline from the onset of neurological symptoms to respiratory failure in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In 100 patients with sporadic ALS, %vital capacity (%VC) was continuously measured from the first visit to the respiratory endpoint (REP). Cox proportional hazards model identified factors influencing the duration from onset of ALS to REP (Onset-REP). We performed Kaplan-Meier survival curve analysis for onset-REP according to identified factors.<br><br>RESULTS: Onset sites were the upper limb (U-ALS), lower limb (L-ALS), bulbar paralysis (B-ALS) and respiratory paralysis (R-ALS) in 37, 19, 32 and 12 patients, respectively. Duration from the onset of ALS to the onset of respiratory symptoms (Onset-Rp) and REP (Onset-REP) was 16.1 (SD 12.1) and 24.9 months (SD 14.6), respectively. Multivariate analysis revealed that age at onset, site of onset, Onset-Rp and %VC decline rate significantly influenced Onset-REP duration. Elderly patients had a significantly shorter Onset-REP duration. Onset-REP duration did not significantly differ between patients with U-ALS and L-ALS, but was longer in these patients than in those with B-ALS and R-ALS. Onset-REP duration was positively associated with Onset-Rp duration. The average monthly %VC decline rate was -5.6% (SD 3.3). Age at onset, onset site and Onset-Rp duration significantly influenced the %VC decline rate.<br><br>CONCLUSIONS: Our findings revealed strong and independent patient-specific factors that influence the Onset-REP duration and the %VC decline rate in patients with ALS. These could inform future clinical trials and interventions considering the respiratory function and natural history of patients with ALS.}, }
@article {pmid39720419, year = {2024}, author = {Haikal, C and Weissert, R}, title = {Editorial: Aging, peripheral inflammation, and neurodegeneration.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1529026}, pmid = {39720419}, issn = {1663-4365}, }
@article {pmid39719859, year = {2025}, author = {Koumasopoulos, E and Stanitsa, E and Angelopoulou, E and Koros, C and Barbarousi, V and Velonakis, G and Michaletou, C and Alevetsovitis, SK and Constantinides, VC and Kyrozis, A and Stefanis, L and Kroupis, C and Papageorgiou, SG}, title = {Heterozygous p62/SQSTM1 mutation and right temporal variant of frontotemporal dementia: Α case report.}, journal = {Neurocase}, volume = {31}, number = {2}, pages = {70-73}, doi = {10.1080/13554794.2024.2446315}, pmid = {39719859}, issn = {1465-3656}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology/physiopathology ; *Sequestosome-1 Protein/genetics ; *Mutation ; Male ; Heterozygote ; Middle Aged ; Female ; }, abstract = {Mutations in sequestosome 1 (SQSTM1) gene have been associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia - ALS (FTD-ALS), and very recently, progressive supranuclear palsy (PSP), paget disease of bone (PDB), distal myopathy with rimmed vacuoles (DMRV), and neurodegenerative disorders in childhood. We present a case of right temporal variant of FTD (rtvFTD) with heterozygous mutation (c.823_824del(p.Ser275Phefs *17)) in SQSTM1 gene.}, }
@article {pmid39719601, year = {2024}, author = {Kelani, KM and Hegazy, MA and Hassan, AM and Nadim, AH}, title = {Ecological multivariate assisted spectrophotometric methods for determination of antipyrine and benzocaine HCl in presence of antipyrine official impurity and benzocaine HCl degradant: toward greenness and whiteness.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {250}, pmid = {39719601}, issn = {2661-801X}, abstract = {A simple and green chemometrics-assisted spectrophotometric technique has beendeveloped and validated for the determination of antipyrine (ANT) and benzocaine HCl (BEN) along with the official impurity of ANT, antipyrine impurity A (ANT imp-A), and the degradation product of BEN, p-amino benzoic acid (PABA), in their quaternary mixture. Three models were developed and compared: partial least squares (PLS), artificial neural networks (ANN), and multivariate curve resolution-alternating least squares (MCR-ALS) where the four studied drugs were successfully quantified. The quantitative determination of the studied drugs was assessed using percentage recoveries, standard errors of prediction, and root mean square errors of prediction. The ANN model demonstrated the lowest error and the best correlation making it the most accurate method for analysis. The models were constructed in the ranges of 5.0-9.0 µg mL[-1] for ANT, 1.0-5.0 µg mL[-1] for BEN, 0.5-2.5 µg mL[-1] for ANT imp-A, and 0.25-1.25 µg mL[-1] for PABA. The established models successfully determined ANT, BEN, ANT imp-A, and PABA with detection limits of 0.312, 0.178, 0.093, and 0.042 µg mL[-1] for PLS, 0.185, 0.085, 0.001, and 0.034 µg mL[-1] for ANN; and 0.473, 0.240, 0.073, and 0.069 µg mL[-1] for MCR-ALS, respectively. The greenness and the whiteness of the proposed method were assessed using two green evaluating approaches: analytical Eco-scale, and AGREE, along with one white analytical chemistry evaluating tool, RGB. The three proposed models were successfully applied for determination of ANT and BEN in their pharmaceutically co-formulated dosage forms. They are also recommended for stability assays and purity testing of these drugs in quality control laboratories.}, }
@article {pmid39719207, year = {2025}, author = {Jirström, E and Matveeva, A and Baindoor, S and Donovan, P and Ma, Q and Morrissey, EP and Arijs, I and Boeckx, B and Lambrechts, D and Garcia-Munoz, A and Dillon, ET and Wynne, K and Ying, Z and Matallanas, D and Hogg, MC and Prehn, JHM}, title = {Effects of ALS-associated 5'tiRNA[Gly-GCC] on the transcriptomic and proteomic profile of primary neurons in vitro.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115128}, doi = {10.1016/j.expneurol.2024.115128}, pmid = {39719207}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; Mice ; *Neurons/metabolism ; *Transcriptome ; Cells, Cultured ; Mice, Transgenic ; Proteome/metabolism ; Proteomics ; Ribonuclease, Pancreatic/metabolism/genetics ; Humans ; Mice, Inbred C57BL ; RNA, Transfer/genetics/metabolism ; RNA, Small Untranslated/genetics ; }, abstract = {tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5'tiRNA[Gly-GCC], which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5'tiRNA[Gly-GCC] revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5'tiRNA[Gly-GCC] binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5'tiRNA[Gly-GCC] is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.}, }
@article {pmid39718981, year = {2024}, author = {Chen, JQA and McNamara, NB and Engelenburg, HJ and Jongejan, A and Wever, DD and Hopman, K and van Rixel, E and Nijhuis, PJH and de Winter, F and Moerland, PD and Smolders, J and Verhaagen, J and Hamann, J and Huitinga, I}, title = {Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae414}, pmid = {39718981}, issn = {1460-2156}, abstract = {Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies. To elucidate distinct molecular signatures underlying the potential to remyelinate, we stratified MS donors from the Netherlands Brain Bank cohort (n=239) based on proportions of remyelinated lesions (RLs) into efficiently remyelinating donors (ERDs; n=21) and poorly remyelinating donors (PRDs; n=19). We performed bulk RNA sequencing of RLs, active lesions with ramified and amoeboid microglia/macrophage morphology (ALs non-foamy), active lesions with foamy microglia/macrophage morphology (ALs foamy), and normal-appearing white matter (NAWM) from ERDs and PRDs. We found that ALs non-foamy were positively correlated with remyelination, whereas ALs foamy were not, indicating a role for microglia/macrophage state in influencing remyelination potential. Bioinformatics analyses were performed to identify key pathways and molecules implicated in the remyelination process. We found distinct differences between the donors with differing remyelination potential in comparable MS lesion types. RLs and ALs non-foamy of ERDs versus PRDs showed upregulation of epithelial-mesenchymal transition pathway, while in ALs foamy of PRDs, inflammation and damage-associated pathways (i.e. MTORC1 signaling, TNF signaling and oxidative phosphorylation) were upregulated compared to ALs foamy of ERDs, suggesting that these latter pathways may counteract remyelination. We found genes significantly upregulated in RLs and/or ALs non-foamy of ERDs that have previously been associated with remyelination, including CXCL12, EGF, HGF, IGF2, IL10, PDGFB, PPARG, and TREM2, illustrating the strength of our donor and lesion stratification. TGFB1, TGFB2, EGF, and IGF1 were determined as key upstream regulators of genes upregulated in RLs and ALs non-foamy of ERDs. We further identified potential novel pro-remyelinating molecules, such as BTC, GDF10, GDF15, CCN1, CCN4, FGF5, FGF10, and INHBB. Our study identified both known and novel genes associated with efficient remyelination that may facilitate the development of therapeutic strategies to promote tissue repair and clinical recovery in MS.}, }
@article {pmid39718871, year = {2025}, author = {Jiang, W and Hua, L and Chakraborty, S}, title = {Degenerate phase-matching for multi-wavelength nonlinear mixing in aperiodic lattice lasers.}, journal = {Optics letters}, volume = {50}, number = {1}, pages = {133-136}, doi = {10.1364/OL.544664}, pmid = {39718871}, issn = {1539-4794}, abstract = {Holographically designed aperiodic lattices (ALs) have proven to be an exciting engineering technique for achieving electrically switchable single- or multi-frequency emissions in terahertz (THz) semiconductor lasers. Here, we employ the nonlinear transfer matrix modeling method to investigate multi-wavelength nonlinear (sum- or difference-) frequency generation within an integrated THz (idler) laser cavity that also supports optical (pump and signal) waves. The laser cavity includes an aperiodic lattice, which engineers the idler photon lifetimes and effective refractive indices. The key findings are the following: (i) the nonlinear conversion efficiency reveals resonant enhancement at those idler frequencies where the photon lifetime is high; (ii) the resonant phase-matching (PM) process between the pump and idler waves has a one-to-one link with the engineered effective index dispersion; and (iii) in the absence of any other dispersion, the lowest threshold, multi-wavelength defect modes of the aperiodic lattice laser have degenerate phase-matched pump frequencies. This set of results will potentially have a significant impact on the wavelength multiplexing in electronically switchable THz-over-fiber communication systems [U.S. patent application 20,150,248,047A1 (3 September 2015)].}, }
@article {pmid39718201, year = {2025}, author = {}, title = {Correction to "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis" J. D. Berry , S. Paganoni , M. B. Harms , et al., "Access for ALL in ALS: A Large-Scale, Inclusive, Collaborative Consortium to Unlock the Molecular and Genetic Mechanisms of Amyotrophic Lateral Sclerosis," Muscle &amp; Nerve 70, no. 6 (2024): 1140-1150, https://doi.org/10.1002/mus.28244.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {2}, pages = {280}, doi = {10.1002/mus.28317}, pmid = {39718201}, issn = {1097-4598}, }
@article {pmid39717968, year = {2024}, author = {Vergini, DE and Hadjipavlou-Litina, D}, title = {"A patent review on arachidonic acid lipoxygenase (LOX) inhibitors for the treatment of neurodegenerative diseases (2018-present)".}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/13543776.2024.2447067}, pmid = {39717968}, issn = {1744-7674}, abstract = {INTRODUCTION: Neuroinflammation is correlated to neurodegenerative diseases like Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington Disease (HD), and Parkinson's disease (PD). A lot of recent research and patents are focused on the design and synthesis of arachidonic acid lipoxygenase (ALOX) inhibitors for the treatment of neurodegenerative diseases.<br><br>AREAS COVERED: The survey covers natural products, synthesis, hybrids, and assessments of biological effects in biological studies as ALOX inhibitors. A survey of patent publications from 2018 to present, taken from Google Scholar, Espanet, Web of Science, Drugbank, Scopus, or PubMed is analyzed.<br><br>EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability, and drug-likeness, the mechanism of action in different animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic method outbalance in the discovery and production of ALOX inhibitors with greater selectivity. Several ALOX inhibitors show promising results for the treatment of neurological disorders. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action and their bioavailability are well defined can be used as lead compounds for the treatment of neurodegenerative diseases.}, }
@article {pmid39717315, year = {2024}, author = {Alhayali, M}, title = {Concomitant Amyotrophic Lateral Sclerosis and Rheumatoid Arthritis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74301}, pmid = {39717315}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease that leads to a gradual loss of motor neurons manifesting as progressive weakness, dysarthria, and respiratory decline, with a relatively short life expectancy. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by polyarthritis and affects multiple systems. Motor neuron involvement is rare in rheumatoid arthritis. Here, we report a unique case of a patient with an established diagnosis of ALS who later developed seropositive RA. A 58-year-old male from Baghdad presented to our center with polyarticular joint pain, stiffness, and swelling for about four months, the patient had a history of progressive neurological deficits. The final diagnosis was seropositive rheumatoid arthritis with concomitant amyotrophic lateral sclerosis. While the patient's joint symptoms responded well to methotrexate and prednisolone, he continued to experience a neurological decline. This is one of the few reported cases of concurrent ALS and RA, highlighting the complexity of managing overlapping neurodegenerative and autoimmune conditions.}, }
@article {pmid39715603, year = {2024}, author = {Dibling, M and Ortholand, J and Salachas, F and Hesters, A and Tezenas du Montcel, S}, title = {Care Pathway Heterogeneity in Amyotrophic Lateral Sclerosis: Effects of Gender, Age, and Onset.}, journal = {Neuroepidemiology}, volume = {}, number = {}, pages = {1-14}, doi = {10.1159/000542300}, pmid = {39715603}, issn = {1423-0208}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration resulting in loss of muscle function. Care management is restricted to symptomatic and palliative strategies, while clinical manifestations are heterogeneous. However, assessing the timing and benefits of ALS major clinical interventions remains challenging, with varying and nonspecific time-to-events estimates reported in the literature. Consequently, we proposed a retrospective cohort study leveraging healthcare system data to investigate ALS patients care pathway stratified by gender, age class, and onset site to describe strategies diversity and temporality.<br><br>METHODS: We developed an algorithm to identify incident ALS patients in the French hospitalization registry and assessed its quality through comparison with literature. We described 7 states, encompassing patient status regarding clinical intervention history, considered 15 transitions, and stratified the analysis depending on 12 different patient profiles, defined according to gender, the presence of symptoms indicative of disease onset site, and age class, to model profile-specific care pathway trajectories. Alongside analysis of median time before transition, we compared acceleration factors resulting from accelerated failure time and time-inhomogeneous models.<br><br>RESULTS: We identified 21,153 incident patients with ALS between 2013 and 2022 with a mean age of 67.7&#xb1;13.1 years at time of in-registry detection, male/female and spinal/bulbar ratios of 1.2 and 1.9, respectively. Noninvasive ventilation (NIV), gastrostomy, tracheostomy, or death at hospital were recorded for 55.24% of the study population. We identified significant variations in utilization based on gender, age class, and onset site. Notably, older age and bulbar onset site accelerated gastrostomy use and spinal onset site was associated with delayed NIV initiation while tracheostomy, mainly considered for younger patients (<64 years), is rarely indicated in ALS care management. Alongside investigation of time-to-event speed, we report extensively the patient profile-specific estimated median delay before clinical event start.<br><br>CONCLUSION: Leveraging real-world data from hospital registries provides a large sample size to investigate low prevalence diseases. In conjunction with multistate models, such data enable a comprehensive analysis of care pathways, which revealed variations in ALS management strategies based on patient profiles. By identifying these disparities, our study contributes to enhancing the foreseeability of support strategies for ALS patients.}, }
@article {pmid39715100, year = {2025}, author = {Wu, Y and Tian, X and Ma, J and Lin, Y and Ye, J and Wang, Y and Lu, J and Yin, W}, title = {Label-free discrimination analysis of breast cancer tumor and adjacent tissues of patients after neoadjuvant treatment using Raman spectroscopy: a diagnostic study.}, journal = {International journal of surgery (London, England)}, volume = {111}, number = {2}, pages = {1788-1800}, doi = {10.1097/JS9.0000000000002201}, pmid = {39715100}, issn = {1743-9159}, mesh = {Humans ; *Spectrum Analysis, Raman ; Female ; *Breast Neoplasms/therapy/pathology ; *Neoadjuvant Therapy ; Middle Aged ; Adult ; Aged ; Support Vector Machine ; Mastectomy, Segmental ; }, abstract = {BACKGROUND AND OBJECTIVE: Breast-conserving surgery (BCS) plays a crucial role in breast cancer treatment, with a primary focus on ensuring cancer-free surgical margins, particularly for patients undergoing neoadjuvant treatment. After neoadjuvant treatment, tumor regression can complicate the differentiation between breast cancer tumor and adjacent tissues. Raman spectroscopy, as a rapid and non-invasive optical technique, offers the advantage of providing detailed biochemical information and molecular signatures of internal molecular components in tissue samples. Despite its potential, there is currently no research on using label-free Raman spectroscopy to distinguish between breast cancer tumors and adjacent tissues after neoadjuvant treatment. This study intends to distinguish between tumor and adjacent tissues after neoadjuvant treatment in breast cancer through label-free Raman spectroscopy.<br><br>METHODS: In this study, the intraoperative frozen samples of breast cancer tumor and adjacent tissue were collected from patients who underwent neoadjuvant treatment during surgery. The samples were examined using Raman confocal microscopy, and Raman spectra were collected by LabSpec6 software. Spectra were preprocessed by Savitz-Golay filter, adaptive iterative reweighted penalized least squares and MinMax normalization method. The differences in Raman spectra between breast cancer tumor and adjacent tissues after neoadjuvant treatment were analyzed by Wilcoxon rank-sum test, with a Bonferroni correction for multiple comparisons. Based on the support vector machine (SVM) method in machine learning, a predictive model for classification was established in the total group and subgroups of different hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and Ki-67 expression level. The independent test set was used to evaluate the performance of the model, and the area under curve (AUC) of the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy of different models were obtained.<br><br>RESULT: This study comprised 4260 Raman spectra of breast cancer tumor and adjacent frozen tissue samples from 142 breast cancer patients treated with neoadjuvant treatment. The Raman peaks associated with nucleotides and their metabolites in the Raman spectra of breast cancer tumor tissues were higher in intensities than those of adjacent tissues after neoadjuvant therapy (676 cm -1 : Bonferroni adjusted P <&#xa0;0.0001; 724 cm -1 : P <&#xa0;0.0001; 754 cm -1 : P <&#xa0;0.0001), and the Raman peaks from amide III bands were more intense (1271 cm -1 : P <&#xa0;0.01). Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectra revealed reduced lipid content and increased collagen and nucleic acid content in breast cancer tumor tissues compared to adjacent tissues following neoadjuvant therapy. The predictive model based on the Raman spectral signature of breast cancer tumor and adjacent tissues after neoadjuvant treatment achieved an AUC of 0.98, with accuracy, sensitivity, and specificity values of 0.89, 0.97, and 0.83, respectively. The AUC of subgroup analysis according to different status of molecular pathological biomarkers was stably around 99%.<br><br>CONCLUSION: This study demonstrated that label-free Raman spectroscopy can differentiate tumor and adjacent tissues of breast cancer patients treated with neoadjuvant therapy thorough getting the panoramic perspective of the biochemical compounds for the first time. Our study provided a novel technique for determining the margin status in BCS in breast cancer following neoadjuvant treatment rapidly and precisely.}, }
@article {pmid39715090, year = {2025}, author = {Huggon, L and Clayton, EL}, title = {Beginning from the end: the presynaptic terminal as a pathomechanism hub in frontotemporal dementia and amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3217-3218}, pmid = {39715090}, issn = {1673-5374}, }
@article {pmid39714593, year = {2024}, author = {Eldeeb, MA and Hohman, G and Shahid, M}, title = {Novel Approaches in Targeting Cell Surface and Secreted Proteins for Lysosomal Degradation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400887}, doi = {10.1002/cbic.202400887}, pmid = {39714593}, issn = {1439-7633}, abstract = {Protein degradation is pivotal for all biochemical aspects of cellular function. In mammalian cells, protein degradation is mediated mainly by the ubiquitin proteasome system (UPS) and the autophagic-lysosomal system (ALS). Over the last two decades, different types of targeted protein degradation approaches have been developed including proteolysis targeting chimeras (PROTACs) and lysosome targeting chimeras (LYTACs), which employ the UPS to degrade intracellular proteins and the ALS to degrade extracellular and membrane proteins respectively. Nevertheless, Current targeted membrane protein degradation approaches face some inherent challenges including limited target protein degradation efficacy and cell type specific applicability. Herein, we highlight some recent developments of novel targeted membrane protein degradation modalities that exhibit wide-applicability and high protein degradation efficiency. These novel membrane protein degraders hold tremendous promise as new pharmacological and biochemical tools in targeting membrane and secretory proteins for lysosomal degradation.}, }
@article {pmid39713159, year = {2024}, author = {Wang, YB and Jin, CZ}, title = {Roles of traditional Chinese medicine extracts in hyperuricemia and gout treatment: Mechanisms and clinical applications.}, journal = {World journal of gastroenterology}, volume = {30}, number = {47}, pages = {5076-5080}, pmid = {39713159}, issn = {2219-2840}, mesh = {*Hyperuricemia/drug therapy/blood ; Humans ; *Gout/drug therapy ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Uric Acid/blood/metabolism ; Gout Suppressants/therapeutic use ; Animals ; }, abstract = {In this manuscript, we comment on the article by Liu et al published in the recent issue of the journal. Hyperuricemia (HUA) has become the second most common metabolic disease after type 2 diabetes mellitus and is the most important risk factor for gout. This discussion focuses on the targets and clinical application value of traditional Chinese medicine (TCM) extracts in the treatment of HUA and gout, emphasizing the role of gut microbiota. Liu et al's study demonstrated that Poecilobdella manillensis protein extract alleviated HUA through multiple mechanisms, including inhibition of uric acid (UA) reabsorption, promotion of UA excretion, repair of intestinal barrier function, and regulation of gut microbiota and metabolome. Unlike the commonly used urate-lowering drugs such as allopurinol and febuxostat, which have clear and single targets, many TCMs have multi-target effects. However, the active components and mechanisms of TCMs are not fully understood, limiting their clinical application in the treatment of HUA and gout. Additionally, the role of gut microbiota in UA metabolic homeostasis needs to be further explored.}, }
@article {pmid39712644, year = {2024}, author = {Yusuf, IO and Camille, W and Thompson, PR and Xu, Z}, title = {Protein Citrullination in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.}, journal = {Journal of experimental neurology}, volume = {5}, number = {4}, pages = {183-191}, pmid = {39712644}, issn = {2692-2819}, support = {R01 NS118145/NS/NINDS NIH HHS/United States ; R35 GM118112/GM/NIGMS NIH HHS/United States ; }, abstract = {Protein citrullination (PC) is a posttranslational modification (PTM) that converts a peptidyl arginine into a peptidyl citrulline. Aberrant PC is a hallmark of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, prion disease, and multiple sclerosis. Common among these diseases is a dramatic increase of PC in reactive astrocytes. Some citrullinated proteins have been identified. The most prominent are astrocytic cytoskeletal proteins such as GFAP and vimentin, and myelin protein MBP. Recent investigation in ALS has revealed new changes, including a decreased PC in neurons and an association of PC with myelin protein aggregates. These findings suggest that PC contributes to protein aggregation, neuronal dysfunction, neuroinflammation, and axonal degeneration. However, how PC impact neurodegeneration remains to be understood. Further studies are needed to understand a range of questions, from how PC modulates individual protein functions to its impact on diseases. Because of the PC's robust changes in neurodegenerative diseases, there are also prospects that this PTM may be harnessed as biomarkers, and modulation of this PTM may be an avenue for therapy. In this review, we summarize the current understanding of PC in ALS and other neurodegenerative diseases, the investigative methods for PC, and PC's potential as a biomarker and a therapeutic target.}, }
@article {pmid39711523, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39711523}, issn = {2693-5015}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, }
@article {pmid39709547, year = {2024}, author = {Bakshi, B and Yerraguntla, S and Armon, C and Barkhaus, P and Bertorini, T and Bowser, R and Breevoort, S and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Fullam, T and Greene, M and Heiman-Patterson, T and Jackson, C and Jhooty, S and Mallon, E and Cadavid, JM and Mcdermott, CJ and Pattee, G and Pierce, K and Ratner, D and Sun, Y and Wang, O and Wicks, P and Wiedau, M and Bedlack, R}, title = {ALSUntangled #77: Psilocybin.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2441274}, pmid = {39709547}, issn = {2167-9223}, abstract = {ALSUntangled reviews alternate and off-label treatments prompted by patient interest. Here, we review psilocybin, a chemical derived from mushrooms and belonging in the category of drugs known as psychedelics. Psilocybin has plausible mechanisms for slowing ALS progression because of its ability to cross the blood brain barrier and effect neurogenesis and inflammation. Currently, there are no pre-clinical ALS models, case reports, or trials for psilocybin and ALS in the context of disease modifying therapy. Depending on dosing, there can be a high risk of psychological side effects including hallucinations and physical harm. Based on the above information, we do not currently support the use of psilocybin as a means to slow ALS progression.}, }
@article {pmid39709476, year = {2024}, author = {Udine, E and Finch, NA and DeJesus-Hernandez, M and Jackson, JL and Baker, MC and Saravanaperumal, SA and Wieben, E and Ebbert, MTW and Shah, J and Petrucelli, L and Rademakers, R and Oskarsson, B and van Blitterswijk, M}, title = {Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {99}, pmid = {39709476}, issn = {1750-1326}, support = {ALS Association//ALS Association/ ; R21 NS099631/NS/NINDS NIH HHS/United States ; Muscular Dystrophy Association//Muscular Dystrophy Association/ ; P01 NS084974/NS/NINDS NIH HHS/United States ; Robert Packard Center for ALS Research, Johns Hopkins University//Robert Packard Center for ALS Research, Johns Hopkins University/ ; RF1 NS123052/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *DNA Repeat Expansion/genetics ; *DNA Methylation/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; Aged ; Frontotemporal Dementia/genetics ; Sequence Analysis, DNA/methods ; }, abstract = {BACKGROUND: The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.<br><br>METHODS: We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method. Our primary goal was to determine the presence and subsequent quantification of observed methylation in the C9orf72 repeat expansion. In addition, we measured the repeat length and purity of the expansion. To do this, we sequenced DNA extracted from blood for 27 individuals with an expanded C9orf72 repeat.<br><br>RESULTS: For these individuals, we obtained a total of 7,765 on-target reads, including 1,612 fully covering the expanded allele. Our in-depth analysis revealed that the expansion itself is methylated, with great variability in total methylation levels observed, as represented by the proportion of methylated CpGs (13 to 66%). Interestingly, we demonstrated that the expanded allele is more highly methylated than the wild-type allele (P-Value&#x2009;=&#x2009;2.76E-05) and that increased methylation levels are observed in longer repeat expansions (P-Value&#x2009;=&#x2009;1.18E-04). Furthermore, methylation levels correlate with age at collection (P-Value&#x2009;=&#x2009;3.25E-04) as well as age at disease onset (P-Value&#x2009;=&#x2009;0.020). Additionally, we detected repeat lengths up to 4,088 repeats (~&#x2009;25&#xa0;kb) and found that the expansion contains few interruptions in the blood.<br><br>CONCLUSIONS: Taken together, our study demonstrates robust ability to quantify methylation of the expanded C9orf72 repeat, capturing differences between individuals harboring this expansion and revealing clinical associations.}, }
@article {pmid39709457, year = {2024}, author = {Keeley, O and Mendoza, E and Menon, D and Coyne, AN}, title = {CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {199}, pmid = {39709457}, issn = {2051-5960}, support = {R00 NS123242/NS/NINDS NIH HHS/United States ; R01 NS132836/NS/NINDS NIH HHS/United States ; R00NS123242//National Institute of Aging/ ; R01NS132836/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; *Nuclear Pore/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Endosomal Sorting Complexes Required for Transport/metabolism/genetics ; Neurons/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent "activation" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.}, }
@article {pmid39708835, year = {2024}, author = {Davalos, L and Kushlaf, H}, title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.}, journal = {Seminars in respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2463-3385}, pmid = {39708835}, issn = {1098-9048}, abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.}, }
@article {pmid39707523, year = {2024}, author = {Straczkiewicz, M and Burke, KM and Calcagno, N and Premasiri, A and Vieira, FG and Onnela, JP and Berry, JD}, title = {Free-living monitoring of ALS progression in upper limbs using wearable accelerometers.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {223}, pmid = {39707523}, issn = {1743-0003}, mesh = {*Upper Extremity/physiopathology ; Disease Progression ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; *Monitoring, Ambulatory/instrumentation/methods ; Accelerometry/instrumentation/methods ; *Wearable Electronic Devices ; *Motor Activity/physiology ; Sensitivity and Specificity ; Humans ; Male ; Female ; Young Adult ; Adult ; Middle Aged ; Aged ; Self Report ; }, abstract = {BACKGROUND: Wearable technology offers objective and remote quantification of disease progression in neurological diseases such as amyotrophic lateral sclerosis (ALS). Large population studies are needed to determine generalization and reproducibility of findings from pilot studies.<br><br>METHODS: A large cohort of patients with ALS (N&#x2009;=&#x2009;202) wore wearable accelerometers on their dominant and non-dominant wrists for a week every two to four weeks and self-entered the ALS Functional Rating Scale-Revised (ALSFRS-RSE) in similar time intervals. Wearable device data were processed to quantify digital biomarkers on four upper limb movements: flexion, extension, supination, and pronation using previously developed and validated open-source methodology. In this study, we determined the association between digital biomarkers and disease progression, studied the impact of study design in terms of required sensor wear-time and sensor position, and determined the impact of self-reported disease onset location on upper limb movements.<br><br>RESULTS: The main investigation considered data from a sensor placed on the non-dominant wrist. Participants with higher ALSFRS-RSE scores performed more frequent and faster upper limb movements compared to participants with more advanced disease status. Digital biomarkers exhibited statistically significant change over time while their rate of change was more profound compared to survey responses. Using data from the dominant wrist and changing data inclusion criteria did not alter our findings. ALS disease onset location significantly impacted use of upper limbs. Results presented here were comparable to an earlier study on twenty patients with ALS.<br><br>DISCUSSION: Digital health technologies provide sensitive and objective means to quantify ALS disease progression. Interpretable approaches, such as the one used in this paper, can improve patient evaluation and hasten therapeutic development.}, }
@article {pmid39706636, year = {2025}, author = {Benatar, M and Robertson, J and Andersen, PM}, title = {Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {77-86}, doi = {10.1016/S1474-4422(24)00479-4}, pmid = {39706636}, issn = {1474-4465}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/prevention &amp; control ; Disease Models, Animal ; Genetic Therapy/methods ; *Superoxide Dismutase-1/genetics ; }, abstract = {Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.}, }
@article {pmid39706627, year = {2025}, author = {Andersen, PM and Benatar, M}, title = {Patrikios syndrome and SOD1 ALS.}, journal = {The Lancet. Neurology}, volume = {24}, number = {1}, pages = {27}, doi = {10.1016/S1474-4422(24)00491-5}, pmid = {39706627}, issn = {1474-4465}, }
@article {pmid39706377, year = {2025}, author = {Rush, CL and Lyons, C and Gittle, J and Seward, M and Scalia, J and Ho, D and Babu, S and Garret, MA and Brizzi, K and Berry, JD and Fava, M and Lindenberger, E and Vranceanu, AM and , }, title = {Clinician Perspectives Highlight the Need for Early Dyadic Coping Skills for People Living With Amyotrophic Lateral Sclerosis.}, journal = {Journal of pain and symptom management}, volume = {69}, number = {3}, pages = {236-242.e4}, doi = {10.1016/j.jpainsymman.2024.12.010}, pmid = {39706377}, issn = {1873-6513}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Adaptation, Psychological ; Male ; Female ; *Caregivers/psychology ; *Focus Groups ; Psychological Distress ; Middle Aged ; Interviews as Topic ; Attitude of Health Personnel ; Adult ; Qualitative Research ; Coping Skills ; }, abstract = {CONTEXT: A diagnosis of ALS can be challenging, and many people find ways to adapt. At the same time, emotional distress can arise early after an ALS diagnosis even when high quality multidisciplinary care is provided. When emotional distress occurs, it can become chronic over time, and can affect both the person living with ALS and their care-partner (together called a dyad).<br><br>OBJECTIVES: We set out to understand ALS multidisciplinary clinicians' perception of the challenges experienced by people with ALS and care-partners who experience emotional distress after diagnosis and potential benefits of a coping skills program to help these patients and their care-partners, Resilient Together-ALS (RT-ALS).<br><br>METHODS: We conducted semi-structured focus groups and individual interviews with 17 clinicians at the Sean M. Healey &amp; AMG Center for ALS at MGH (N = 2 focus groups and five interviews) to elicit feedback on four domains: 1) Psychosocial Needs of ALS Dyads seen in the clinic; 2) Clinic Flow and Referral System to RT-ALS; 3) Clinic Partnership Approach in Support of RT-ALS; 4) RT-ALS Program Content and Manual Format. We conducted rapid data analyses for a time-efficient hybrid inductive-deductive thematic approach.<br><br>RESULTS: Clinicians noted that dyadic distress (distress experienced by both patient and their care-partner individually and as a unit), though not universal, is often present early after diagnosis. The response to the proposed program content (dyadic and individual coping skills) and structure (6 weekly virtual sessions delivered within about 2 months after diagnosis) was positive. Multidisciplinary clinicians emphasized the importance of a skills-based program for dyads experiencing elevated early emotional distress for which referral can be easily integrated within clinic flow so as not to not increase provider and dyad burden.<br><br>CONCLUSION: RT-ALS program content and structure is acceptable to clinicians. It is imperative to next seek further input from dyads about whether this type of program would be of interest and if yes, to pilot and refine the program for feasibility testing and then efficacy.}, }
@article {pmid39706179, year = {2025}, author = {Setsu, S and Morimoto, S and Nakamura, S and Ozawa, F and Utami, KH and Nishiyama, A and Suzuki, N and Aoki, M and Takeshita, Y and Tomari, Y and Okano, H}, title = {Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging.}, journal = {Stem cell reports}, volume = {20}, number = {1}, pages = {102377}, pmid = {39706179}, issn = {2213-6711}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *Motor Neurons/metabolism/cytology ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Single-Cell Analysis/methods ; *Cell Differentiation ; Machine Learning ; Cells, Cultured ; }, abstract = {This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.}, }
@article {pmid39705668, year = {2024}, author = {Khandia, R and Gurjar, P and Priyanka,  and Romashchenko, V and Al-Hussain, SA and Zaki, MEA}, title = {Recent advances in stem cell therapy: efficacy, ethics, safety concerns, and future directions focusing on neurodegenerative disorders - a review.}, journal = {International journal of surgery (London, England)}, volume = {110}, number = {10}, pages = {6367-6381}, pmid = {39705668}, issn = {1743-9159}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegeneration refers to the gradual loss of neurons and extensive changes in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behavior. Common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxia (SCA), and supranuclear palsy. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2',3'-cyclic nucleotide 3'-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein (MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF), and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and amyloid beta (Aβ) production has been observed in Alzheimer's patients. A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.}, }
@article {pmid39705453, year = {2024}, author = {Jeong, J and Song, KJ and Lee, JC and Shin, SD and Kim, YJ}, title = {Optimal wearable camera mount locations for medical supervision during simulated out-of-hospital cardiopulmonary resuscitation.}, journal = {Medicine}, volume = {103}, number = {51}, pages = {e40973}, pmid = {39705453}, issn = {1536-5964}, support = {2020R1F1A1076561//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Cardiopulmonary Resuscitation/instrumentation/methods ; Prospective Studies ; *Video Recording ; *Out-of-Hospital Cardiac Arrest/therapy ; *Wearable Electronic Devices ; Male ; Female ; Emergency Medical Technicians/education ; Emergency Medical Services/methods ; Adult ; Simulation Training/methods ; }, abstract = {The quality of the visual information transmitted from a scene is crucial for effective medical supervision in prehospital settings. This study investigated the influence of wearable camera mount locations on visibility during simulated out-of-hospital cardiopulmonary resuscitation. A prospective, observational, non-randomized simulation study was conducted to replicate a cardiac arrest scenario adhering to an advanced life support (ALS) protocol. Seven advanced emergency medical technicians (AEMTs) participated, and 5 camera mount locations were tested: the sternum, forehead, lateral side of the eyelid, mid-nasal, and glabella. Video recordings were captured from the Airway, Intravenous (IV), and Leading providers. Five experienced medical directors independently evaluated visibility scores (1-5) for each procedure with optimal visibility defined as a score of 4 to 5. Glabella mount demonstrated the highest median visibility score and interquartile range (5 [4-5]) and proportion of optimal visibility (77.5%) for most procedures across provider positions. Mixed models revealed significant estimates for the lateral side of the eyelid, mid-nasal, and glabella mounts compared to the sternum, with glabella having the largest effect size (estimate = 1.62). Generalized linear mixed models showed that the glabella mount had the highest odds ratio (OR = 8.07, 95% confidence interval [CI]: 3.01-21.6) to achieve optimal visibility. Wearable camera mount location significantly affected visibility during simulated resuscitation. Mounting cameras closer to eye level provided the most accurate visual data. Further research using objective measures, such as artificial intelligence, and evaluating the visibility of wearable cameras in real-world situations is warranted to optimize simulation-based training for prehospital care.}, }
@article {pmid39705326, year = {2025}, author = {}, title = {Correction to Supporting Information for Le et al., Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {2}, pages = {e2424914121}, doi = {10.1073/pnas.2424914121}, pmid = {39705326}, issn = {1091-6490}, }
@article {pmid39705260, year = {2024}, author = {Lima, TBWE and Fonseca, JDMD and Silva, AAMD and Vieira, RGDS and Montemezzo, D and Otto-Yáñez, M and Torres-Castro, R and Júnior, METD and Resqueti, VR and Fregonezi, GAF}, title = {Methods to normalize surface electromyography in respiratory muscles: Is it similar between amyotrophic lateral sclerosis and healthy people?.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0315846}, pmid = {39705260}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Electromyography/methods ; Male ; Female ; *Respiratory Muscles/physiopathology ; Middle Aged ; Adult ; Cross-Sectional Studies ; Aged ; Case-Control Studies ; Isometric Contraction/physiology ; }, abstract = {The normalization process is important to determine the best approach for normalizing electromyographic signals from respiratory muscles in healthy subjects and those with ALS. The aim of this study is to compare different methods of normalizing the sEMG signal of respiratory muscles in both healthy subjects and those with Amyotrophic Lateral Sclerosis (ALS). This cross-sectional study was conducted in 67 subjects (50 healthy and 17 with ALS). The electrical activity of the sternocleidomastoid (SCM), scalene (ESC), diaphragm (DIA), parasternal (PS), external intercostal (EI), external oblique (EO), and rectus abdominal (RA) muscles were analyzed during maximal inspiratory pressure maneuvers (MIP), maximal nasal inspiratory pressure (SNIP), maximal expiratory pressure (MEP), and maximal voluntary isometric contraction of SCM and ESC (MVICSCM/ESC) and RA (MVICRA) using surface electromyography (sEMG). In the healthy group, inspiratory and expiratory muscles displayed higher electrical activity during MVICSCM/ESC and MIVCRA maneuvers, respectively (p<0.05). In the ALS group, inspiratory muscle activity was higher during the SNIP maneuver, while expiratory muscles showed higher activity during MVICRA (p<0.05). Based on the findings, it can be concluded that the MVIC resulted in greater inspiratory muscle activity, being the ideal method of normalization for inspiratory and expiratory muscles in healthy subjects. In ALS patients, the SNIP maneuver resulted in greater inspiratory muscle activity, while MVIC resulted in greater muscle activity in expiratory muscles.}, }
@article {pmid39703667, year = {2024}, author = {Lewis, RD and Keilholz, AN and Smith, CL and Burd, EA and Nichols, NL}, title = {Spinal TNF-α receptor 1 is differentially required for phrenic long-term facilitation (pLTF) over the course of motor neuron death in adult rats.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1488951}, pmid = {39703667}, issn = {1664-042X}, support = {T32 OD011126/OD/NIH HHS/United States ; }, abstract = {INTRODUCTION: Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) result in selective respiratory (e.g., phrenic) motor neuron death and mimics aspects of motor neuron disease [(e.g., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)], such as breathing deficits. This rodent model allows us to study the impact motor neuron death has on the output of surviving phrenic motor neurons as well as the compensatory mechanisms that are recruited. Microglial density in the phrenic motor nucleus as well as cervical gene expression of markers associated with inflammation (e.g., tumor necrosis factor α; TNF-α) are increased following CTB-SAP-induced phrenic motor neuron death, and ketoprofen (nonsteroidal anti-inflammatory drug) delivery attenuated phrenic long-term facilitation (pLTF) in 7 day (d) CTB-SAP rats but enhanced pLTF in 28d CTB-SAP rats.<br><br>METHODS: Here, we worked to determine the impact of TNF-&#x3b1; in the phrenic motor nucleus by: 1) quantifying TNFR1 (a high affinity transmembrane receptor for TNF-&#x3b1;) expression; 2) investigating astrocytes (glial cells known to release TNF-&#x3b1;) by performing a morphological analysis in the phrenic motor nucleus; and 3) determining whether acute TNFR1 inhibition differentially affects phrenic plasticity over the course of CTB-SAP-induced motor neuron loss by delivering an inhibitor for TNF-&#x3b1; receptor 1 (sTNFR1i) in 7d and 28d male CTB-SAP and control rats.<br><br>RESULTS: Results revealed that TNFR1 expression was increased on phrenic motor neurons of 28d CTB-SAP rats (p < 0.05), and that astrocytes were increased and exhibited reactive morphology (consistent with an activated phenotype; p < 0.05) in the phrenic motor nucleus of CTB-SAP rats. Additionally, we found that pLTF was attenuated in 7d CTB-SAP rats but enhanced in 28d CTB-SAP rats (p < 0.05) following intrathecal sTNFR1i delivery.<br><br>CONCLUSION: This work suggests that we could harness TNFR1 as a potential therapeutic agent in CTB-SAP rats and patients with respiratory motor neuron disease by increasing compensatory plasticity in surviving neurons to improve phrenic motor neuron function and breathing as well as quality of life. Future studies will focus on microglial and astrocytic cytokine release, the role they play in the differential mechanisms of pLTF utilized by 7d and 28d CTB-SAP rats, and potential therapies that target them.}, }
@article {pmid39703459, year = {2024}, author = {Oliveira, D and Nishimura, AL}, title = {Editorial: Mechanisms of neurodegeneration in amyotrophic lateral sclerosis and related disorders.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1531449}, doi = {10.3389/fncel.2024.1531449}, pmid = {39703459}, issn = {1662-5102}, }
@article {pmid39703273, year = {2024}, author = {Solano, J and Eni, G and Viswanath, A and Enany, B}, title = {Successful Rescue of Ventricular Fibrillation Electrical Storm Secondary to Acute Myocardial Infarction in a Patient Presenting to a District General Hospital: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73959}, pmid = {39703273}, issn = {2168-8184}, abstract = {Ventricular arrhythmia is a critical and challenging cardiovascular complication of myocardial infarction (MI). An electrical storm (ES), characterised by three or more episodes of sustained ventricular arrhythmia within 24 hours, poses a significant life-threatening risk. Standard management includes advanced life support (ALS) protocols and specialised pharmacological interventions. We present the case of a 43-year-old female who presented to the emergency department (ED) following an out-of-hospital ventricular fibrillation (OOHVF) arrest, with the return of spontaneous circulation (ROSC) achieved after multiple defibrillation shocks. Electrocardiography (ECG) revealed anterior ST-segment elevation MI (STEMI) involving the left anterior descending (LAD) artery. During her ED stay, she experienced recurrent ventricular fibrillation (VF) arrests requiring repeated defibrillation, adrenaline, amiodarone, and thrombolysis with alteplase. She was subsequently intubated and transferred to a primary percutaneous coronary intervention (PPCI) centre with intensive care support. Angiography confirmed a 100% occlusion of the LAD, which was successfully treated with stenting. The patient was admitted to the intensive care unit (ICU) and later discharged with full neurological recovery, on secondary prevention and heart failure therapy, with follow-up planned. This case underscores the complexity of managing electrical storms in MI, particularly in non-PPCI centres. It emphasises the importance of thrombolysis as an early reperfusion strategy in STEMI, especially when PPCI is not immediately available.}, }
@article {pmid39703094, year = {2025}, author = {De Decker, M and Zelina, P and Moens, TG and Beckers, J and Contardo, M and Dittlau, KS and Van Schoor, E and Ronisz, A and Eggermont, K and Moisse, M and Chandran, S and Veldink, JH and Thal, DR and Van Den Bosch, L and Pasterkamp, RJ and Van Damme, P}, title = {C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {3}, pages = {803-816}, pmid = {39703094}, issn = {1460-2156}, support = {C1-C14-17-107//KU Leuven/ ; //Opening the Future Fund (KU Leuven)/ ; 150031//Agency for Innovation by Science and Technology/ ; //ALS Liga Belgi&#xeb;/ ; //National Lottery of Belgium/ ; //European E-Rare-3 project INTEGRALS/ ; //European E-Rare-3 project MAXOMOD/ ; //Stichting ALS Nederland/ ; //Vlaanderen/ ; 772376/ERC_/European Research Council/International ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Humans ; *Cilia/pathology/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mutation ; Animals ; Cells, Cultured ; Male ; Neuromuscular Junction/metabolism/pathology/genetics ; Female ; }, abstract = {Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.}, }
@article {pmid39702138, year = {2024}, author = {Chen, C and Meng, J and Cheng, K and Kang, C and Zhou, L and Guo, H and Zhu, X}, title = {Spatial and morphologic features of lenses with different axial lengths in cataract patients: a swept-source optical coherence tomography-based study.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {542}, pmid = {39702138}, issn = {1471-2415}, support = {82122017, 82271069, 81870642, 82371040, 81970780, 81470613 and 81670835//National Natural Science Foundation of China/ ; 23Y11909800 and 21S31904900//Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission/ ; SHDC12020111//Clinical Research Plan of Shanghai Shenkang Hospital Development Center/ ; shslczdzk01901//Shanghai Municipal Key Clinical Specialty Program/ ; }, mesh = {Humans ; *Tomography, Optical Coherence/methods ; Female ; Male ; *Cataract/pathology ; *Axial Length, Eye/pathology/diagnostic imaging ; Aged ; Middle Aged ; *Lens, Crystalline/diagnostic imaging/pathology ; Visual Acuity/physiology ; Myopia/physiopathology ; Retrospective Studies ; Aged, 80 and over ; Cataract Extraction ; }, abstract = {BACKGROUND: To investigate the spatial and morphologic features of lenses with different axial length (ALs) in cataract patients using swept-source optical coherence tomography (SS-OCT).<br><br>METHODS: Totally 105 eyes of 105 patients scheduled to have cataract surgery were included. Eyes were divided into the control (AL&#x2009;<&#x2009;24.5&#xa0;mm), moderate myopia (MM, 24.5&#x2009;&#x2264;&#x2009;AL&#x2009;<&#x2009;26&#xa0;mm) and high myopia (HM, AL&#x2009;&#x2265;&#x2009;26&#xa0;mm) groups. Spatial features including lens vault (LV) and iris-to-lens distance (ILD), and morphologic features including radii of curvature of anterior and posterior surface (Ra, Rp), lens diameter (LD) and lens thickness (LT) were measured in eight directions by SS-OCT.<br><br>RESULTS: Spatially, the HM group had larger LV and ILD than the control group (both P&#x2009;<&#x2009;.05). LV and ILD were negatively correlated with AL, respectively (LV: r&#xa0;=&#xa0;-.484, P&#x2009;<&#x2009;.0001; ILD: r&#xa0;=&#xa0;-.656, P&#x2009;<&#x2009;.0001). Morphologically, both MM and HM groups had greater Ra and Rp than the control group. Ra was positively correlated with AL (r&#x2009;=&#x2009;.622, P&#x2009;<&#x2009;.0001), while the relationship between Rp and AL was non-linear. Moreover, the MM and HM groups had larger LD than the control group (both P&#x2009;<&#x2009;.001). Anterior LT was thinner in the HM than in the MM group (P&#x2009;=&#x2009;.026), while posterior LT between these two groups was similar. When compared in eight directions, similar trends were seen in Ra, Rp and LD, and the HM group showed a greater difference in Ra between horizontal and vertical directions.<br><br>CONCLUSIONS: This SS-OCT-based study showed that longer axial length is associated with a flatter lens, which was mainly attributed to the increase of Ra and LD. Longitudinal studies would be necessary to establish a causal relationship and temporal progression.}, }
@article {pmid39701414, year = {2025}, author = {Tantoco, AM and Peterson, R and Corbin, B and Coyne, F and Herbst, B and Hunt, S and Levoy, E and Luttrell, H and Shanske, S and Sanyal, S and Dwyer-Matzky, K and Jenkins, AM}, title = {Pediatric to Adult Care Transition in the Hospital Context (PATCH) Tool: A Novel Tool to Assess Pediatric Institutional Guidelines for Inpatient Care of Adults.}, journal = {Academic pediatrics}, volume = {25}, number = {3}, pages = {102625}, doi = {10.1016/j.acap.2024.102625}, pmid = {39701414}, issn = {1876-2867}, mesh = {Humans ; *Transition to Adult Care/standards ; Adult ; *Hospitals, Pediatric ; *Practice Guidelines as Topic ; Reproducibility of Results ; Adolescent ; Chronic Disease/therapy ; Child ; }, abstract = {OBJECTIVE: The growing number of adults with childhood onset chronic conditions (COCC) is reflected in the increase of adult-aged admissions to pediatric institutions. Despite national bodies advising pediatric institutions to have a pediatric to adult health care transition (HCT) policy, little guidance is available on if or how to include inpatient care. We sought to create a framework-based Pediatric to Adult Transitional Care in the Hospital Context (PATCH) tool to assess how inpatient care of adults is addressed in pediatric institutional guidelines or policies (hereafter guidelines) as a first step towards informing future PATCH guideline development.<br><br>METHODS: We used convenience and snowball sampling to obtain 11 pediatric institutional guidelines. Combining the GotTransition&#xa0;core elements with Coller et al's inpatient transition conceptual model through iterative consensus building, we developed the PATCH tool. Interrater reliability was assessed by using mean percent agreement among raters. A three-phase content validity process utilizing existing guidelines refined the finalized tool.<br><br>RESULTS: The PATCH tool included 42 items within nine domains. There was a high degree of agreeability among reviewers, and qualitative analysis revealed no missing items. Twenty-five (59%) of our 42 PATCH tool items were present in at least one of the reviewed guidelines, with age being present in all.<br><br>CONCLUSIONS: We developed the PATCH tool as a guide for pediatric institutions regarding the care of adolescent and adult patients. The PATCH tool, embedded in multidisciplinary stakeholder discussion and patient- and system-specific knowledge, may help institutions incorporate HCT into processes for adolescent and adult patients with COCCs.}, }
@article {pmid39701395, year = {2025}, author = {Force, E and Alvarez, C and Fuentes, A and Maria, A and Bozzolan, F and Debernard, S}, title = {Diet influence on male sexual maturation through interplay between insulin signaling and juvenile hormone in insects.}, journal = {Insect biochemistry and molecular biology}, volume = {177}, number = {}, pages = {104252}, doi = {10.1016/j.ibmb.2024.104252}, pmid = {39701395}, issn = {1879-0240}, mesh = {Animals ; Male ; *Juvenile Hormones/metabolism ; *Moths/metabolism/growth &amp; development ; *Insulin/metabolism ; *Signal Transduction ; *Sexual Maturation ; *Diet ; Receptor, Insulin/metabolism/genetics ; Corpora Allata/metabolism ; }, abstract = {In animals, sexual maturation coincides with the development of sexual behaviors and reproductive system. These developmental events are influenced by diet and governed by endocrine signals. Here, for the first time in insects, we explored functional links between nutrition and juvenile hormone (JH) in the male reproductive physiology through the insulin signaling pathway (ISP) acting as a transducer of nutritional signals. We turned to the male moth Agrotis ipsilon for which sexual maturation, including accessory sex glands (ASGs) development concomitantly with antennal lobes (ALs) maturation for female sex pheromone processing and display of sexual behavior, is known to be JH- and diet-dependent. Indeed, a diet rich in sugars with sodium was previously shown to accelerate sexual maturation, which was achieved from the third day of adult life. In this study, we demonstrated that such a diet raised i) the expression of JH signaling actors (Methoprene-tolerant, Taiman, and Krüppel homolog 1) in ALs and ASGs, ii) the biosynthesis and circulating levels of JH, and iii) the expression of both insulin receptor (InR) and insulin-like peptides (ILPs) in corpora allata (CAs) and brain respectively. Insulin injection raised JH biosynthesis following increased HMG-CoA reductase expression in CAs; opposite effects were induced in InR-deficient males. Thus, we highlighted that promoting effects of a diet composed of sugars with sodium on male sexual maturation results from an early induction of ISP causing an increase in JH biosynthesis followed by a potentiation of JH actions on the development of ASGs and ALs in A. ipsilon.}, }
@article {pmid39700696, year = {2025}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Current evidence of arterial spin labeling in amyotrophic lateral sclerosis: A systematic review.}, journal = {Clinical neurology and neurosurgery}, volume = {249}, number = {}, pages = {108691}, doi = {10.1016/j.clineuro.2024.108691}, pmid = {39700696}, issn = {1872-6968}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/diagnosis ; Humans ; *Spin Labels ; *Cerebrovascular Circulation/physiology ; Brain/diagnostic imaging/blood supply/physiopathology ; Magnetic Resonance Imaging/methods ; }, abstract = {OBJECTIVE: This study aimed to evaluate the utility of arterial spin labeling (ASL) in assessing cerebral blood flow (CBF) changes in amyotrophic lateral sclerosis (ALS), and its potential as a biomarker for early diagnosis.<br><br>METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies that employed ASL to compare CBF between ALS patients and healthy controls were included.<br><br>RESULTS: Seven studies were included. A consistent finding across these studies was hypoperfusion in both the motor and non-motor regions, particularly in the frontotemporal cortex. Hypoperfusion in motor regions was correlated with functional impairment and was observed prior to structural changes, suggesting its potential as an early biomarker. There is limited evidence to suggest that monitoring changes in CBF patterns in the brain. Besides, limited findings showed initial hyperperfusion in regions not yet involved in the pathological process, and progressing hypoperfusion in regions with increasing pathological burden.<br><br>CONCLUSIONS: This review highlights the potential of ASL as a valuable tool for understanding the neurovascular dysfunction in ALS. Further research is required to validate its clinical utility for diagnosing ALS and monitoring disease progression.}, }
@article {pmid39698283, year = {2024}, author = {Kos, JA and Langiu, M and Hellyer, SD and Gregory, KJ}, title = {Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.}, journal = {ACS pharmacology &amp; translational science}, volume = {7}, number = {12}, pages = {3671-3690}, pmid = {39698283}, issn = {2575-9108}, abstract = {Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu5) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified. mGlu5 negative allosteric modulators (NAMs) are promising novel therapeutics for developmental, neuropsychiatric and neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, autism spectrum disorders, substance use disorders, stroke, anxiety and depression) and show promise in ameliorating adverse effects induced by other medications (e.g., L-dopa induced dyskinesia in Parkinson's Disease). However, despite preclinical success, mGlu5 NAMs are yet to reach the market due to poor safety and efficacy profiles in clinical trials. Herein, we review the physiology and signal transduction of mGlu5. We provide a comprehensive critique of therapeutic options with respect to mGlu5 inhibitors, spanning from orthosteric antagonists to NAMs. Finally, we address the challenges associated with drug development and highlight future directions to guide rational drug discovery of safe and effective novel therapeutics.}, }
@article {pmid39697625, year = {2024}, author = {Zhao, X and Huang, S}, title = {Plasma extracellular vesicle: a novel biomarker for neurodegenerative disease diagnosis.}, journal = {Extracellular vesicles and circulating nucleic acids}, volume = {5}, number = {3}, pages = {569-573}, pmid = {39697625}, issn = {2767-6641}, abstract = {Extracellular vesicles (EVs) are membrane-bound structures that carry proteins, lipids, RNA, and DNA, playing key roles in cell communication and material transport. Recent research highlights their potential as disease biomarkers due to their stability in bodily fluids. This study explores using tau and TDP-43 proteins in plasma EVs as diagnostic biomarkers for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Analyzing plasma EVs from clinical cohorts, the study found that the 3R/4R tau ratio and TDP-43 levels effectively differentiate between diagnostic groups with high accuracy. Notably, plasma EV biomarkers demonstrate higher diagnostic accuracy and stability compared to direct plasma testing, providing new insights and approaches for future research and clinical practice. Further research is needed to validate these biomarkers in diverse populations and to establish standardized protocols. Future studies should continue to explore the potential of EV biomarkers in a broader range of neurodegenerative diseases and delve deeper into the mechanisms of EV secretion and sorting to enhance their diagnostic utility.}, }
@article {pmid39697444, year = {2024}, author = {He, SY and Cai, WC and Su, WM and Duan, QQ and Jiang, Z and Yin, KF and Gu, XJ and Chen, YP and Cao, B}, title = {Quantifying the split-elbow sign: a comprehensive study in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1499668}, pmid = {39697444}, issn = {1664-2295}, abstract = {PURPOSE: The split-elbow sign (SES), characterized by preferential dysfunction of the biceps brachii compared to the triceps, is a clinical feature observed in amyotrophic lateral sclerosis (ALS). However, the quantified SES index has not been extensively investigated, and its role in diagnosing ALS remains unknown. Therefore, this study aimed to investigate the split-elbow index (SEI) derived from compound muscle action potential (CMAP), motor unit number index (MUNIX), and echo intensity (EI) in ALS.<br><br>METHODS: A cohort comprising 70 individuals diagnosed with ALS, along with 41 disease controls and 40 healthy controls, was recruited for the study. The SEI was calculated by dividing the recorded values of CMAP, MUNIX, and EI obtained over the biceps brachii by the corresponding value measured in the triceps, resulting in SEICMAP, SEIMUNIX, and SEIEI, respectively. Receiver operating characteristic (ROC) curves of the three methods were used for comparison. Statistical analyses were performed using SPSS V.26.0 and R software.<br><br>RESULTS: Both SEICMAP and SEIMUNIX exhibited significant reductions in ALS patients compared to that in controls (PSEICMAp &#x2009;<&#x2009;0.0001, PSEIMUNIX&#x2009;<&#x2009;0.0001), while SEIEI showed an elevation (P&#x2009;<&#x2009;0.0001). Furthermore, there was a notable decrease in SEIMUNIX values as the disease progressed (p&#x2009;<&#x2009;0.001). Moreover, ROC for SEIMUNIX exhibited superior diagnostic performance (AUC&#x2009;=&#x2009;0.846), and a comprehensive diagnostic approach combining SEICMAP, SEIMUNIX, and SEIEI resulted in AUC (0.90) on the ROC curve.<br><br>CONCLUSION: Our study suggested that SES has emerged as a significant clinical characteristic in ALS and indicated the potential of SES indicators as biomarkers for both diagnosis and assessment of disease progression in ALS.}, }
@article {pmid39696694, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Baulch, JE and Ng, DQ and Du, M and Johnston, KG and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {190}, pmid = {39696694}, issn = {2051-5960}, support = {R01 CA276212/CA/NCI NIH HHS/United States ; P30CA062203//National Institutes of Health (UC Irvine Comprehensive Cancer Center)/ ; P30 CA062203/CA/NCI NIH HHS/United States ; UL1TR001414//National Institutes of Health (UC Irvine and National Center for Advancing Translational Sciences, NCATS)/ ; UL1 TR001414/TR/NCATS NIH HHS/United States ; R01CA276212/NH/NIH HHS/United States ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Cognitive Dysfunction/etiology/metabolism ; *Cranial Irradiation/adverse effects ; Mice ; Male ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Neurodegenerative Diseases/radiotherapy ; Hippocampus/metabolism/radiation effects/drug effects ; Female ; }, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, }
@article {pmid39696212, year = {2024}, author = {Giusti, A and Pukrittayakamee, P and Wannarit, K and Thongchot, L and Janwanishstaporn, S and Nkhoma, K and Venkatapuram, S and Harding, R}, title = {How to deliver person-centred care for people living with heart failure: a multi stakeholder interview study with patients, caregivers and healthcare professionals in Thailand.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1570}, pmid = {39696212}, issn = {1472-6963}, support = {GHRU 16/136/54//National Institute of Health Research (NIHR) Global Health Research Unit on Health System Strengthening in Sub-Saharan Africa, King's College London/ ; GA-00937//Funds for Graduate Women (FfGW)/ ; }, mesh = {Humans ; *Heart Failure/therapy/psychology ; Thailand ; *Caregivers/psychology ; Male ; *Patient-Centered Care ; Cross-Sectional Studies ; Female ; Middle Aged ; *Qualitative Research ; *Health Personnel/psychology ; Aged ; Adult ; Interviews as Topic ; }, abstract = {CONTEXT: Heart failure has high, growing global prevalence, morbidity and mortality, and is a leading cause of death with serious health-related suffering in low- and middle-income countries. Person-centred care (PCC) is a critical component of high-quality healthcare and is particularly vital in the context of a serious illness such as heart failure. However, there are limited data exploring PCC in this population in low- and middle-income settings.<br><br>AIM: The aim of this study was to explore how clinical services could respond to the PCC needs of individuals living with heart failure in Thailand, with potential for adaptation in other settings. The specific objectives were (i) to understand the experiences and needs of persons living with heart failure, their caregivers and HCPs; (ii) to explore specific practical actions that can help deliver PCC for heart failure patients in this setting.<br><br>METHODS: Cross-sectional qualitative study. In depth, semi-structured interviews were conducted in Thailand with heart failure patients (n&#x2009;=&#x2009;14), their caregivers (n&#x2009;=&#x2009;10) and healthcare professionals (n&#x2009;=&#x2009;12). Framework analysis was conducted with deductive coding to populate an a priori coding frame based on Santana et al's PCC model (2018) and Giusti et al's systematic review (2020), with further inductive coding of novel findings to expand the frame. The study is reported in accordance with the consolidated criteria for reporting qualitative research guidelines (COREQ).<br><br>RESULTS: The findings reveal specific practice actions that deliver PCC for persons living with heart failure in Thailand, such as (i) compassionate communication by healthcare professionals; (ii) effective teamwork amongst multidisciplinary healthcare professionals; (iii) proactive responses to physical, psychosocial, relational and information needs of patients and caregivers; (iv) engaging patients and families in symptom management; (v) providing opportunities for patients to be cared for in the community; and (vi) responding to the social determinants of health, illness and healthcare access.<br><br>CONCLUSION: Person-centred healthcare systems must aim to address the social determinants of illness and place focus on community- and home-based care. Heart failure patients and caregivers must be supported to self-manage, including how to recognise symptoms and take appropriate action. Delivering PCC in such a way has the potential to improve outcomes for patients, enhance patients' sense of agency and experiences of care, improve health equity, and reduce hospital admissions, relieving pressure on the hospital system and reducing overall costs of care.}, }
@article {pmid39694549, year = {2024}, author = {Ma, YL and Qiu, T and Xu, XL and Wang, LX and Zhuang, PY}, title = {[Analysis of clinical characteristics of amyotrophic lateral sclerosis patients initially diagnosed with abnormal laryngeal function].}, journal = {Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery}, volume = {59}, number = {12}, pages = {1293-1298}, doi = {10.3760/cma.j.cn115330-20240630-00388}, pmid = {39694549}, issn = {1673-0860}, support = {82271155//National Natural Science Foundation of China/ ; 2020J011212//Fujian Provincial Natural Science Foundation/ ; }, mesh = {Humans ; Male ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Adult ; Larynx/physiopathology ; }, abstract = {Objective: To study the laryngeal functional characteristics of patients with amyotrophic lateral sclerosis (ALS)disease diagnosed at the voice clinic. Methods: A retrospective analysis(case series study) was conducted on the laryngeal functional characteristics of 7 patients [2 males, 5 females, age ranged from 43 to 76(60.85±13.18)]with motor neuron disease who visited the voice clinic and were ultimately diagnosed by neurologists. The data included laryngostroboscopy, fiberoptic endoscopic examination of swallowing(FEES), acoustic analysis and laryngeal electromyography(LEMG). Descriptive methods were used for analysis. Results: ①There were 2 males and 5 females, with an average age of (60.85±13.18) years. They had previously visited the otolaryngology department more than twice, visit frequency with an average of 3.57 and an average diagnosis time of 12.28 months. The main complaints of the patient at the time of treatment were voice change, dysphagia or vocal fatigue. ②LEMG: Among 7 cases, 4 cases demonstrated neurogenic damage, all of which were bilateral, and 3 cases showed normal findings on examination. Spontaneous potentials (SP) were present in three cases for more than 6 months, with the longest duration being 24 months. Three cases exhibited the coexistence of spontaneous potential and reinnervated motor unit potentials (MUPs), and two cases showed bundle tremor potential.③Laryngostroboscopy revealed bilateral vocal fold asymmetry and glottic insufficiency in 7 cases, and decreased vocal cord movement in 4 cases, and vocal cord atrophy in 5 cases. FEES showed that 7 patients presented with mild to severe swallowing dysfunction, 3 cases had soft palate insufficiency and mild to severe food residues in the epiglottic valley and pyriform fossa. 1 case showed leakage and 1 case showed aspiration. Conclusions: Patients presenting with initial symptoms of abnormal laryngeal function should be vigilant for the possibility of motor neuron disease, especially when laryngostroboscopy reveals abnormal vocal fold movement and swallowing dysfunction. LEMG examination reveals bilateral neurogenic damage, prolonged spontaneous potential, coexistence of spontaneous potential and reinnervated MUPs, and the appearance of bundle tremor potential, which is beneficial for early detection of motor neuron disease.}, }
@article {pmid39694468, year = {2025}, author = {Cornell, PY and Gadkari, G and Hua, CL and Smith, L and Johnson, A and Schwartz, L and Rahman, M and Thomas, KS}, title = {Risk of Hospitalization Among Assisted Living Residents Dually Enrolled in Medicare and Medicaid.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {2}, pages = {105421}, doi = {10.1016/j.jamda.2024.105421}, pmid = {39694468}, issn = {1538-9375}, mesh = {Humans ; United States ; *Hospitalization/statistics &amp; numerical data ; *Assisted Living Facilities ; Male ; Female ; Retrospective Studies ; Aged ; *Medicare ; *Medicaid/statistics &amp; numerical data ; Aged, 80 and over ; }, abstract = {OBJECTIVES: To examine how risk of hospitalization among assisted living (AL) residents differs by dual enrollment in Medicare and Medicaid and by the percent of dually enrolled individuals in an AL community.<br><br>DESIGN: Retrospective cohort study.<br><br>SETTING AND PARTICIPANTS: We used Medicare data from 2008 to 2018 and a national directory of licensed AL communities to identify Medicare beneficiaries with a change in their ZIP+4 code suggesting a new residence in an AL.<br><br>METHODS: We estimated linear regression models of hospitalization onto interactions of residents' dual enrollment status and categories of the AL community's percentage of dually enrolled residents. In the models, we adjusted for person-level clinical and demographic characteristics, year-fixed effects, and fixed effects for the AL residents' prior ZIP code.<br><br>RESULTS: Among 620,542 Medicare beneficiaries who moved to an AL community, the 1-year risk of hospitalization was higher for dually enrolled residents compared with Medicare-only residents. In adjusted models, dually enrolled residents in high-dual AL communities (>50% dually enrolled) had an 7.4% higher risk of hospital admission compared with dually enrolled residents in low-dual AL communities. Medicare-only beneficiaries in high-dual AL communities had a 9.4% higher risk of hospitalization than Medicare-only beneficiaries in low-dual ALs.<br><br>CONCLUSIONS AND IMPLICATIONS: The proportion of residents in an AL community who were dually enrolled was associated with residents' risk of hospitalization, regardless of their dual enrollment status. Additional research is needed to understand whether differences observed in residents' risk of hospitalization are due to differences in the types of services provided, unmeasured resident acuity, or the quality of care delivered in these settings.}, }
@article {pmid39693933, year = {2025}, author = {Taisei Ito,  and Ohuchi, K and Kurita, H and Murakami, T and Takizawa, S and Fujimaki, A and Murata, J and Oida, Y and Hozumi, I and Kitaichi, K and Inden, M}, title = {Neuroprotective effects of activated fibroblast growth factor receptor 1 via the suppression of p53 accumulation against poly-PR-mediated toxicity.}, journal = {Biochemical and biophysical research communications}, volume = {743}, number = {}, pages = {151181}, doi = {10.1016/j.bbrc.2024.151181}, pmid = {39693933}, issn = {1090-2104}, mesh = {*Tumor Suppressor Protein p53/metabolism/genetics ; *Receptor, Fibroblast Growth Factor, Type 1/metabolism/genetics/antagonists &amp; inhibitors ; Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-mdm2/metabolism/genetics ; Cell Survival/drug effects ; Motor Neurons/metabolism/drug effects ; Humans ; }, abstract = {A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. Nevertheless, there has been no previous report of its neuroprotective effects against poly-PR toxicity. The objective of this study was to investigate the neuroprotective effects of FGFR1 activation in poly-PR-expressing NSC34 motor neuron-like cells. RT-qPCR analysis in NSC34 cells showed that Fgfr1 was the most highly expressed member of the Fgfr family in NSC34 cells. The activation of FGFR1 by FGF2, a common ligand for all FGFRs, exerted neuroprotective effects against the toxicity of poly-PR. Additionally, FGFR1 activation was observed to enhance cell viability through the PI3K-AKT pathway, while the contribution of the MEK-ERK pathway was found to be limited. Furthermore, FGFR1 activation suppressed the accumulation of p53 protein and promoted its degradation through increased murine double minute 2 (MDM2), an E3 ubiquitin ligase that targets p53. The neuroprotective effects were attenuated by PD173074, a selective FGFR1 inhibitor or Nutlin-3a, an inhibitor of the p53-MDM2 interaction. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity. Consequently, this study suggests the potential utility of FGFR1 activation as a therapeutic strategy for ALS.}, }
@article {pmid39693632, year = {2024}, author = {Hausmann, F and Caldi Gomes, L and Hänzelmann, S and Khatri, R and Oller, S and Gebelin, M and Parvaz, M and Tzeplaeff, L and Pasetto, L and Zhou, Q and Zelina, P and Edbauer, D and Pasterkamp, RJ and Rehrauer, H and Schlapbach, R and Carapito, C and Bonetto, V and Bonn, S and Lingor, P}, title = {A dataset profiling the multiomic landscape of the prefrontal cortex in amyotrophic lateral sclerosis.}, journal = {GigaScience}, volume = {13}, number = {}, pages = {}, pmid = {39693632}, issn = {2047-217X}, support = {01GM1917A//Bundesministerium f&#xfc;r Bildung und Forschung/ ; CRC1192//DFG/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Prefrontal Cortex/metabolism/pathology ; Humans ; Female ; Mice ; Male ; Animals ; Mice, Transgenic ; Transcriptome ; Proteome ; Disease Models, Animal ; Aged ; Gene Expression Profiling/methods ; Middle Aged ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, which still lacks effective disease-modifying therapies. Similar to other neurodegenerative disorders, such as Alzheimer and Parkinson disease, ALS pathology is presumed to propagate over time, originating from the motor cortex and spreading to other cortical regions. Exploring early disease stages is crucial to understand the causative molecular changes underlying the pathology. For this, we sampled human postmortem prefrontal cortex (PFC) tissue from Brodmann area 6, an area that exhibits only moderate pathology at the time of death, and performed a multiomic analysis of 51 patients with sporadic ALS and 50 control subjects. To compare sporadic disease to genetic ALS, we additionally analyzed PFC tissue from 4 transgenic ALS mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS) using the same methods. This multiomic data resource includes transcriptome, small RNAome, and proteome data from female and male samples, aimed at elucidating early and sex-specific ALS mechanisms, biomarkers, and drug targets.}, }
@article {pmid39691755, year = {2025}, author = {Sood, A and Mishra, GV and Kar, P and Khandelwal, S and Gaur, S and Manuja, N}, title = {Amyotrophic lateral sclerosis in a tricenarian female.}, journal = {Radiology case reports}, volume = {20}, number = {2}, pages = {1121-1123}, pmid = {39691755}, issn = {1930-0433}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by the progressive degeneration of the upper and lower motor neurons. This disease is mostly observed in patients of the 6th decade or above, and it is extremely rare to observe this pathology in patients less than 50 years of age. This manuscript depicts the magnetic resonance imaging findings of ALS showing a wine glass sign in a 31-year-old female from a rural area with complaints of progressive limb weakness and muscle wasting.}, }
@article {pmid39691422, year = {2024}, author = {Fang, K}, title = {Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases.}, journal = {Ibrain}, volume = {10}, number = {4}, pages = {462-476}, pmid = {39691422}, issn = {2769-2795}, abstract = {The immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells. In addition to providing neuroprotection, these immune responses must be carefully balanced to prevent excessive inflammation that can lead to neuronal damage and contribute to neurodegenerative diseases. Dysregulated immune responses in the CNS are implicated in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Wnt signaling is a crucial pathway in the CNS that regulates various cellular processes critical for brain development, function, and maintenance. Despite enhancing immune responses in the health CNS, dysregulated Wnt signaling exacerbates neuroinflammation in the neurodegenerative brains. This review summarized the role of Wnt signaling in regulating immune response under different conditions. We then examined the role of immune response in healthy brains and during the development of neurodegenerative diseases. We also discussed therapeutic intervention in various neurodegenerative diseases through the modulation of the Wnt signaling pathway and neuroinflammation and highlighted challenges and limitations in current clinical trials.}, }
@article {pmid39690447, year = {2025}, author = {Koch, R and Nagoshi, E}, title = {Examining the potential involvement of NONO in TDP-43 proteinopathy in Drosophila.}, journal = {The European journal of neuroscience}, volume = {61}, number = {1}, pages = {e16632}, pmid = {39690447}, issn = {1460-9568}, support = {310030_189169//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung/ ; 310030_189169//The Swiss National Science Foundation/ ; }, mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; *TDP-43 Proteinopathies/metabolism/pathology/genetics ; *Drosophila Proteins/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Drosophila ; Neurons/metabolism ; Longevity ; Cell Nucleus/metabolism ; }, abstract = {The misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalise with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. Here, we demonstrate that pathological phenotypes caused by TDP-43 gain of function-locomotor defects and life span shortening-are exacerbated by silencing the Drosophila homolog of NONO, no on or off transient A (NonA). Additionally, NonA silencing results in an increase in nuclear TDP-43 NBs. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms.}, }
@article {pmid39690343, year = {2025}, author = {Lamichhane, S and Seo, JE and Jeong, JH and Lee, S and Lee, S}, title = {Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges.}, journal = {Archives of pharmacal research}, volume = {48}, number = {1}, pages = {62-88}, pmid = {39690343}, issn = {1976-3786}, support = {Research grant 2024//Chung-Ang University/ ; NRF-2016R1A6A1A03011325//Ministry of Education/ ; }, mesh = {Animals ; *Disease Models, Animal ; Humans ; *Nervous System Diseases/metabolism ; Translational Research, Biomedical/methods ; }, abstract = {Neurological disorders, encompassing conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pose a significant global health challenge, affecting millions worldwide. With an aging population and increased life expectancy, the prevalence of these disorders is escalating rapidly, leading to substantial economic burdens exceeding trillions of dollars annually. Animal models play a crucial role in understanding the underlying mechanisms of these disorders and developing effective treatments. Various species, including rodents, non-human primates, and fruit flies, are utilized to replicate specific aspects of human neurological conditions. However, selecting the ideal animal model requires careful consideration of its proximity to human disease conditions and its ability to mimic disease pathobiology and pharmacological responses. An Animal Model Quality Assessment (AMQA) tool has been developed to facilitate this selection process, focusing on assessing models based on their similarity to human conditions and disease pathobiology. Therefore, integrating intrinsic and extrinsic factors linked to the disease into the study's objectives aids in constructing a biological information matrix for comparing disease progression between the animal model and human disease. Ultimately, selecting an ideal animal disease model depends on its predictive, face, and construct validity, ensuring relevance and reliability in translational research efforts.}, }
@article {pmid39689069, year = {2024}, author = {Junedahl, E and Lundgren, P and Andersson, E and Gupta, V and Råmunddal, T and Rawshani, A and Rawshani, A and Riva, G and Arnetorp, I and Hessulf, F and Herlitz, J and Djärv, T}, title = {The evidence supporting AHA guidelines on adult cardiopulmonary resuscitation (CPR).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0309241}, pmid = {39689069}, issn = {1932-6203}, mesh = {Humans ; *Cardiopulmonary Resuscitation/standards/methods ; *American Heart Association ; Adult ; *Practice Guidelines as Topic ; United States ; *Heart Arrest/therapy ; Evidence-Based Medicine/standards ; }, abstract = {BACKGROUND: Guidelines for the management of cardiac arrest play a crucial role in guiding clinical decisions and care. We examined the strength and quality of evidence underlying these recommendations in order to elucidate strengths and gaps in knowledge.<br><br>METHODS: Using the 2020 American Heart Association (AHA) Guidelines for Adult CPR, we subdivided all recommendations into advanced life support (ALS), basic life support (BLS), and recovery after cardiac arrest, as well as a more granular categorization by topic (i.e. the intervention or evaluation recommended). The Class of Recommendation (COR) and Level of Evidence (LOE) for each were reviewed. Additionally, we reviewed the 2023 guidelines to ensure the inclusion of the most recent updates.<br><br>RESULTS: We noted 254 recommendations, of which 181 were ALS, 69 were BLS, and 4 were recovery after resuscitation. In total, only 2 (1%) had the most robust evidence (LOE A), while 23% were at LOE B-NR (Non-Randomized), 15% at LOE B-R (Randomized), 50% at LOE C-LD (Limited Data), and 12% relied on expert opinion LOE C-EO (Expert Opinion). Despite the strength of ALS recommendations (Class 1, 2a, or 2b), none had LOE A. In BLS, no recommendations were supported by LOE A. For BLS, 7% of recommendations had LOE C (C-LD or C-EO). The evidence for specific BLS topics, such as airway management, was notably low. Among ALS topics, neurological prognostication had relatively stronger evidence.<br><br>CONCLUSIONS: Only 26 out of the 81 COR 1 recommendations (32%) were supported by LOE A or B, indicating a strong discrepancy between the strength of recommendation and the underlying evidence in cardiac arrest guidelines. The findings underscore a pressing need for more rigorous research, particularly randomized trials.}, }
@article {pmid39688956, year = {2024}, author = {Spargo, TP and Gilchrist, L and Hunt, GP and Dobson, RJB and Proitsi, P and Al-Chalabi, A and Pain, O and Iacoangeli, A}, title = {Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39688956}, issn = {2050-084X}, support = {DRIVE-Health Centre for Doctoral Training//King's College London/ ; 772376-EScORIAL//Horizon 2020/ ; ES/L008238/1//Economic and Social Research Council/ ; 633413//Horizon 2020/ ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; 259867//European Community's Health Seventh Framework Programme/ ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; 10.35802/222811/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Genome-Wide Association Study ; Genetic Predisposition to Disease ; Mental Disorders/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Schizophrenia/genetics ; Genetic Loci ; Parkinson Disease/genetics ; Alzheimer Disease/genetics ; }, abstract = {Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant 'local' genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.}, }
@article {pmid39688717, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Mohammadi, S and Batouli, SAH}, title = {Involvement of the left uncinate fasciculus in the amyotrophic lateral sclerosis: an exploratory longitudinal multi-modal neuroimaging and neuropsychological study.}, journal = {Brain structure &amp; function}, volume = {230}, number = {1}, pages = {8}, pmid = {39688717}, issn = {1863-2661}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/physiopathology ; Female ; Male ; Middle Aged ; *Diffusion Tensor Imaging/methods ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Aged ; Neuropsychological Tests ; Adult ; Neural Pathways/diagnostic imaging/physiopathology/pathology ; White Matter/diagnostic imaging/pathology ; Neuroimaging/methods ; Multimodal Imaging ; }, abstract = {To investigate the microstructural integrity, tract volume analysis, and functional connectivity (FC) alterations of the left uncinate fasciculus (UF) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls (HCs). Fourteen limb-onset ALS patients were recruited at baseline and ten at follow-up, along with 14 HCs. All participants underwent 3D T1-weighted, diffusion tensor imaging and kurtosis imaging (DTI/DKI), and resting-state functional MRI (rs-fMRI) using a 3 Tesla scanner with 64-channel coils. Eight metrics of diffusion, rs-FC of the left UF, and graph theory analyses were extracted. Statistical group comparisons and correlation analysis for significant diffusion metrics were also conducted. Significantly lower radial kurtosis (RK), mean kurtosis (MK), and higher DTI diffusivity metrics were observed in the left UF of ALS patients than in HCs. RK and MK were correlated with various cognitive scores, particularly executive function and visuospatial ability. The volume of the left UF was positively correlated only with RK and MK at follow-up. While rs-FC analysis did not reveal group differences, a negative functional link between the left UF and cerebellum was observed in HCs but not in patients. Graph theory analysis suggested decreased connectivity in baseline patients and potential compensatory effects during the follow-up. Our study reveals microstructural abnormalities and potential network changes in left UF. DKI metrics, especially RK and MK, may be more sensitive biomarkers than DTI metrics, particularly longitudinally. Diffusion changes appear to precede volume and functional connectivity alterations, suggesting diffusion as a potential early biomarker.}, }
@article {pmid39688317, year = {2025}, author = {Tseriotis, VS and Eleftheriadou, K and Mavridis, T and Konstantis, G and Falkenburger, B and Arnaoutoglou, M}, title = {Is the Swallow Tail Sign a Useful Imaging Biomarker in Clinical Neurology? A Systematic Review.}, journal = {Movement disorders clinical practice}, volume = {12}, number = {2}, pages = {134-147}, pmid = {39688317}, issn = {2330-1619}, support = {//Hellenic Academic Libraries Link/ ; }, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Substantia Nigra/diagnostic imaging/pathology ; Parkinson Disease/diagnostic imaging/diagnosis/pathology ; Parkinsonian Disorders/diagnostic imaging ; Biomarkers/analysis ; }, abstract = {BACKGROUND: Loss of dorsolateral nigral hyperintensity (DNH) in iron-sensitive sequences of Magnetic Resonance Imaging (MRI), also described as "swallow tail sign" (STS) loss, has shown promising diagnostic value in Parkinson's Disease (PD) and Atypical Parkinsonian Syndromes (APS).<br><br>OBJECTIVE: To conduct a bibliometric analysis on substantia nigra MRI and a systematic review on the clinical utility of STS visual assessment on Susceptibility-Weighted Imaging in various clinical entities.<br><br>METHODS: VOSviewer's keyword co-occurrence network was employed using Web of Science (WOS). Complying with the PRISMA statement, we searched MEDLINE, WOS, SCOPUS, ProQuest and Google Scholar for peer-reviewed studies conducted in vivo, excluding quantitative imaging techniques.<br><br>RESULTS: DNH is a relatively novel parameter in substantia nigra MRI literature. Our SWI-focused review included 42 studies (3281 patients). Diagnostic accuracy of STS loss for PD/APS differentiation from controls and for Lewy Body Dementia differentiation from other dementias was 47.8-98.5% and 76-90%, respectively, with poorer capacity, however, in delineating PD from APS. STS evaluation in idiopathic REM sleep behavior disorder, a sign of prodromal PD, was typically concordant with nuclear scans, identifying subjects with high conversion risk. Iron deposition can affect STS in Multiple Sclerosis and STS loss in Amyotrophic Lateral Sclerosis is linked with multisystem degeneration, with poorer prognosis. In healthy individuals iron-induced microvessel changes are suspected for false positive results.<br><br>CONCLUSION: STS assessment exhibits potential in different settings, with a possibly intermediate role in the diagnostic work-up of various conditions. Its clinical utility should be explored further, through standardized MRI protocols on larger cohorts.}, }
@article {pmid39687363, year = {2024}, author = {Stal, C and Covătaru, C and De Wolf, Q and Ignat, T and Pecheniuk, D and Lazăr, C}, title = {Towards a spatial data repository for archaeological research in the Romanian Mostiștea Basin and Danube Valley.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {111119}, doi = {10.1016/j.dib.2024.111119}, pmid = {39687363}, issn = {2352-3409}, abstract = {Spatial data are crucial in archaeological research, where orthophotos, digital elevation models, and 3D models are widely used for mapping, documenting, and monitoring archaeological sites. The introduction of affordable and compact unmanned aerial vehicles (UAVs) has significantly advanced the use of UAV-based photogrammetry in the past 20 years. Recently, compact airborne systems have also enabled the capture of thermal, multispectral, and aerial laser scanning data. This paper presents the data acquired with different platforms and sensors at Chalcolithic archaeological sites in Romania's Mostiștea Basin and Danube Valley. Since laser scanning and photogrammetry generate large data volumes, data storage and dissemination must also be carefully considered. Based on a thorough study of system performance, data acquisition and processing methods, and data outputs, a workflow for the systematic mapping and documentation of sites has been proposed. Given the experience obtained in the last 5 summer campaigns (2018-2023), 19 sites have been accurately mapped, of which 5 sites are mapped using airborne laser scanning. 18 sites are documented using multispectral photogrammetry, and for 17 sites, interactive image-based 3D models are acquired using true-color photogrammetry. All data are stored on a publicly accessible website for visualization, as well as on an open-data platform for data exchange. For the multispectral data, a raster tile service has been implemented, allowing the use of the data in a GIS environment.}, }
@article {pmid39687198, year = {2024}, author = {Pappalardo, XG and Jansen, G and Amaradio, M and Costanza, J and Umeton, R and Guarino, F and De Pinto, V and Oliver, SG and Messina, A and Nicosia, G}, title = {Inferring gene regulatory networks of ALS from blood transcriptome profiles.}, journal = {Heliyon}, volume = {10}, number = {23}, pages = {e40696}, pmid = {39687198}, issn = {2405-8440}, abstract = {One of the most robust approaches to the prediction of causal driver genes of complex diseases is to apply reverse engineering methods to infer a gene regulatory network (GRN) from gene expression profiles (GEPs). In this work, we analysed 794 GEPs of 1117 human whole-blood samples from Amyotrophic Lateral Sclerosis (ALS) patients and healthy subjects reported in the GSE112681 dataset. GRNs for ALS and healthy individuals were reconstructed by ARACNe-AP (Algorithm for the Reconstruction of Accurate Cellular Networks - Adaptive Partitioning). In order to examine phenotypic differences in the ALS population surveyed, several datasets were built by arranging GEPs according to sex, spinal or bulbar onset, and survival time. The designed reverse engineering methodology identified a significant number of potential ALS-promoting mechanisms and putative transcriptional biomarkers that were previously unknown. In particular, the characterization of ALS phenotypic networks by pathway enrichment analysis has identified a gender-specific disease signature, namely network activation related to the radiation damage response, reported in the networks of bulbar and female ALS patients. Also, focusing on a smaller interaction network, we selected some hub genes to investigate their inferred pathological and healthy subnetworks. The inferred GRNs revealed the interconnection of the four selected hub genes (TP53, SOD1, ALS2, VDAC3) with p53-mediated pathways, suggesting the potential neurovascular response to ALS neuroinflammation. In addition to being well consistent with literature data, our results provide a novel integrated view of ALS transcriptional regulators, expanding information on the possible mechanisms underlying ALS and also offering important insights for diagnostic purposes and for developing possible therapies for a disease yet incurable.}, }
@article {pmid39686920, year = {2025}, author = {Sodagari, S and Sodagari, N}, title = {Examining vaccination-related adverse events in frequent neurodegenerative diseases.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {43}, number = {}, pages = {100902}, pmid = {39686920}, issn = {2666-3546}, abstract = {This study investigates adverse events following vaccination in patients with four neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Multiple Sclerosis (MS), and Parkinson's disease. We applied advanced data processing techniques to analyze symptom patterns and severity scores across these disease groups. Patients were identified through filtering, and symptom clusters were extracted to group similar symptoms into distinct clusters, and severity scores were computed based on hospitalization and death reports. A chi-squared test was performed to assess the statistical significance of adverse event distributions among the diseases for different vaccines. The results reveal that ALS patients exhibit severe respiratory symptoms post-vaccination, while Alzheimer's patients report significant respiratory and gastrointestinal issues. MS patients commonly experience general symptoms such as fatigue, while Parkinson's patients face exacerbated motor symptoms. Notably, our analysis showed no significant difference in adverse event reporting rates between COVID-19 and pneumococcal vaccines across these disease groups. This research provides new insights into disease-specific responses to vaccines, emphasizing the importance of personalized monitoring and treatment strategies to mitigate risks and improve clinical outcomes in these vulnerable populations.}, }
@article {pmid39684507, year = {2024}, author = {Tournezy, J and Léger, C and Klonjkowski, B and Gonzalez-Dunia, D and Szelechowski, M and Garenne, A and Mathis, S and Chevallier, S and Le Masson, G}, title = {The Neuroprotective Effect of the X Protein of Orthobornavirus Bornaense Type 1 in Amyotrophic Lateral Sclerosis.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684507}, issn = {1422-0067}, support = {Evaluation of the therapeutic potential of the Borna virus X protein and X-derived peptides in ALS//Association pour la recherche sur la Scl&#xe9;rose Lat&#xe9;rale Amyotrophique/ ; Award Fabrice Le Mouaher 2020//Fondation pour la Recherche M&#xe9;dicale/ ; trampoline grant 20219//Association Francaise contre les Myopathies/ ; X protein and ALS//Rotary Club of Bergerac/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Motor Neurons/metabolism/pathology ; Mice ; *Neuroprotective Agents/pharmacology ; *Disease Models, Animal ; Adenosine Triphosphate/metabolism ; Viral Proteins/metabolism/genetics ; Mice, Transgenic ; Humans ; }, abstract = {In amyotrophic lateral sclerosis (ALS), early mitochondrial dysfunction may contribute to progressive motor neuron loss. Remarkably, the ectopic expression of the Orthobornavirus bornaense type 1 (BoDV-1) X protein in mitochondria blocks apoptosis and protects neurons from degeneration. Therefore, this study examines the neuroprotective effects of X protein in an ALS mouse model. We first tested in vitro the effect of the X-derived peptide (PX3) on motoneurons primary cultures of SOD1[G93A] mice. The total intracellular adenosine triphosphate (ATP) content was measured after incubation of the peptide. We next tested in vivo the intramuscular injection of X protein using a canine viral vector (CAV2-X) and PX3 intranasal administrations in SOD1[G93A] mice. Disease onset and progression were assessed through rotarod performance, functional motor unit analysis via electrophysiology, and motor neuron survival by immunohistochemistry. The results showed that in vitro PX3 restored the ATP level in SOD1[G93A] motor neurons. In vivo, treated mice demonstrated better motor performance, preserved motor units, and higher motor neuron survival. Although life expectancy was not extended in this severe mouse model of motor neuron degeneration, the present findings clearly demonstrate the neuroprotective potential of X protein in a model of ALS. We are convinced that further studies may improve the therapeutic impact of X protein with optimized administration methods.}, }
@article {pmid39684324, year = {2024}, author = {Toader, C and Tataru, CP and Munteanu, O and Serban, M and Covache-Busuioc, RA and Ciurea, AV and Enyedi, M}, title = {Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684324}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/genetics ; *Parkinson Disease/therapy/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/therapy/genetics/metabolism ; Animals ; Neurodegenerative Diseases/therapy/metabolism/genetics ; Drug Delivery Systems ; Gene Editing ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.}, }
@article {pmid39684308, year = {2024}, author = {Ścibior, A and Llopis, J and Dobrakowski, PP and Męcik-Kronenberg, T}, title = {Magnesium (Mg) and Neurodegeneration: A Comprehensive Overview of Studies on Mg Levels in Biological Specimens in Humans Affected Some Neurodegenerative Disorders with an Update on Therapy and Clinical Trials Supplemented with Selected Animal Studies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684308}, issn = {1422-0067}, mesh = {Humans ; *Magnesium/therapeutic use ; Animals ; *Neurodegenerative Diseases/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Neuroprotective Agents/therapeutic use/pharmacology ; Parkinson Disease/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Neurodegenerative diseases, characterized by neuron loss, are a group of neurological disorders that adversely affect the lives of millions of people worldwide. Although several medicines have been approved for managing neurodegenerative diseases, new therapies allowing for a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Magnesium (Mg), a crucial mineral necessary for the functioning of organisms, is important to normal central nervous system (CNS) activity. Although the effects of this bioelement on the CNS are relatively well recognized, its role in the pathophysiology of neurological disorders in humans is not yet well characterized. Therefore, the main goal of this review is to collect data about a possible association between Mg and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's Disease (PD), and Amyotrophic lateral sclerosis (ALS) in humans. Hence, the levels of Mg in blood, cerebrospinal fluid (CSF), urine, and hair from subjects with AD, PD, and ALS are compiled to detect possible variations in the levels of this mineral in the biological specimens of people with neurodegenerative illnesses. Additionally, the findings from an animal model are summarized to offer the reader a deeper insight into studies on Mg in the context of neuroprotection and neurodegeneration. Data provided in the present review indicate that Mg, due to its neuroprotective, antioxidant, anti-inflammatory, and mitochondrial-supportive properties, could be a potential therapeutic agent for AD, PD, and ALS. However, more epidemiological studies with standardized methods of dietary assessment and Mg measurement are necessary to recognize its exact role in neurodegenerative disorders. Moreover, extensive well-designed clinical trials are also needed to establish definitive therapeutic protocols and optimal dosages, and to ensure long-term safety of this mineral supplementation in AD, PD, and ALS patients.}, }
@article {pmid39684197, year = {2024}, author = {García-González, N and Gonçalves-Sánchez, J and Gómez-Nieto, R and Gonçalves-Estella, JM and López, DE}, title = {Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {23}, pages = {}, pmid = {39684197}, issn = {1422-0067}, mesh = {Humans ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/therapy/genetics ; Animals ; Amyotrophic Lateral Sclerosis/therapy/genetics ; }, abstract = {This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.}, }
@article {pmid39682764, year = {2024}, author = {Huang, R and Xia, H and Lin, W and Wang, Z and Li, L and Deng, J and Ye, T and Li, Z and Yang, Y and Huang, Y}, title = {Riluzole Reverses Blood-Testis Barrier Loss to Rescue Chemotherapy-Induced Male Infertility by Binding to TRPC.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682764}, issn = {2073-4409}, support = {No. U22A20277, 32170865, and 82071634//National Natural Science Foundation of China/ ; No. 2022A1515012178//Natural Science Foundation of Guangdong Province/ ; No. 202103030003//Guangzhou Key R&amp;D Program/ ; No.2022B1111080007//Kea-Area Research and Development Program of Guangdong Province/ ; }, mesh = {Male ; *Riluzole/pharmacology/therapeutic use ; Animals ; *Blood-Testis Barrier/drug effects/metabolism ; *Infertility, Male/chemically induced/drug therapy/pathology ; Mice ; TRPC Cation Channels/metabolism ; Busulfan/pharmacology/adverse effects ; Antineoplastic Agents/pharmacology/adverse effects ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Protein Binding/drug effects ; }, abstract = {Cancer treatments, including cytotoxic therapy, often result in male infertility, necessitating the development of safe and effective strategies to preserve male reproductive potential during chemotherapy. Notably, our study uncovers the potential of repurposing riluzole, an FDA-approved drug for amyotrophic lateral sclerosis (ALS), in enhancing spermatogenesis. Hence, this research aims to explore the feasibility of utilizing riluzole to alleviate male infertility induced by busulfan (BSF), a commonly used chemotherapy drug. We established a BSF-induced oligospermia model in 4-week-old male mice and found that riluzole could effectively counter the detrimental effects of BSF on sperm production in mice with oligospermia. By restoring blood-testis barrier (BTB) functionality, riluzole improves sperm quality and reduces testicular atrophy. Through transcriptomic and molecular docking analyses, we identify transient receptor potential canonical subfamily member 5 (TRPC5) as a potential target for riluzole-mediated regulation of blood-testis barrier function. These findings propose riluzole as a promising therapeutic option for chemotherapy-induced male infertility, thereby addressing the fertility challenges associated with cancer treatments. Moreover, repurposing riluzole could streamline the drug development process, providing a cost-effective approach with reduced risk compared to developing entirely new drugs.}, }
@article {pmid39681722, year = {2025}, author = {Weiner, HL}, title = {Immune mechanisms and shared immune targets in neurodegenerative diseases.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {2}, pages = {67-85}, pmid = {39681722}, issn = {1759-4766}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/therapy ; Microglia/immunology ; Animals ; Immunotherapy/methods/trends ; Alzheimer Disease/immunology/therapy ; }, abstract = {The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.}, }
@article {pmid39681698, year = {2025}, author = {Aschemacher, NA and Siano, &#xc1;S and Teglia, CM and Goicoechea, HC}, title = {Development, optimization and comparison of solid-liquid and liquid-liquid microextraction for the determination of four flavonols in Schinus molle L. using high-performance liquid chromatography coupled with second-order data modeling.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {7}, pages = {1381-1392}, pmid = {39681698}, issn = {1618-2650}, support = {PICT 2020-0304//Fondo para la Investigaci&#xf3;n Cient&#xed;fica y Tecnol&#xf3;gica/ ; }, mesh = {Chromatography, High Pressure Liquid/methods ; *Liquid Phase Microextraction/methods ; Flavonols/analysis ; Solid Phase Microextraction/methods ; Limit of Detection ; Plant Extracts/chemistry ; Flavonoids/analysis/isolation &amp; purification ; Schinus ; }, abstract = {Flavonoids are particularly interesting because they have a broad spectrum of biological effects, including antioxidant and free radical scavenging activities. In this work, solid-liquid microextraction and dispersive liquid-liquid microextraction enhanced by ultrasound were developed and compared with the conventional method (Soxhlet extraction) to optimize the extraction of four flavonoids: rutin, quercitrin, quercetin, and myricetin in samples of Schinus molle (Aguaribay). During the development of the analytical method, different chemometric tools were used to optimize the microextraction procedure. In addition, an analytical method based on high-performance liquid chromatography with diode array detector (HPLC-DAD) and second order calibration using multivariate curve resolution-alternating least square (MCR-ALS) is presented to quantify the flavonoids with limits of quantification between 0.011 and 0.082 µg mL[-1]. Finally, solid-liquid microextraction using 4.00 mL water/ethanol (54.3:45.7%), 14 s vortex, and 45 min was selected as the most suitable method due to its high recovery rate and environmental friendliness (with a greenness score of 0.78). After the optimization step, the concentrations found in the plant samples were 1825.3, 632.6, 110.2, and 18.9 µg g[-1] for rutin, quercitrin, quercetin, and myricetin, respectively. The present work is the first achievement of simultaneously determining these four analytes with exceptional sensitivity, demonstrating lower LOQs compared to previous reports.}, }
@article {pmid39680524, year = {2024}, author = {Rocha, PS and Bento, N and Folgado, D and Carreiro, AV and Santos, MO and de Carvalho, M and Miranda, B}, title = {Evaluation of smartphone-based cough data in amyotrophic lateral sclerosis as a potential predictor of functional disability.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301734}, pmid = {39680524}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Cough/physiopathology ; Male ; Female ; *Smartphone ; Middle Aged ; Case-Control Studies ; Aged ; Cross-Sectional Studies ; Support Vector Machine ; Adult ; }, abstract = {OBJECTIVES: Cough dysfunction is a feature of patients with amyotrophic lateral sclerosis (ALS). The cough sounds carry information about the respiratory system and bulbar involvement. Our goal was to explore the association between cough sound characteristics and the respiratory and bulbar functions in ALS.<br><br>METHODS: This was a single-center, cross-sectional, and case-control study. On-demand coughs from ALS patients and healthy controls were collected with a smartphone. A total of 31 sound features were extracted for each cough recording using time-frequency signal processing analysis. Logistic regression was applied to test the differences between patients and controls, and in patients with bulbar and respiratory impairment. Support vector machines (SVM) were employed to estimate the accuracy of classifying between patients and controls and between patients with bulbar and respiratory impairment. Multiple linear regressions were applied to examine correlations between cough sound features and clinical variables.<br><br>RESULTS: Sixty ALS patients (28 with bulbar dysfunction, and 25 with respiratory dysfunction) and forty age- and gender-matched controls were recruited. Our results revealed clear differences between patients and controls, particularly within the frequency-related group of features (AUC 0.85, CI 0.79-0.91). Similar results were observed when comparing patients with and without bulbar dysfunction. Sound features related to intensity displayed the strongest correlation with disease severity, and were the most significant in distinguishing patients with and without respiratory dysfunction.<br><br>DISCUSSION: We found a good relationship between specific cough sound features and clinical variables related to ALS functional disability. The findings relate well with some expected impact from ALS on both respiratory and bulbar contributions to the physiology of cough. Finally, our approach could be relevant for clinical practice, and it also facilitates home-based data collection.}, }
@article {pmid39680215, year = {2024}, author = {Wu, H and Erenay, FS and Özaltın, OY and Dalgıç, &#xd6;O and Sır, MY and He, QM and Crum, BA and Pasupathy, KS and , }, title = {Prognostic factors affecting ALS progression through disease tollgates.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {69}, pmid = {39680215}, issn = {1432-1459}, support = {2018-06596//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; 2017-04001//NSERC (Natural Sciences and Engineering Research Council of Canada)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Disease Progression ; Male ; Female ; Prognosis ; Middle Aged ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Understanding factors affecting the timing of critical clinical events in ALS progression.<br><br>METHODS: We captured ALS progression based on the timing of critical events (tollgates), by augmenting 6366 patients' data from the PRO-ACT database with tollgate-passed information using classification. Time trajectories of passing ALS tollgates after the first visit were derived using Kaplan-Meier analyses. The significant prognostic factors were found using log-rank tests. Decision-tree-based classifications identified significant ALS phenotypes characterized by the list of body segments involved at the first visit.<br><br>RESULTS: Standard (e.g., gender and onset type) and tollgate-related (phenotype and initial tollgate level) prognostic factors affect the timing of ALS tollgates. For instance, by the third year after the first visit, 80-100% of bulbar-onset patients vs. 43-48% of limb-onset patients, and 65-73% of females vs. 42-49% of males lost the ability to talk and started using a feeding tube. Compared to the standard factors, tollgate-related factors had a stronger effect on ALS progression. The initial impairment level significantly impacted subsequent ALS progression in a segment while affected segment combinations further characterized progression speed. For instance, patients with normal speech (Tollgate Level 0) at the first visit had less than a 10% likelihood of losing speech within a year, while for patients with Tollgate Level 1 (affected speech), this likelihood varied between 23 and 53% based on additional segment (leg) involvement.<br><br>CONCLUSIONS: Tollgate- and phenotype-related factors have a strong effect on the timing of ALS tollgates. All factors should be jointly considered to better characterize patient groups with different progression aggressiveness.}, }
@article {pmid39679928, year = {2024}, author = {Bhattacharjee, T and Vengalil, S and Belur, Y and Atchayaram, N and Ghosh, PK}, title = {Inter-speaker acoustic differences of sustained vowels at varied dysarthria severities for amyotrophic lateral sclerosis.}, journal = {JASA express letters}, volume = {4}, number = {12}, pages = {}, doi = {10.1121/10.0034613}, pmid = {39679928}, issn = {2691-1191}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Dysarthria/etiology/physiopathology ; *Speech Acoustics ; Male ; Female ; Middle Aged ; Aged ; Severity of Illness Index ; Phonetics ; }, abstract = {We study inter-speaker acoustic differences during sustained vowel utterances at varied severities of Amyotrophic Lateral Sclerosis-induced dysarthria. Among source attributes, jitter and standard deviation of fundamental frequency exhibit enhanced inter-speaker differences among patients than healthy controls (HCs) at all severity levels. Though inter-speaker differences in vocal tract filter attributes at most severity levels are higher than those among HCs for close vowels /i/ and /u/, these are comparable with or lower than those among HCs for the relatively more open vowels /a/ and /o/. The differences typically increase with severity except for a few parameters for /a/ and /i/.}, }
@article {pmid39679063, year = {2024}, author = {Kodavati, M and Hegde, ML}, title = {A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.}, journal = {Neuroscience insights}, volume = {19}, number = {}, pages = {26331055241305151}, pmid = {39679063}, issn = {2633-1055}, support = {R01 NS088645/NS/NINDS NIH HHS/United States ; R01 NS094535/NS/NINDS NIH HHS/United States ; R03 AG064266/AG/NIA NIH HHS/United States ; RF1 NS112719/NS/NINDS NIH HHS/United States ; }, abstract = {Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.}, }
@article {pmid39678608, year = {2024}, author = {Dong, F}, title = {Bioinformatic materials science reconsidered.}, journal = {American journal of translational research}, volume = {16}, number = {11}, pages = {7200-7204}, pmid = {39678608}, issn = {1943-8141}, abstract = {Bioinformatic materials science integrates medical science, materials science, informatics, and other disciplines, aiming to maintain the balance of tissues and organs in the human body. This paper explores the relationship between structural information and the structures synthesized through regulated gene expression. Specifically, it describes the transformation of information into substances via biological structural systems, using mathematical formulas to develop bioinformatic materials. These materials have applications in medical treatments, functional foods for preventive healthcare, and cosmetic products for health maintenance. Notably, bioinformatic materials have been applied in treating acromegaly, a rare and life-threatening disease of unknown etiology, and have improved the neurofilament light chain (NFL) index and typical symptoms of Amyotrophic Lateral Sclerosis (ALS). In summary, bioinformatic materials science holds potential for enhancing human health and contributing to advances in medicine.}, }
@article {pmid39678458, year = {2024}, author = {Sulek, A}, title = {Secretome - the role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases.}, journal = {Postepy psychiatrii neurologii}, volume = {33}, number = {3}, pages = {147-162}, pmid = {39678458}, issn = {2720-5371}, abstract = {PURPOSE: Extracellular vesicles are the subject of many studies in various medical specialties. Their role in neurodegenerative diseases is increasing and they worth introducing in more detail.<br><br>METHODS: This review was performed following an electronic search of the database PubMed/Medline and Web of Science for English-language articles between 2010 and 2024 in the fields of medicine, molecular biology, and biochemistry. Keywords searches included combinations of the following terms: "extracellular vesicles" OR "exosomes" AND "neurodeg*" AND "microRNA" OR "miRNA" AND "AD" OR "PD" OR "ALS" OR "HD". Articles had to be original work or reviews.<br><br>RESULTS: The classification of extracellular vesicles is based on their size or origin. Their content is of key importance in communication between cells and can be treated as a physiological determinant of the normal or pathological condition of a body. The cargo transported in the extracellular space and over longer distances in various body fluids is diversified and may be nucleic acids (DNA, RNA, miRNA) as well as proteins and lipids, and, in the case of apoptotic bodies also a cell's organelles. Exosomes are the most thoroughly studied extracellular vesicles and the most often considered for therapeutic applications. Vesicles carrying biological substances in the body perform three basic functions: participation in a pathological mechanism, a biomarker role that also has diagnostic and prognostic functions, and a role in therapeutic activities. In the case of neurodegenerative diseases, it appears that extracellular vesicles can transport misfolded proteins, initiating pathological processes in previously normal cells.<br><br>CONCLUSIONS: The transport of various substances enclosed in vesicles seems to be very promising in therapeutic prospects in various diseases, and the possibility of their crossing the blood-brain barrier particularly indicates diseases of the central nervous system. Despite many years of research on extracellular vesicles in the context of neurodegenerative diseases, their practical use is currently limited to studies on animal and cellular models, and their practical application in clinical trials in neurodegenerative diseases is to date extremely rare.}, }
@article {pmid39678223, year = {2025}, author = {Banos, M and Preuilh, A and Pradat, PF and Lackmy-Vallée, A and Marchand-Pauvert, V}, title = {Exercises and Brain Stimulation to Preserve Function in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {1}, pages = {e200408}, pmid = {39678223}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to the loss of motor function and muscle strength. Nonpharmacologic neuromodulative therapeutic approaches such as active exercise may contribute to preserve motor functions in ALS, but this hypothesis remains debated. The present meta-analysis first aimed to evaluate the effect of active exercise on function and muscle strength preservation. Moreover, since the responsiveness to induced neuroplasticity of patients with ALS is being discussed, the second objective was to review the analogous effects of noninvasive brain stimulation (NIBS).<br><br>METHODS: Following PRISMA guidelines, we systematically reviewed PubMed, CENTRAL, NIH PMC, PEDro, ScienceDirect, and Web of Science databases from the period between January 10 and July 1, 2023. Criteria limited inclusion to randomized controlled trials comparing active exercise (aerobic or resistance) with usual care or NIBS with sham. The primary outcome was assessed based on functional assessment scores reported on validated clinical scales, and the secondary outcome analysis included muscle strength and neurophysiologic changes. Methodologic quality of the selected studies was assessed using the Physiotherapy Evidence-Based (PEDro) scale. Relative risk (RR) and heterogeneity (I[2]) were calculated with Revman software, and evidence quality was estimated by the GRADE quality scale.<br><br>RESULTS: Thirteen studies were included. Analysis involved 393 patients among whom 164 underwent active exercise and 155 received usual care, 41 received NIBS and 33 underwent sham stimulations. The nature of active exercise was consistent across studies but varied in frequency. NIBS parameters were consistent for stimulation sites and session frequency. Function was significantly preserved in 5 of 9 studies on active exercise and 2 of 4 NIBS trials. Meta-analysis on functional scales indicated a moderate quality of evidence for the effectiveness of active exercises (RR = 0.61 [0.18, 1.04] with I[2] = 69%) compared with usual care and very low quality of evidence for NIBS (RR = -1.41 [-0.44, 3.26] with I[2] = 89%). Only 1 NIBS study revealed neuroplastic changes in the brain.<br><br>DISCUSSION: Active exercise likely slows functional loss in ALS, but the effects of NIBS need further investigation to support their neuroprotective effectiveness. Moreover, both interventions require further neurophysiologic investigation to elucidate ALS neuroplasticity.<br><br>This review has been registered in PROSPERO (CRD42023408121).}, }
@article {pmid39678056, year = {2024}, author = {Baslo, SA and Şirin, NG and Orhan, EK and Baslo, MB and Öge, AE}, title = {Selective Muscle Involvement in Amyotrophic Lateral Sclerosis: Evidence Inferred from the Point of Motor Unit Firing Rates.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {296-305}, pmid = {39678056}, issn = {1300-0667}, abstract = {INTRODUCTION: The aim of the study is to determine the role of upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction as the primary initiator of distal-proximal and lateral-medial gradients of muscle involvement in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Concentric needle electromyography recordings were performed in deltoid, abductor digiti minimi, and first dorsal interosseous (FDI) muscles in patients with ALS and controls during slight voluntary contraction needed to activate two motor units (MU). Five motor unit potential (MUP) pairs were recorded from each muscle. Motor unit potential analyses were performed offline using Multi-MUP analysis program. Quantitative MUP parameters, MU firing rate (FR), FR variability (FRV), and mean consecutive difference (MCD) were calculated. Motor-evoked potentials and the triple stimulation technique (TST) were performed to evaluate UMN involvement.<br><br>RESULTS: Twenty patients with ALS along with 20 age and sex-matched healthy volunteers were enrolled. Quantitative MUP parameters compatible with denervation and reinnervation were found in patients with ALS, who also showed higher FR, FRV, and MCD values, most prominently in FDI. First dorsal interosseous FRV was lower in patients with abnormal central motor conduction time (CMCT). Firing rate and FRV were negatively correlated with CMCT, but not with TST.<br><br>CONCLUSION: Distal limb muscles, particularly FDI, revealed more prominent FR abnormalities in patients with ALS in parallel with the distal-proximal and lateral-medial gradients of the selective muscle involvement pattern which seems predominantly to be correlated with LMN dysfunction. Reduced FRV may be associated with the presence of UMN dysfunction in ALS.}, }
@article {pmid39678053, year = {2024}, author = {Finsterer, J and Mehri, S}, title = {The Causality Spectrum of Dropped Head Syndrome is Broad and Includes Myopathy, Neurodegenerative Disorders, and Varia.}, journal = {Noro psikiyatri arsivi}, volume = {61}, number = {4}, pages = {382-383}, pmid = {39678053}, issn = {1300-0667}, abstract = {Dropped head syndrome is a common complication of various neurological disorders. Most commonly, dropped head syndrome is due to primary or secondary myopathy. However, neurodegenerative diseases and various other conditions can also be complicated by dropped head syndrome. Among the primary myopathies, dropped head occurs most commonly in association with mitochondrial disorders, congenital myasthenic syndrome, and axial myopathies. Among the secondary myopathies, dropped occurs most commonly in association with inflammatory myopathies. Myasthenia is the most common transmission disorder associated with dropped head syndrome. The neurodegenerative disorder most commonly associated with dropped head syndrome is Parkinson syndrome. The diagnosis and treatment of dropped head syndrome from any cause requires a multidisciplinary approach. Outcome varies considerably but early diagnosis and early treatment are associated with a more favourable outcome.}, }
@article {pmid39677679, year = {2024}, author = {Chen, L and Smith, M and Roe, DR and Miranda-Quintana, RA}, title = {Extended Quality (eQual): Radial threshold clustering based on n-ary similarity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677679}, issn = {2692-8205}, support = {R35 GM150620/GM/NIGMS NIH HHS/United States ; }, abstract = {We are transforming Radial Threshold Clustering (RTC), an O (N 2) algorithm, into Extended Quality Clustering, an O (N) algorithm with several novel features. Daura et al's RTC algorithm is a partitioning clustering algorithm that groups similar frames together based on their similarity to the seed configuration. Two current issues with RTC is that it scales as O (N 2) making it inefficient at high frame counts, and the clustering results are dependent on the order of the input frames. To address the first issue, we have increased the speed of the seed selection by using k -means++ to select the seeds of the available frames. To address the second issue and make the results invariant with respect to frame ordering, whenever there is a tie in the most populated cluster, the densest and most compact cluster is chosen using the extended similarity indices. The new algorithm is able to cluster in linear time and produce more compact and separate clusters.}, }
@article {pmid39677629, year = {2024}, author = {Park, S and Park, SK and Liebman, SW}, title = {A model of inborn metabolism errors associated with adenine amyloid-like fiber formation reduces TDP-43 aggregation and toxicity in yeast.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.03.626668}, pmid = {39677629}, issn = {2692-8205}, abstract = {TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1Δ aah1Δ yeast model of disorders of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from a liquid-like, toward a more amyloid-like, state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like and not amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1Δ aah1Δ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine/TDP-43 fiber interactions as seen for other heterologous fibers. The work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.}, }
@article {pmid39677625, year = {2024}, author = {Li, A and Dong, L and Li, X and Yi, J and Ma, J and Zhou, J}, title = {ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39677625}, issn = {2692-8205}, support = {R01 NS105621/NS/NINDS NIH HHS/United States ; R01 NS129219/NS/NINDS NIH HHS/United States ; }, abstract = {Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels of ALDH3A1 in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1[G93A]) reaching end-stage, ALDH3A1 expression was sustained at high level in EOMs, whereas substantial upregulation of ALDH3A1 occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation marker ANKRD1 expression. Interestingly, sciatic nerve transection in wildtype mice induced ALDH3A1 and ANKRD1 expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression of ALDH3A1 protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate that ALDH3A1 may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.}, }
@article {pmid39676614, year = {2024}, author = {Roscoe, S and Allen, SP and McDermott, C and Stavroulakis, T}, title = {Exploring the role of anthropometric measurements to assess nutritional status in amyotrophic lateral sclerosis: a longitudinal prospective cohort study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/21678421.2024.2434176}, pmid = {39676614}, issn = {2167-9223}, abstract = {OBJECTIVE: To observe longitudinal correlations between limb anthropometry against weight, BMI and functional decline in patients with amyotrophic lateral sclerosis.<br><br>METHODS: A longitudinal, prospective, cohort study was undertaken. Four consecutive measurements of weight, height, triceps skinfold thickness (TSF), mid-upper arm (MUAC) and calf circumferences were collected at three-monthly intervals. Fat- and lean body mass were estimated using measurements of TSF and derivations of arm muscle area, respectively. Correlation analyses indicated associations between anthropometric assessments and functional decline (ALSFRS-R). Longitudinal changes were assessed using repeated measures analyses.<br><br>RESULTS: Data from 18 participants was analyzed. At enrollment, weight positively correlated with MUAC (n&#x2009;=&#x2009;17, p&#x2009;=&#x2009;0.0001), arm muscle area (n&#x2009;=&#x2009;17, p&#x2009;=&#x2009;0.04) and calf circumference (n&#x2009;=&#x2009;17, p&#x2009;<&#x2009;0.0001). The ALSFRS-R score negatively correlated with weight (n&#x2009;=&#x2009;17, p&#x2009;=&#x2009;0.03), MUAC (n&#x2009;=&#x2009;18, p&#x2009;=&#x2009;0.01), TSF (n&#x2009;=&#x2009;18, p&#x2009;=&#x2009;0.04), and calf circumference (n&#x2009;=&#x2009;18, p&#x2009;=&#x2009;0.003). Function significantly declined by a difference of 6.3 points per month (p&#x2009;=&#x2009;0.009). A positive correlation was observed between the changes in weight and calf circumference over nine months (r&#x2009;=&#x2009;0.70, p&#x2009;=&#x2009;0.02, n&#x2009;=&#x2009;10).<br><br>CONCLUSION: Limb anthropometric measurements may be surrogate indicators of weight and BMI; TSF may be a practical, reliable indicator of fat mass, whilst changes in calf circumference may be alternatively used to monitor changes in nutritional status in the clinic.}, }
@article {pmid39674407, year = {2025}, author = {Xue, S and Bao, W and Lyu, J and Wang, C and Zhang, Y and Li, H and Chen, D and Lu, Y}, title = {In vitro nephrotoxicity and structure-toxicity relationships of eight natural aristolactams.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {254}, number = {}, pages = {108214}, doi = {10.1016/j.toxicon.2024.108214}, pmid = {39674407}, issn = {1879-3150}, mesh = {Humans ; Structure-Activity Relationship ; Cell Line ; *Reactive Oxygen Species/metabolism ; *Cell Survival/drug effects ; *Transforming Growth Factor beta1/metabolism ; Aristolochic Acids/toxicity ; Hepatitis A Virus Cellular Receptor 1 ; Epithelial Cells/drug effects ; Fibronectins/metabolism ; Kidney Tubules/drug effects/pathology/cytology ; }, abstract = {The structural similarity between aristolactams (ALs) and aristolochic acids (AAs) raises constant concerns about the safety of ALs-containing plants. Natural ALs are distributed more extensively than AAs, leading to a higher risk of ALs exposure in daily consumption. This study aimed to evaluate and compare the in vitro nephrotoxicity on human renal tubular epithelial cells (HK-2 cells) of eight natural ALs with different substituents on the phenanthrene ring and amide ring, including aristolactam Ⅰ (AL Ⅰ), AL BⅡ, velutinam, AL AⅡ, sauristolactam, AL AⅠa, AL FⅠ and N-methyl piperolactam A. Their IC50 values of cell viability were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of kidney injury molecule-1 (KIM-1), transforming growth factor-β1 (TGF-β1) and fibronectin (FN). The reactive oxygen species (ROS) assay was used to detect the intracellular oxidative stress level. The results showed that the eight ALs all had specific nephrotoxicity on HK-2 cells. Particularly, AL Ⅰ, AL BⅡ and velutinam exhibited more potent cytotoxicity on HK-2 cells (IC50 = 2.49-2.78 μM) than the other five ALs (IC50 = 12.33-43.84 μM). The structure-toxicity relationships indicated that both methylenedioxy (-OCH2O-) and methoxy (-OCH3) were positively contributing functional groups of ALs on nephrotoxicity, while the hydroxy group (-OH) and methyl substitution on nitrogen (N-CH3) accounted for a detrimental effect conversely. Consistent with this structure-toxicity relationship, the eight ALs increased KIM-1 levels in the same trend as their cytotoxicity at the same concentration of 2.5 μg/mL, associating with different levels of ROS generation. And the four most toxic ALs, AL Ⅰ, AL BⅡ, velutinam and AL AⅡ, could also induce fibrosis by increasing TGF-β1 and FN levels.}, }
@article {pmid39674307, year = {2025}, author = {Pistolesi, A and Ranieri, G and Calvani, M and Guasti, D and Chiarugi, A and Buonvicino, D}, title = {Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis.}, journal = {Experimental neurology}, volume = {385}, number = {}, pages = {115095}, doi = {10.1016/j.expneurol.2024.115095}, pmid = {39674307}, issn = {1090-2430}, mesh = {Animals ; *Microglia/drug effects/metabolism ; Mice ; *Peroxidase/metabolism ; *Multiple Sclerosis, Chronic Progressive/drug therapy ; *Disease Models, Animal ; Mice, Inbred NOD ; Female ; Enzyme Inhibitors/pharmacology/therapeutic use ; Piperidines/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Nerve Degeneration/drug therapy/pathology ; Spinal Cord/drug effects/pathology/metabolism ; }, abstract = {Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.}, }
@article {pmid39657109, year = {2025}, author = {Benatar, M and McDermott, C and Turner, MR and van Eijk, RPA}, title = {Rethinking phase 2 trials in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1106-1111}, pmid = {39657109}, issn = {1460-2156}, support = {/NH/NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/drug therapy ; *Clinical Trials, Phase II as Topic/methods ; }, abstract = {There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on phase 2 data, which then fail in phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to phase 2 go/no-go decisions. Over-interpretation of phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritization for the investment needed for definitive phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to phase 2 design and implementation.}, }
@article {pmid39656857, year = {2024}, author = {Alvarado, M and Gómez-Navajas, JA and Blázquez-Muñoz, MT and Gómez-Molero, E and Fernández-Sánchez, S and Eraso, E and Munro, CA and Valentín, E and Mateo, E and de Groot, PWJ}, title = {The good, the bad, and the hazardous: comparative genomic analysis unveils cell wall features in the pathogen Candidozyma auris typical for both baker's yeast and Candida.}, journal = {FEMS yeast research}, volume = {24}, number = {}, pages = {}, pmid = {39656857}, issn = {1567-1364}, support = {PID2020-117983RB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; SBPLY/23/180225/000029//UCLM/ ; //European Regional Development Fund/ ; JDC2023-051226-I//European Social Fund Plus/ ; }, mesh = {*Cell Wall/metabolism ; *Saccharomyces cerevisiae/genetics/metabolism ; Computational Biology ; Genomics ; Candida auris/genetics/metabolism/drug effects ; beta-Glucans/metabolism ; Genome, Fungal ; Fungal Proteins/genetics/metabolism ; Glycosylphosphatidylinositols/metabolism/genetics ; Candida albicans/genetics/pathogenicity ; Candida/genetics/metabolism/pathogenicity ; }, abstract = {The drug-resistant pathogenic yeast Candidozyma auris (formerly named Candida auris) is considered a critical health problem of global importance. As the cell wall plays a crucial role in pathobiology, here we performed a detailed bioinformatic analysis of its biosynthesis in C. auris and related Candidozyma haemuli complex species using Candida albicans and Saccharomyces cerevisiae as references. Our data indicate that the cell wall architecture described for these reference yeasts is largely conserved in Candidozyma spp.; however, expansions or reductions in gene families point to subtle alterations, particularly with respect to β--1,3--glucan synthesis and remodeling, phosphomannosylation, β-mannosylation, and glycosylphosphatidylinositol (GPI) proteins. In several aspects, C. auris holds a position in between C. albicans and S. cerevisiae, consistent with being classified in a separate genus. Strikingly, among the identified putative GPI proteins in C. auris are adhesins typical for both Candida (Als and Hyr/Iff) and Saccharomyces (Flo11 and Flo5-like flocculins). Further, 26 putative C. auris GPI proteins lack homologs in Candida genus species. Phenotypic analysis of one such gene, QG37_05701, showed mild phenotypes implicating a role associated with cell wall β-1,3-glucan. Altogether, our study uncovered a wealth of information relevant for the pathogenicity of C. auris as well as targets for follow-up studies.}, }
@article {pmid39656589, year = {2024}, author = {Nascimento, F and Özyurt, MG and Halablab, K and Bhumbra, GS and Caron, G and Bączyk, M and Zytnicki, D and Manuel, M and Roselli, F and Brownstone, R and Beato, M}, title = {Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115046}, pmid = {39656589}, issn = {2211-1247}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 NS110953/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Motor Neurons/metabolism/pathology ; Mice ; *Homeostasis ; *Disease Models, Animal ; *Spinal Cord/pathology/metabolism ; Synaptic Transmission/physiology ; Receptors, Glycine/metabolism ; Nerve Degeneration/pathology ; Mice, Inbred C57BL ; Renshaw Cells/metabolism ; }, abstract = {In many neurological conditions, early-stage neural circuit adaptation preserves relatively normal behavior. In some diseases, spinal motoneurons progressively degenerate yet movement remains initially preserved. This study investigates whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we find that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that, in this motoneuron degenerative condition, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.}, }
@article {pmid39673573, year = {2024}, author = {Riaz, S and Steinsland, H and Andersen, AZ and Boysen, A and Hanevik, K}, title = {Proportions of IgA antibodies targeting glycosylated epitopes of secreted Escherichia coli mucinase YghJ in initial plasmablast response differ from salivary and intestinally secreted IgA.}, journal = {Medical microbiology and immunology}, volume = {214}, number = {1}, pages = {2}, pmid = {39673573}, issn = {1432-1831}, support = {234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 234364//Research Council of Norway/ ; 7041-00220//Innovation Fund Denmark/ ; 7041-00220//Innovation Fund Denmark/ ; }, mesh = {Humans ; Glycosylation ; *Saliva/immunology ; *Epitopes/immunology ; Enterotoxigenic Escherichia coli/immunology ; Escherichia coli Proteins/immunology ; Antibodies, Bacterial/immunology/blood ; Plasma Cells/immunology ; Immunoglobulin A, Secretory/immunology ; Immunoglobulin A/immunology/blood ; Adult ; Male ; Female ; Escherichia coli Infections/immunology ; Young Adult ; }, abstract = {Mucosal infections normally cause an immune response including activation of antigen-specific B cells in regional mucosa-associated lymphoid tissue. After recirculation of plasmablasts, and maturation at mucosal surfaces or bone marrow, plasma cells produce secretory or systemic IgA. It remains uncertain to what extent secretory and systemic IgA share the same target specificities. For vaccine candidate optimization, it is important to know whether IgA targeting of glycosylated epitopes of a protein antigen vary between mucosal and systemic sites. We evaluated glycosylated epitope specificity of systemic and mucosally secreted IgA against YghJ, a potential vaccine candidate antigen secreted by most pathogenic Escherichia coli. IgA from intestinal lavage, saliva, serum, and blood-derived antibody in lymphocyte supernatants (ALS) were collected from 21 volunteers following experimental infection with enterotoxigenic E. coli. Methods for preparing IgA from saliva and ALS were developed, and multiplex bead flow cytometric immunoassays were used to determine levels of IgA targeting natively glycosylated YghJ and estimating what proportion of these antibodies specifically targeted glycosylated epitopes. Following infection, anti-YghJ IgA levels increased substantially for most volunteers across all four specimen types. Target specificity of ALS IgA correlated well with serum IgA, but not with mucosally secreted IgA. Furthermore, glycosylation-specific proportion of salivary IgA was higher than, and did not correlate with, intestinally secreted IgA. These results indicate a new degree of complexity to our understanding of epitope-targeting and tissue specificity of mucosal antibody responses. Our findings also suggest that all features of an intestinal IgA response may not be well reflected in serum, saliva, or ALS, which are commonly used proxy specimens for evaluating intestinal immune responses.}, }
@article {pmid39673548, year = {2024}, author = {Alzahrani, AK and Imran, M and Alshrari, AS}, title = {Investigating the impact of SOD1 mutations on amyotrophic lateral sclerosis progression and potential drug repurposing through in silico analysis.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/07391102.2024.2439577}, pmid = {39673548}, issn = {1538-0254}, abstract = {Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for attenuating oxidative stress through its ability to facilitate the dismutation of the superoxide radical into oxygen and hydrogen peroxide. The progressive loss of motor neurons characterize amyotrophic lateral sclerosis (ALS), a crippling neurodegenerative disease that is caused by mutations in the SOD1 gene. In this study, in silico mutational analysis was performed to study the various mutations, the pathogenicity and stability ΔΔG (binding free energy) of the variant of SOD1. x in the protein variant analysis showed a considerable destabilizing effect with a ΔΔG value of -4.2 kcal/mol, signifying a notable impact on protein stability. Molecular dynamics simulations were conducted on both wild-type and C146R mutant SOD1. RMSD profiles indicated that both maintained consistent structural conformation over time. Additionally, virtual screening of 3067 FDA-approved drugs against the mutant SOD1 identified two potential binders, Tucatinib (51039094) and Regorafenib (11167602), which interacted with Leu106, similar to the control drug, Ebselen. Further simulations assessed the dynamic properties of SOD1 in monomeric and dimeric forms while bound to these compounds. 11167602 maintained stable interaction with the monomeric SOD1 mutant, whereas 51039094 and Ebselen dissociated from the monomeric protein's binding site. However, all three compounds were stably bound to the dimeric SOD1. MM/GBSA analysis revealed similar negative binding free energies for 11167602 and 51039094, identifying them as strong binders due to their interaction with Cys111. Experimental validation, including in vitro, cell-based, and in vivo assays are essential to confirm these candidates before advancing to clinical trials.}, }
@article {pmid39672239, year = {2025}, author = {Cocozza, G and Busdraghi, LM and Chece, G and Menini, A and Ceccanti, M and Libonati, L and Cambieri, C and Fiorentino, F and Rotili, D and Scavizzi, F and Raspa, M and Aronica, E and Inghilleri, M and Garofalo, S and Limatola, C}, title = {GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {124}, number = {}, pages = {280-293}, doi = {10.1016/j.bbi.2024.12.010}, pmid = {39672239}, issn = {1090-2139}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Growth Differentiation Factor 15/metabolism/genetics ; Mice ; *Lipid Metabolism/physiology ; *Weight Loss ; *Disease Models, Animal ; *Signal Transduction ; *Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism/genetics ; Humans ; Male ; Mice, Transgenic ; Female ; Brain Stem/metabolism ; Adipose Tissue/metabolism ; Muscular Atrophy/metabolism ; Microglia/metabolism ; Mice, Inbred C57BL ; }, abstract = {Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1[G93A] mouse model and that GFRAL is upregulated in the brainstem of hSOD1[G93A] mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1[G93A] mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.}, }
@article {pmid39672208, year = {2025}, author = {Liu, Y and Wu, L and Peng, W and Mao, X}, title = {Glial polarization in neurological diseases: Molecular mechanisms and therapeutic opportunities.}, journal = {Ageing research reviews}, volume = {104}, number = {}, pages = {102638}, doi = {10.1016/j.arr.2024.102638}, pmid = {39672208}, issn = {1872-9649}, mesh = {Humans ; Animals ; *Nervous System Diseases/therapy ; *Neuroglia/metabolism/physiology ; Cell Polarity/physiology ; Astrocytes/metabolism/physiology ; }, abstract = {Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.}, }
@article {pmid39671529, year = {2024}, author = {Katzman, D and Kalman, G and Almog, O and Fogel, I}, title = {Deployment of Physician Resources and Innovative Medical Strategies in the 2023-2024 Israel-Hamas War: Israel's Strategy to Deliver Advanced Life Support and Whole Blood Transfusion to the Battlefield via Forward Medical Teams and the Impact on the Case Fatality Rate.}, journal = {Military medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/milmed/usae553}, pmid = {39671529}, issn = {1930-613X}, abstract = {The 2023-2024 Israel-Hamas War, which began following a Hamas attack on Israel on October 7, 2023, has seen a case fatality rate (CFR) among the lowest in the history of warfare. In resultant ground maneuvers, the Israel Defense Forces Medical Corps (IDF-MC) doctrine for the delivery of combat casualty care has been battle tested. We suggest the decreased CFR in part reflects a paradigm shift in combat deployment of medical resources, so as to introduce life-saving strategies not previously seen on the battlefield in large scale to date. These changes, which began in the 2006 Lebanon war and have been in evolution since, include strategic physician deployment to positions more forward than in previous wars and in teams smaller than the previous standard. These forward medical teams have replaced the battalion aid station in the Gaza theater of operations and serve to increase the availability of Advanced Life Support (ALS) level care at the point of injury, wherever a casualty might be on a multidimensional battlefield. These forward medical teams deploy with advanced medical capabilities, including in some cases the ability to transfuse low titer O whole blood. This article reviews aspects of the IDF-MC combat casualty care doctrine as implemented during the current war, the role and advantages of transfusion-capable ALS forward medical teams, and the apparent impact on the CFR thereof.}, }
@article {pmid39671291, year = {2024}, author = {Lin, J and Carman, PJ and Gambogi, CW and Kendsersky, NM and Chuang, E and Gates, SN and Yokom, AL and Rizo, AN and Southworth, DR and Shorter, J}, title = {Design principles to tailor Hsp104 therapeutics.}, journal = {Cell reports}, volume = {43}, number = {12}, pages = {115005}, pmid = {39671291}, issn = {2211-1247}, support = {R01 GM099836/GM/NIGMS NIH HHS/United States ; R01 GM110001/GM/NIGMS NIH HHS/United States ; T32 GM008076/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Adenosine Triphosphate/metabolism ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; HSP40 Heat-Shock Proteins/metabolism/genetics ; HEK293 Cells ; Adenosine Diphosphate/metabolism ; Protein Binding ; }, abstract = {The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can (1) reduce Hsp70 collaboration without enhancing activity, (2) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s, (3) produce Hsp70-independent potentiated variants, or (4) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting an NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS and TDP-43 proteinopathies in human cells. Thus, we establish design principles to tailor Hsp104 therapeutics.}, }
@article {pmid39671140, year = {2025}, author = {Ikehata, A}, title = {Extension of the molar absorption coefficient for non-ideal mixtures: an application to aqueous monovalent alcohol solutions.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {41}, number = {4}, pages = {353-363}, pmid = {39671140}, issn = {1348-2246}, abstract = {The hydration state of the alcohols was investigated using the extended molar absorption coefficient, which redefines the molar absorption coefficient as a differential coefficient of concentration. The extended molar absorption coefficient is a function of the concentration calculated from the difference in absorbance, and is consistent with the conventional molar absorption coefficient, allowing a complete quantitative comparison. The quantitative performance was verified using IR and NIR absorption spectra of aqueous solutions of monovalent alcohols (methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol) that were soluble in water at any mixing ratio. Extended molar absorption coefficient spectra were calculated for the combination bands of water, which were further separated by multivariate curve resolution-alternating least squares (MCR-ALS) into molecular species with different peak wavenumbers: strongly hydrogen-bonded (SHB), weakly hydrogen-bonded (WHB), and free OH species. The number of water species that change when one alcohol molecule increases, i.e., the perturbed hydration number (PHN), was calculated by comparison with the conventional molar absorption coefficient of pure water. The calculated PHN indicates that the numbers of SHB and WHB species are reversed at approximately 20 wt%, and that the free OH species increase at higher alcohol concentrations and are more pronounced for alcohols with bulky alkyl groups. These results provide a quantitative answer to the long-debated question of anomalies in water-alcohol mixing.}, }
@article {pmid39670820, year = {2025}, author = {Lagiakos, HR and Zou, Y and Igawa, H and Therrien, E and Lawrenz, M and Kato, M and Svensson, M and Gray, F and Jensen, K and Dahlgren, MK and Pelletier, RD and Dingley, K and Bell, JA and Liu, Z and Jiang, Y and Zhou, H and Skene, RJ and Nie, Z}, title = {In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {3}, pages = {2720-2741}, doi = {10.1021/acs.jmedchem.4c02074}, pmid = {39670820}, issn = {1520-4804}, mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; Humans ; Mice ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use/chemical synthesis ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; MAP Kinase Kinase Kinases/antagonists &amp; inhibitors/metabolism ; Neurons/drug effects/pathology/metabolism ; Drug Discovery ; Computer Simulation ; Structure-Activity Relationship ; Rats ; }, abstract = {Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.}, }
@article {pmid39670434, year = {2024}, author = {Piga, G and Fadda, L and Borghero, G and Maccabeo, A and Pala, F and Murru, MR and Giglio, S and Puligheddu, M and Floris, G}, title = {Semantic behavioral variant frontotemporal dementia and semantic dementia associated with TARDBP mutations.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2439448}, pmid = {39670434}, issn = {2167-9223}, abstract = {Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations' association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations' association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.}, }
@article {pmid39670345, year = {2024}, author = {D'Anna, L and Wragg, D and Mauro, D and Rubino, S and Terenzi, A and Barone, G and Thomas, SR and Casini, A and Bonsignore, R and Spinello, A}, title = {Unraveling the Molecular Basis for G-Quadruplex-Binders to ALS/FTD-Associated G4C2 Repeats of the C9orf72 Gene.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400974}, doi = {10.1002/cbic.202400974}, pmid = {39670345}, issn = {1439-7633}, support = {PNRR-M4C2-I1.3//European Union-NextGenerationEU/ ; PE_00000019//European Union-NextGenerationEU/ ; B73C22001250006//European Union-NextGenerationEU/ ; }, abstract = {The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G4C2) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G4C2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof-of-principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the Au[I] bis-N-heterocyclic carbene (NHC) complex - Au(TMX)2 - showing that it moderately stabilizes G4C2 G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)2 binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders.}, }
@article {pmid39670112, year = {2024}, author = {Pinkerton, M and Adler, GL and Ledger, M and Ni, CY and Yang, Y and Tan, RH}, title = {Heterogeneous nuclear ribonucleoprotein D - an understudied subfamily affected in sporadic TDP-43 proteinopathies.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae352}, pmid = {39670112}, issn = {2632-1297}, abstract = {Despite the recognition that heterogeneous nuclear ribonucleoproteins (hnRNPs) modulate TDP-43 and can limit aberrant splicing events to compensate for TDP-43 loss, their role in TDP-43 proteinopathies remains poorly understood and studies in patient tissue are lacking. This study assesses seven heterogeneous nuclear ribonucleoproteins from the A/B, C, D and H subfamilies in two cortical regions implicated in early TDP-43 dysfunction versus late TDP-43 dysfunction in sporadic amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. Our results reveal significant nuclear loss of hnRNPD, hnRNPC and hnRNPA1 in the frontal cortex of frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis but not in the motor cortical neurons or Betz cells of amyotrophic lateral sclerosis cases. Cytoplasmic co-occurrence was observed between hnRNPA1 and hnRNPC but not with phosphorylated TDP-43 (pTDP-43). Interestingly, nuclear hnRNPD loss associated with increasing cytoplasmic pTDP-43, highlighting an understudied subfamily in sporadic TDP-43 proteinopathies. In summary, this study identifies the nuclear loss of hnRNPD, C and A1 in a predilection brain region of TDP-43 in frontotemporal lobar degeneration compared to amyotrophic lateral sclerosis cases without significant pTDP-43 in this region. This highlights the need for further investigation into the involvement of these heterogeneous nuclear ribonucleoproteins in disease pathogenesis and potential to serve as modulatory targets and/or proximal markers of TDP-43 dysfunction in sporadic TDP-43 proteinopathies.}, }
@article {pmid39669591, year = {2024}, author = {Beauregard-Lacroix, &#xc9; and Scott, A and Nguyen, TTM and Wierenga, KJ and Purcarin, G and Karstensen, AB and Carvalho, DR and Alessandri, JL and Payet, F and Girisha, KM and Ferron, M and Campeau, PM}, title = {Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.}, journal = {Genetics in medicine open}, volume = {2}, number = {}, pages = {101837}, pmid = {39669591}, issn = {2949-7744}, abstract = {PURPOSE: Biallelic variants in FIG4 or VAC14 are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of FIG4-associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model.<br><br>METHODS: Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in Fig4 [plt/plt] mice and compared with wild type. Relevant literature from the last 10 years was reviewed.<br><br>RESULTS: All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic FIG4 variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation.<br><br>CONCLUSION: This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in FIG4 or VAC14 and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.}, }
@article {pmid39669124, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and McKeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, &#x141;J and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 repeat expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {NAR molecular medicine}, volume = {1}, number = {4}, pages = {ugae019}, pmid = {39669124}, issn = {2976-856X}, support = {P50 NS048843/NS/NINDS NIH HHS/United States ; R01 GM122880/GM/NIGMS NIH HHS/United States ; R35 GM144215/GM/NIGMS NIH HHS/United States ; U54 NS048843/NS/NINDS NIH HHS/United States ; }, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown. Here, we show C9orf72Exp in pre-symptomatic and amyotrophic lateral sclerosis-frontotemporal dementia patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb of C9orf72 as highly compacted chromatin embedded in an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72Exp patient contained a highly rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72Exp repeat instability and chromosomal fragility are sensitive to folate deficiency. Age-dependent repeat instability, chromosomal fragility and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72Exp mice, implicating C9orf72Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, }
@article {pmid39667814, year = {2025}, author = {Rousseau, JA and Maier, M and Ait-Mohand, S and Dumulon-Perreault, V and Sarrhini, O and Tremblay, S and Rousseau, E and Salzmann, M and Guérin, B}, title = {Antibody-Based PET Imaging of Misfolded Superoxide Dismutase 1 in an Amyotrophic Lateral Sclerosis Mouse Model.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {1}, pages = {130-135}, pmid = {39667814}, issn = {1535-5667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Positron-Emission Tomography/methods ; *Disease Models, Animal ; *Zirconium/chemistry ; Protein Folding ; Mice, Transgenic ; Deferoxamine/chemistry ; Antibodies/chemistry ; Radioisotopes ; Tissue Distribution ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron loss in the motor cortex, brain stem, and spinal cord. Mutations in the superoxide dismutase 1 (SOD1) gene, resulting in misfolding of its protein product, are a common cause of ALS. Currently, there is no approved ALS diagnostic tool. Here, we present the development of a PET radiotracer, [[89]Zr]Zr-desferoxamine (DFO)-α-miSOD1, targeting selectively misfolded SOD1 (misSOD1). Methods: DFO-α-miSOD1 was prepared by conjugating α-miSOD1 antibody with DFO and labeled with [89]Zr. A longitudinal imaging study was performed to identify the optimal mouse age and time after administration of [[89]Zr]Zr-DFO-α-miSOD1 for the detection of misSOD1 aggregation in transgenic mice overexpressing misSOD1 and in wild-type mice. Subsets of mice were either coinjected with an excess of α-miSOD1 or imaged with deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 to assess target specificity. The internal radiation dose for [[89]Zr]Zr-DFO-α-miSOD1 was estimated by extrapolating data from mouse biodistribution experiments. Results: Imaging with [[89]Zr]Zr-DFO-α-miSOD1 was optimal in 136-d-old transgenic mice on day 10 after administration. Significant accumulation of [[89]Zr]Zr-DFO-α-miSOD1 was detected in the spinal cord and cartilage of ALS transgenic mice compared with the wild-type mice (P = 0.01). The radiotracer accumulation is selective and blockable with an excess of α-miSOD1. Deglycosylated [[89]Zr]Zr-DFO-α-miSOD1 results in high-contrast detection of misSOD1 but is prone to aggregation. The dosimetry for [[89]Zr]Zr-DFO-α-miSOD1 is comparable to that for other [89]Zr-based tracers currently used in humans. Conclusion: This work thus establishes that [[89]Zr]Zr-DFO-α-miSOD1 PET can detect misSOD1 in transgenic mice, paving the way for application in early diagnosis of ALS and therapeutic monitoring.}, }
@article {pmid39667295, year = {2025}, author = {Spencer, PS and Berntsson, SG and Buguet, A and Butterfield, P and Calne, DB and Calne, SM and Giménez-Roldán, S and Hugon, J and Kahlon, S and Kisby, GE and Lagrange, E and Landtblom, AE and Ludolph, AC and Nunn, PB and Palmer, VS and Reis, J and Román, GC and Sipilä, JOT and Spencer, SS and Angues, RV and Vernoux, JP and Yabushita, M}, title = {Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123340}, doi = {10.1016/j.jns.2024.123340}, pmid = {39667295}, issn = {1878-5883}, mesh = {Humans ; *Neurodegenerative Diseases/epidemiology/prevention &amp; control/etiology ; *Primary Prevention/methods ; Brain ; Environmental Exposure/adverse effects ; Amyotrophic Lateral Sclerosis/epidemiology/prevention &amp; control ; Environment ; }, abstract = {While rising global rates of neurodegenerative disease encourage early diagnosis and therapeutic intervention to block clinical expression (secondary prevention), a more powerful approach is to identify and remove environmental factors that trigger long-latencybrain disease (primary prevention) by acting on a susceptible genotype or acting alone. The latter is illustrated by the post-World War II decline and disappearance of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC), a prototypical often-familial neurodegenerative disease formerly present in very high incidence on the island of Guam. Lessons learned from 75 years of investigation on the etiology of ALS/PDC include: the importance of focusing field research on the disease epicenter and patients with early-onset disease; soliciting exposure history from patients, family, and community to guide multidisciplinary biomedical investigation; recognition that disease phenotype may vary with exposure history, and that familial brain disease may have a primarily environmental origin. Furthermore, removal from exposure to the environmental trigger effects primary disease prevention.}, }
@article {pmid39666202, year = {2024}, author = {van Eijk, RPA and van Loon, FT and van Unnik, JWJ and Weemering, DN and Seitidis, G and Mavridis, D and van den Berg, LH and Nikolakopoulos, S}, title = {Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {40}, pmid = {39666202}, issn = {1432-1459}, support = {EVIDENCE//Stichting ALS Nederland/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Randomized Controlled Trials as Topic ; Patient Dropouts/statistics &amp; numerical data ; }, abstract = {OBJECTIVES: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.<br><br>METHODS: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm. Subsequently, we meta-analyzed attrition rates across studies, evaluated the difference between study arms, and explored the impact of study-level characteristics. Finally, a meta-regression model predicting study discontinuation for future clinical trials was translated into a web application.<br><br>RESULTS: In total, 60 randomized placebo-controlled clinical trials were included in the meta-analysis, randomizing 14,493 patients with ALS. Attrition varied significantly between studies, ranging from 3.1% to 75.7% of all randomized patients, with a pooled effect of 32.0% (90% prediction interval 6.1% to 66.3%). Attrition was similar between the intervention and placebo arm (odds ratio 1.08, 95% CI 0.89 to 1.31, p&#x2009;=&#x2009;0.43). The follow-up duration was identified as the sole study-level predictor (0.032, 95% CI 0.026 to 0.039, p&#x2009;<&#x2009;0.001), resulting in predicted attrition of 19.3% for 6-month, 36.4% for 12-month, and 55.6% for 18-month clinical trials.<br><br>CONCLUSIONS: ALS clinical trials encounter high attrition, which increases with the follow-up duration. These findings underscore the need to refine our strategies to manage attrition, preserving the integrity and generalizability of ALS clinical trials.}, }
@article {pmid39666144, year = {2024}, author = {Levison, LS and Blicher, JU and Andersen, H}, title = {Incidence and mortality of ALS: a 42-year population-based nationwide study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {44}, pmid = {39666144}, issn = {1432-1459}, support = {A3520//Health Research Fund of Central Denmark Region/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Male ; Female ; Incidence ; Middle Aged ; Denmark/epidemiology ; Aged ; Adult ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND AND AIM: Recent studies have suggested that the incidence rate (IR) and the rate of death (MR) of amyotrophic lateral sclerosis (ALS) are increasing. Still, it remains unclear whether this is due to improved case ascertainment or represents a true increase. We examined the development in the incidence and mortality of ALS in Denmark for 42 years.<br><br>METHODS: We retrieved individual-level data of all patients aged above 18 years with first-time ALS diagnosed at any Danish department of neurology. The IR and MR were calculated based on data from 1980 to 2021, stratified by gender and age.<br><br>RESULTS: We identified 5,943 patients with ALS and identified a total of 5,069 deaths in the nationwide population. Overall, the IR was 3.4 per 100,000 persons per year (95% CI 3.4-3.5). ALS incidence rose gradually during the study period, and the IR was 2.8 times higher (95% CI 2.4-3.2) when comparing the latest period (2018-2021) with the first (1980-1983). Parallel to the IR, the MR increased over time and was associated with male gender and rose with age at diagnosis, peaking in the 70-79-year age group.<br><br>CONCLUSION: In Denmark, the IR and MR of ALS increased threefold from 1980 to 2021, with steadily increasing risk related to male gender and in particular to higher age. Considering our aging societies, the number of elderly patients with ALS can be expected to increase considerably.}, }
@article {pmid39666121, year = {2024}, author = {Okubo, S and Naruse, H and Ishiura, H and Sudo, A and Esaki, K and Mitsui, J and Matsukawa, T and Satake, W and Greimel, P and Shingai, N and Oya, Y and Yoshikawa, T and Tsuji, S and Toda, T}, title = {Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {36}, pmid = {39666121}, issn = {1432-1459}, support = {JPMH23FC1008//Ministry of Health, Labour and Welfare/ ; JP23ek0109673//Japan Agency for Medical Research and Development/ ; JP23ek0109617//Japan Agency for Medical Research and Development/ ; JP23ek0109631//Japan Agency for Medical Research and Development/ ; JP24K18698//Japan Society for the Promotion of Science/ ; JP23K27514//Japan Society for the Promotion of Science/ ; 21K07512//Japan Society for the Promotion of Science/ ; Glyco-lipidologue Initiative Program//RIKEN/ ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood ; Mutation ; Pedigree ; *Serine C-Palmitoyltransferase/genetics ; Sphingolipids/blood ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. Pathogenic variants in SPTLC1, encoding a subunit of serine palmitoyltransferase, cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), and have recently been associated with juvenile ALS. SPTLC1 variants associated with ALS cause elevated levels of sphinganines and ceramides. Reports on ALS associated with SPTLC1 remain limited. This study aimed to investigate the frequency of SPTLC1 variants in ALS and relevant clinical characteristics.<br><br>METHODS: We analyzed whole-exome and whole-genome sequence data from 40 probands with familial ALS and 413 patients with sporadic ALS without previously identified causative variants. Reverse transcription polymerase chain reaction (RT-PCR) analysis and droplet digital PCR (ddPCR) were used to assess splicing and mosaicism, respectively. Plasma sphingolipid levels were quantified to analyze biochemical consequences.<br><br>RESULTS: The heterozygous c.58G>A, p.Ala20Thr variant was identified in a 21-year-old Japanese female patient presenting with symmetric weakness which slowly progressed over 15&#xa0;years. RT-PCR analysis showed no splice defects. Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents. ddPCR revealed that the asymptomatic father harbored a mosaic variant with 17% relative mutant allele abundance in peripheral blood leukocytes.<br><br>CONCLUSIONS: We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism. Lipid analysis results are consistent with previous findings on SPTLC1-associated ALS. Further studies are necessary to determine the clinical effect of mosaic variants of SPTLC1.}, }
@article {pmid39666115, year = {2024}, author = {Psychogios, I and Hu, Y and Seitz, C and Joyce, EE and Lovik, A and Ingre, C and Fang, F}, title = {Exploring clinical chemistry markers in amyotrophic lateral sclerosis: insights into survival and disease trajectories.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {7}, pmid = {39666115}, issn = {1432-1459}, support = {2019-01088//Swedish Research Council/ ; 2023-02428//Swedish Research Council/ ; MegaALS 802091//European Research Council Starting Grant/ ; R01 TS000324/TS/ATSDR CDC HHS/United States ; R01TS000324-01-00/CC/CDC HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/mortality/diagnosis/physiopathology ; Male ; Female ; Middle Aged ; *Biomarkers/blood ; Aged ; *Disease Progression ; Cohort Studies ; Sweden ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: Commonly measured clinical chemistry markers might be indicative of survival and disease progression in amyotrophic lateral sclerosis (ALS).<br><br>METHODS: In a cohort study of 270 ALS patients diagnosed from April 2014 to May 2021 in Stockholm, Sweden, we examined the link between 29 clinical chemistry markers at diagnosis and mortality risk at 6&#xa0;months, 1&#xa0;year, and 3&#xa0;years after diagnosis. Summary variables from exploratory factor analysis (EFA) assessed the markers' collective impact on survival. We integrated ALS functional rating scale-revised (ALSFRS-R) scores with survival data using a joint latent class model to identify patterns of functional decline. Multinomial logistic regression determined how the EFA-derived factors predicted the decline trajectories post-diagnosis.<br><br>RESULTS: Higher levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and albumin at diagnosis were linked to lower mortality in ALS patients, while increased neurofilament light chain (NfL), leukocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and carbon dioxide (CO2) levels indicated higher mortality. The 'Red blood cell profile' factor, derived from EFA, emerged as a significant predictor of survival, independent of other prognostic indicators. The joint latent class model identified three distinct patient groups based on functional decline, with 'Red blood cell profile' suggesting a lower likelihood of being in the groups with slower progression.<br><br>CONCLUSION: Clinical chemistry markers, including NfL, lipids, albumin, leukocyte count, MCV, MCH, CO2, and the 'Red blood cell profile,' were associated with ALS survival. As these markers represent broader bodily functions, integrating them in ALS patient care could improve disease management.}, }
@article {pmid39666103, year = {2024}, author = {Zimmermann, M and Mengel, D and Raupach, K and Haack, T and Neumann, M and Synofzik, M}, title = {Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {58}, pmid = {39666103}, issn = {1432-1459}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Female ; *Huntingtin Protein/genetics ; Middle Aged ; Aged ; *Trinucleotide Repeat Expansion/genetics ; Brain/pathology/diagnostic imaging ; }, abstract = {INTRODUCTION: While ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington's disease (HD), an enrichment of HTT repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions.<br><br>METHODS: Screening of HTT repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified HTT repeat expansion carrier.<br><br>RESULTS: One HTT repeat expansion [40/22 repeats (&#xb1;&#x2009;1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03-0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed-in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions-HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration.<br><br>CONCLUSIONS: Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which-given the low repeat number-is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.}, }
@article {pmid39666071, year = {2024}, author = {de Boer, EMJ and de Vries, BS and Van Hecke, W and Mühlebner, A and Vincken, KL and Mol, CP and van Rheenen, W and Westeneng, HJ and Veldink, JH and Höglinger, GU and Morris, HR and Litvan, I and Raaphorst, J and Ticozzi, N and Corcia, P and Vandenberghe, W and Pijnenburg, YAL and Seelaar, H and Ingre, C and Van Damme, P and van den Berg, LH and van de Warrenburg, BPC and van Es, MA}, title = {Diagnosing primary lateral sclerosis: a clinico-pathological study.}, journal = {Journal of neurology}, volume = {272}, number = {1}, pages = {46}, pmid = {39666071}, issn = {1432-1459}, mesh = {Humans ; Amyotrophic Lateral Sclerosis/diagnosis/pathology/genetics ; Autopsy ; Brain/pathology/diagnostic imaging ; Diagnosis, Differential ; *Motor Neuron Disease/diagnosis/pathology ; }, abstract = {BACKGROUND: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.<br><br>METHODS: This study reports on 5 cases in which the diagnostic&#xa0;criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.<br><br>RESULTS: Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.<br><br>CONCLUSIONS: This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS.&#xa0;Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.}, }
@article {pmid39665821, year = {2025}, author = {Serneels, PJ and De Schutter, JD and De Groef, L and Moons, L and Bergmans, S}, title = {Oligodendroglial heterogeneity in health, disease, and recovery: deeper insights into myelin dynamics.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3179-3192}, pmid = {39665821}, issn = {1673-5374}, abstract = {Decades of research asserted that the oligodendroglial lineage comprises two cell types: oligodendrocyte precursor cells and oligodendrocytes. However, recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states, prompting a revision of the existing terminology. Going forward, the oligodendroglial lineage should be delineated into five distinct cell states: oligodendrocyte precursor cells, committed oligodendrocyte precursor cells, newly formed oligodendrocytes, myelin-forming oligodendrocytes, and mature oligodendrocytes. This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts. Adopting this uniform terminology will facilitate comparison and integration of data across studies. This, including the consolidation of findings from various demyelinating models, is essential to better understand the pathogenesis of demyelinating diseases. Additionally, comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure. Thus, by standardizing terminology and synthesizing data from diverse studies across different animal models, we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, all of which involve oligodendroglial and myelin dysfunction.}, }
@article {pmid39664805, year = {2025}, author = {Xing, H and McGregor, SKM and Batista, BD and Whitefield, C and Stone, ISJ and Murray, CE and Hurst, RM and Liu, Y and Chow, S and Fahrenhorst-Jones, T and Zhao, Q and Houston, SD and Hu, SH and Lonhienne, T and Nouwens, A and Burns, JM and Savage, GP and Walter, GH and Guddat, LW and Rafter, MA and Williams, CM}, title = {In search of herbistasis: COT-metsulfuron methyl displays rare herbistatic properties.}, journal = {Chemical science}, volume = {16}, number = {2}, pages = {649-658}, pmid = {39664805}, issn = {2041-6520}, abstract = {Weed management is an essential intervention for maintaining food security and protecting biodiversity but is heavily reliant on chemical control measures (i.e., herbicides). Concerningly, only one herbicide has been developed with a new mode of action (MOA) since the 1980s. Therefore, alternative strategies for preventing weed growth need to be explored. The lesser-known concept of halting weed growth through herbistasis could be one strategy to alleviate the lack of success in obtaining new MOA leads, but this type of activity has rarely been investigated. Herein reported is a bioisosteric cyclooctatetraene (COT) for phenyl ring replacement tactic, using the commercial acetolactate synthase (ALS) inhibitor metsulfuron methyl, that has unearthed a rare agent displaying herbistatic properties against the weed, Cryptostegia grandiflora (rubber vine).}, }
@article {pmid39664295, year = {2024}, author = {Chen, LX and Zhang, MD and Xu, HF and Ye, HQ and Chen, DF and Wang, PS and Bao, ZW and Zou, SM and Lv, YT and Wu, ZY and Li, HF}, title = {Single-Nucleus RNA Sequencing Reveals the Spatiotemporal Dynamics of Disease-Associated Microglia in Amyotrophic Lateral Sclerosis.}, journal = {Research (Washington, D.C.)}, volume = {7}, number = {}, pages = {0548}, pmid = {39664295}, issn = {2639-5274}, abstract = {Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human SOD1 gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord. Using reverse transcription quantitative polymerase chain reaction, RNAscope in situ hybridization, and flow cytometry, we found that DAM increased in number as the disease progressed, reaching their peak in the late disease stage. DAM responded to disease progression in both SOD1[G93A] mice and sporadic ALS and C9orf72-mutated patients. Motor neuron loss in SOD1[G93A] mice exhibited 2 accelerated phases: P90 to P110 (early stage) and P130 to P150 (late stage). Some markers were synchronized with the accelerated phase of motor neuron loss, suggesting that these proteins may be particularly responsive to disease progression. Through pseudotime trajectory analysis, we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia. Interestingly, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in SOD1[G93A] mice and observed that DAM survival is independent of CSF1R. An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes. These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS. Inducing the DAM phenotype and enhancing its function during the early phase of disease progression, or the time window between P130 and P150 where motor neuron loss slows, could serve as a neuroprotective strategy for ALS.}, }
@article {pmid39663989, year = {2025}, author = {Das, U and Gayan, A and Biswas, R}, title = {A highly sensitive facile plasmonic scheme for assessment of melamine in raw milk.}, journal = {Analytical methods : advancing methods and applications}, volume = {17}, number = {3}, pages = {552-561}, doi = {10.1039/d4ay01764a}, pmid = {39663989}, issn = {1759-9679}, mesh = {*Triazines/chemistry/analysis ; *Milk/chemistry ; Animals ; *Metal Nanoparticles/chemistry ; *Gold/chemistry ; *Silver/chemistry ; Food Contamination/analysis ; Limit of Detection ; Colorimetry/methods ; }, abstract = {This work presents two novel devices with a microcontroller and two different light sensors, namely, Light Dependent Resistor (LDR) and Ambient Light Sensor (ALS), which can provide a quantitative output from the colorimetric variations of citrate capped borohydride reduced silver nanoparticles (AgNPs) and citrate capped gold nanoparticles (AuNPs) upon addition of melamine adulterated milk. The limit of detection (LOD) of the LDR setup with AgNPs and AuNPs was found to be 1.24 ppm and 1.68 ppm, respectively, and the corresponding recovery rates were 92.86% and 88.57%, respectively. The device fabricated with the ALS with AgNPs displayed a recovery rate of 97.14% with a LOD value of 0.64 ppm.}, }
@article {pmid39662855, year = {2025}, author = {Yang, ZF and Jiang, XC and Gao, JQ}, title = {Present insights into the progress in gene therapy delivery systems for central nervous system diseases.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125069}, doi = {10.1016/j.ijpharm.2024.125069}, pmid = {39662855}, issn = {1873-3476}, mesh = {Humans ; *Genetic Therapy/methods ; *Central Nervous System Diseases/therapy ; Animals ; *Gene Transfer Techniques ; *Genetic Vectors/administration &amp; dosage ; Dependovirus/genetics ; }, abstract = {Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases. Despite the remarkable progress in refining and enhancing the structural design of gene therapy agents, substantial obstacles persist in their effective and safe delivery within living systems. To surmount these obstacles, a diverse array of gene delivery systems has been devised and continuously improved. Notably, Adeno-Associated Virus (AAVs)-based viral gene vectors and lipid-based nanocarriers have each advanced the in vivo delivery of gene therapies to various extents. This review aims to concisely summarize the pathophysiological foundations of CNS diseases and to shed light on the latest advancements in gene delivery vector technologies. It discusses the primary categories of these vectors, their respective advantages and limitations, and their specialized uses in the context of gene therapy delivery.}, }
@article {pmid39662651, year = {2025}, author = {Keethedeth, N and Anantha Shenoi, R}, title = {Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment.}, journal = {Mitochondrion}, volume = {81}, number = {}, pages = {102000}, doi = {10.1016/j.mito.2024.102000}, pmid = {39662651}, issn = {1872-8278}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism ; Drug Delivery Systems ; Nanoparticles/chemistry ; Animals ; }, abstract = {Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.}, }
@article {pmid39662532, year = {2025}, author = {Bayansan, O and Bhan, P and Chang, CY and Barmaver, SN and Shen, CP and Wagner, OI}, title = {UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106766}, doi = {10.1016/j.nbd.2024.106766}, pmid = {39662532}, issn = {1095-953X}, mesh = {Animals ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Caenorhabditis elegans/metabolism ; *rab3 GTP-Binding Proteins/metabolism/genetics ; *Synaptic Vesicles/metabolism ; Kinesins/metabolism/genetics ; Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Animals, Genetically Modified ; Pleckstrin Homology Domains ; Nerve Tissue Proteins ; Intercellular Signaling Peptides and Proteins ; }, abstract = {Kinesin-3 KIF1A (UNC-104 in C. elegans) is the major axonal transporter of synaptic vesicles and mutations in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), encompassing Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis and hereditary spastic paraplegia. UNC-104 binds to lipid bilayers of synaptic vesicles via its C-terminal PH (pleckstrin homology) domain. Since this interaction is relatively weak and non-specific, we hypothesize that other, more specific, interaction schemes exist. From the literature, it is evident that UNC-104 regulator SYD-2 interacts with UNC-10 and that UNC-10 itself interacts with RAB-3 bound to synaptic vesicles. RT-PCR and Western blot experiments expose genetic relationships between unc-10 and syd-2, but not between unc-10 and rab-3. Also, neither unc-10 nor rab-3 affects UNC-104 expression. However, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays reveal functional interactions between UNC-104, SYD-2, UNC-10 and RAB-3. Though both SNB-1 and RAB-3 are actively transported by UNC-104, motility of RAB-3 is facilitated in the presence of SYD-2 and UNC-10. Deletion of UNC-104's PH domain did not affect UNC-104/RAB-3 colocalization, but significantly affected UNC-104/SNB-1 colocalization. Similarly, motility of RAB-3-labeled vesicles is only slightly altered in nematodes carrying a point mutation in the PH domain, whereas movement of SNB-1 is significantly reduced in this mutant. Western blots from purified fractions of synaptic vesicles reveal strong reduction of UNC-104 in rab-3/unc-10 double mutants. Our findings suggest that the UNC-10/SYD-2 complex acts as a functional linker to connect UNC-104 to RAB-3-containing vesicles. Thus, this linker complex contributes to the specificity of motor/cargo interactions.}, }
@article {pmid39662462, year = {2025}, author = {Huang, C and Qiu, L and Zhou, W and Shao, C and Wang, X and Zhang, Q and Chen, W and Xiong, M and Huang, M and Tang, M and Zou, L and Xu, X}, title = {A human-induced pluripotent stem cell (iPSC) line (SMUSHi006-A) from an ALS patient carrying a mutation c.1126C &gt; T in the FUS gene.}, journal = {Stem cell research}, volume = {82}, number = {}, pages = {103604}, doi = {10.1016/j.scr.2024.103604}, pmid = {39662462}, issn = {1876-7753}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; *RNA-Binding Protein FUS/genetics ; *Mutation ; Cell Line ; Cell Differentiation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Four major genes associated with ALS-SOD1, TARDBP, FUS, and C9orf72-have been identified, with the fused in sarcoma (FUS) gene demonstrating considerable genetic heterogeneity. Our research group has previously established an induced pluripotent stem (iPS) cell line harboring the c.1562G > A mutation in the FUS gene. The objective of this study is to create another iPS cell line featuring the pathogenic c.1126C > T mutation in the FUS gene. This research aims not only to establish a disease model for ALS linked to FUS mutations but also to pave the way for potential therapeutic interventions.}, }
@article {pmid39660938, year = {2025}, author = {Kashiwagi-Hakozaki, M and Ikemura, M and Naruse, H and Takahashi, Y and Toda, T and Ushiku, T}, title = {An autopsy case report of amyotrophic lateral sclerosis with unusual basophilic inclusions exhibiting immunopositivity for optineurin.}, journal = {Pathology international}, volume = {75}, number = {2}, pages = {121-123}, doi = {10.1111/pin.13501}, pmid = {39660938}, issn = {1440-1827}, }
@article {pmid39659975, year = {2024}, author = {Kim, HJ and Ban, JJ and Kang, J and Im, HR and Ko, SH and Sung, JJ and Park, SH and Park, JE and Choi, SJ}, title = {Single-cell analysis reveals expanded CD8[+] GZMK [high] T cells in CSF and shared peripheral clones in sporadic amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae428}, pmid = {39659975}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brain and spinal cord. Despite the crucial role of aberrant immune responses in ALS pathogenesis, studies investigating immunological profiles in the cerebrospinal fluid (CSF) of patients with ALS have reported inconsistent findings. Herein, we explored the intrathecal adaptive immune response and features of circulating T cells between CSF and blood of patients with ALS using single-cell RNA and T-cell receptor (TCR) sequencing. This study comprised a total of 11 patients with apparently sporadic ALS and three controls with non-inflammatory diseases. We collected CSF from all participants, and for three patients with ALS, we additionally obtained paired samples of peripheral blood mononuclear cells (PBMCs). Utilizing droplet-based single-cell RNA and TCR sequencing, we analysed immunological profiles, gene expression characteristics and clonality. Furthermore, we examined T-cell characteristics in both PBMC and CSF samples, evaluating the shared T-cell clones across these compartments. In the CSF, patients with ALS exhibited a lower proportion of CD4[+] T cells (45.2 versus 61.2%, P = 0.005) and a higher proportion of CD8[+] GZMK [hi] effector memory T cells (TEMs) than controls (21.7 versus 16.8%, P = 0.060). Higher clonality was observed in CD8[+] TEMs in patients with ALS compared with controls. In addition, CSF macrophages of patients with ALS exhibited a significant increase in chemokines recruiting CD8[+] TEMs. Immunohistochemical analysis showed slightly higher proportions of T cells in the perivascular and parenchymal spaces in patients with ALS than in controls, and CD8[+] TEMs co-localized with neurons or astrocytes in the motor cortices of patients with ALS. Clonally expanded CD8[+] GZMK [hi] TEMs primarily comprised shared T-cell clones between CSF and PBMCs. Moreover, the shared CD8[+] TEMs of PBMCs exhibited gene expression profiles similar to CSF T cells. Patients with ALS showed an increase in proportion and clonality of CD8[+] GZMK [hi] TEMs and activated features of macrophages in CSF. The shared T-cell clone between CSF and blood was mainly composed of expanded CD8[+] GZMK [hi] TEMs. In conclusion, single-cell immune profiling provided novel insights into the pathogenesis of ALS, characterized by activated macrophages and clonally expanded CD8[+] T cells potentially communicating with the central nervous system and peripheral circulation.}, }
@article {pmid39659885, year = {2024}, author = {Wan, H and Qian, W and Wei, B and Tian, K and Chen, Z and Zhang, J and Chen, F}, title = {A bibliometric analysis of gene editing and amyotrophic lateral sclerosis (from 2004 to 2024).}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1499025}, pmid = {39659885}, issn = {1662-4548}, abstract = {OBJECTIVE: To learn more about gene editing and ALS, and to provide a comprehensive view of gene editing for further treatment of amyotrophic lateral sclerosis.<br><br>METHODS: We searched 1981 records from Web of Science core collection and Pubmed, Scopus, of which 1,292 records were obtained after exclusion. We then scientifically and metrologically analyzed these records for spatial and temporal distribution, author distribution, subject categories, subject distribution, references, and keywords using R, software CiteSpace and VOSviewer.<br><br>RESULTS: Our analysis provides basic information about research in the field, suggests that the field has stabilized over the past decade, and identifies potential partners for interested researchers. Current research in this area is focused on inflammatory mechanisms, immune mechanisms, related diseases, and associated cytokines in ALS.<br><br>CONCLUSION: RNA Editing, Antisense Bligonucleotide, and Glycine Receptor are cutting-edge research topics in this field, which is undergoing rapid development. We hope that this work will provide new ideas for advancing the scientific research and clinical application of ALS.}, }
@article {pmid39659205, year = {2024}, author = {Alzahrani, AK and A S, A and Imran, M}, title = {Unraveling the molecular mechanisms of ALS: a network biology and structural modeling approach of investigating the impact of C9orf72 mutations.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/07391102.2024.2437682}, pmid = {39659205}, issn = {1538-0254}, abstract = {C9orf72 is a major genetic factor in Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder affecting brain and spinal cord neurons, and comprehending its mutational impact is crucial for developing ALS therapies. Therefore, the current study's protein-protein interaction (PPI) network for C9orf72 was meticulously mapped to identify key interactors that might influence the disease mechanism. Among the identified proteins, SMCR8 emerged as a prominent candidate due to its high connectivity (total network contribution = 7.896) within the C9orf72-associated network, suggesting a potential role in modulating the effects of C9orf72 mutations. Analysis of C9orf72 mutations highlighted the I525T mutation, which significantly destabilizes the protein, as indicated by a ΔΔG value of -2.02 kcal/mol. Further investigation involved comparing the structural dynamics of the wild-type C9orf72 and its mutant variants through molecular docking and dynamics simulations. The wild-type demonstrated more stable structural conformation over time, as shown by its RMSD profile than its mutant counterpart. However, after 80 nanoseconds, the mutant variant achieved a similar RMSD stability level. Intriguingly, the mutant formed a more stable complex with SMCR8, evident from its lower binding free energy (-64.18 kcal/mol compared to the wild type's -34.82 kcal/mol). Moreover, per-residue decomposition analysis further revealed critical interactions at specific residues. The wild-type protein showed a significant stabilizing interaction at Arg785, whereas the mutant favored Arg262, indicating a potential shift in binding affinity and site due to the mutation. This shift suggests an altered binding landscape in the mutant C9orf72, which might contribute to the dysregulated protein interactions and cellular processes associated with ALS pathology. The study thus underscores the pathological hyper-stability of the mutant C9orf72, highlighting its potential role in the progression of ALS.}, }
@article {pmid39656022, year = {2024}, author = {Prentiss, AM and Baggio, C and Pagett, J and Kulinich, AO and Ethell, IM and Muzzarelli, K and Assar, Z and Pellecchia, M}, title = {Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {24}, pages = {22245-22253}, pmid = {39656022}, issn = {1520-4804}, support = {R01 CA168517/CA/NCI NIH HHS/United States ; P41 GM103311/GM/NIGMS NIH HHS/United States ; R01 NS129555/NS/NINDS NIH HHS/United States ; P20 CA242620/CA/NCI NIH HHS/United States ; R01 NS107479/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptor, EphA4/metabolism/antagonists &amp; inhibitors/chemistry ; Ligands ; Humans ; Binding Sites ; Protein Binding ; Peptides, Cyclic/chemistry/pharmacology/metabolism/chemical synthesis ; Drug Design ; Protein Domains/drug effects ; Models, Molecular ; }, abstract = {The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) and neurodegenerative diseases (amyotrophic lateral sclerosis and Alzheimer's disease). However, advances in validating EphA4 as a possible drug target have been limited by the lack of suitable pharmacological inhibitors. Recently, we reported on the design of potent EphA4 agonistic agents targeting its ligand binding domain (LBD). Based on previous studies with a phage display cyclic peptide inhibitor, we designed a β-hairpin mimetic with high affinity for EphA4-LBD. These agents hold great promise for further validation and development of EphA4-based therapeutics. Moreover, our studies introduce a possible strategy for the design of constrained β-hairpin peptides.}, }
@article {pmid39655696, year = {2025}, author = {Di Iacovo, A and D'Agostino, C and Bhatt, M and Romanazzi, T and Giovannardi, S and Cinquetti, R and Roseti, C and Bossi, E}, title = {The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16265}, pmid = {39655696}, issn = {1471-4159}, support = {860954//H2020 Marie Sk&#x142;odowska-Curie Actions/ ; }, mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism/biosynthesis ; *Excitatory Amino Acid Transporter 2/metabolism/genetics/biosynthesis ; *Xenopus laevis ; Humans ; Oocytes/metabolism ; Female ; Neuroglia/metabolism ; }, abstract = {Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.}, }
@article {pmid39655539, year = {2025}, author = {Canosa, A and Martino, A and Manera, U and Giuliani, A and Vasta, R and Palumbo, F and Grassano, M and Morbelli, SD and Pardini, M and Chiaravalloti, A and Schillaci, O and Leenders, KL and Kogan, RV and Polverari, G and Zocco, G and Pede, FD and Mattei, F and Cabras, S and Matteoni, E and Moglia, C and Calvo, A and Chiò, A and Pagani, M}, title = {Sex-related differences in amyotrophic lateral sclerosis: A 2-[[18]F]FDG-PET study.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16588}, pmid = {39655539}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; RF-2016- 02362405//Ministero della Salute/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Universit&#xe0; e della Ricerca/ ; //Fondation Thierry Latran/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/metabolism ; Male ; Female ; Middle Aged ; *Positron-Emission Tomography ; *Fluorodeoxyglucose F18 ; Aged ; *Sex Characteristics ; *Brain/diagnostic imaging/metabolism ; Adult ; }, abstract = {PURPOSE: We investigated sex-related brain metabolic differences in Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC).<br><br>METHODS: We collected two equal-sized groups of male (m-ALS) and female ALS (f-ALS) patients (n&#x2009;=&#x2009;130 each), who underwent 2-[[18]F]FDG-PET at diagnosis, matched for site of onset, cognitive status and King's stage. We included 168 age-matched healthy controls, half female (f-HC) and half male (m-HC). We compared brain metabolism of males and females separately for ALS and HC, including age as covariate. A differential network analysis was performed to evaluate brain connectivity.<br><br>RESULTS: M-ALS showed relative hypometabolism of bilateral medial frontal, parietal and occipital cortices, and left temporal cortex, compared to f-ALS. In node-wise comparison, f-ALS showed significantly higher connectivity in right middle cingulate cortex and left superior and medial frontal gyrus. In HC we did not find any sex-related differences.<br><br>CONCLUSION: Sex resulted a major determinant of brain metabolism and connectivity in ALS patients.}, }
@article {pmid39655175, year = {2024}, author = {Palm, A and Ekström, M and Emilsson, &#xd6; and Ersson, K and Ljunggren, M and Sundh, J and Grote, L}, title = {Control of hypercapnia and mortality in home mechanical ventilation: the population-based DISCOVERY study.}, journal = {ERJ open research}, volume = {10}, number = {6}, pages = {}, pmid = {39655175}, issn = {2312-0541}, abstract = {BACKGROUND: Studies on the survival of patients with home mechanical ventilation (HMV) are sparse. We aimed to analyse the impact of controlled hypercapnia on survival over 27 years among patients with HMV in Sweden.<br><br>STUDY DESIGN AND METHODS: Population-based cohort study of adult patients starting HMV in the Swedish Registry for Respiratory Failure (Swedevox) during 1996-2022 cross-linked with the National Cause of Death registry. Mortality risk factors were analysed using crude and multivariable Cox regression models, including adjustments for anthropometrics, comorbidities, the underlying diagnosis causing chronic hypercapnic respiratory failure (CRF) and the control of hypercapnia (P aCO2 &#x2264;6.0&#x2005;kPa) at follow-up.<br><br>RESULTS: We included 10&#x2009;190 patients (50.1% women, age 62.9&#xb1;14.5&#x2005;years). Control of hypercapnia at follow-up after 1.3&#xb1;0.9&#x2005;years was associated with lower mortality, hazard ratio (HR) 0.74 (95% CI 0.68-0.80) and the association was strongest in those with pulmonary disease, restrictive thoracal disease (RTD), obesity hypoventilation syndrome (OHS) and amyotrophic lateral sclerosis (ALS). Predictors for increased mortality included age, Charlson Comorbidity Index, supplemental oxygen therapy and acute start of HMV therapy. Median survival varied between 0.8&#x2005;years (95% CI 0.8-0.9 (n=1401)) for ALS and 7.6&#x2005;years (95% CI 6.9-8.6 (n=1061)) for neuromuscular disease. Three-year survival decreased from 76% (95% CI 71-80) between 1996 and 1998 to 52% (95% CI 50-55) between 2017 and 2019. When adjusting for underlying diagnosis and age, the association between start year and decreased survival disappeared, HR 1.00 (95% CI 0.99-1.01).<br><br>CONCLUSION: Controlling P aCO2 is a key treatment goal for survival in HMV therapy. Survival differed markedly between diagnosis and age groups, and survival rates have declined as the patient group has aged.}, }
@article {pmid39655131, year = {2024}, author = {Mori, Y and Kenzaka, T}, title = {Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e73320}, pmid = {39655131}, issn = {2168-8184}, abstract = {Amyloid light chain (AL) amyloidosis is a disease in which ALs, which are proteins with fibrous structures, are deposited in systemic organs, causing functional impairment. Diagnosis is often difficult because of non-specific and varied symptoms. We report a case of systemic AL amyloidosis that was diagnosed as a result of repeated syncope. A 76-year-old woman was brought to the emergency room with multiple episodes of loss of consciousness over the past five years. She visited the major hospital, where pulmonary thromboembolism and symptomatic epilepsy were considered possible causes. Orthostatic hypotension was observed after being transferred to our hospital for rehabilitation. We performed diagnostic tests, including blood tests, imaging, and a head-up tilt test, which confirmed severe orthostatic hypotension. A gastrointestinal biopsy with Congo red staining confirmed the presence of amyloid deposits. AL amyloidosis (λ) was diagnosed using immunohistochemical staining. Given her age and prolonged bed rest, she was determined that she could not tolerate chemotherapy and was discharged upon her request. To the best of our knowledge, this is the first report of systemic AL amyloidosis presenting with orthostatic hypotension severe enough to cause syncope due to autonomic neuropathy. Autonomic neuropathy should be considered, and amyloidosis should be included in the differential diagnosis when a patient presents with recurrent syncope.}, }
@article {pmid39654963, year = {2024}, author = {Sun, P and Niu, L and He, P and Yu, H and Chen, J and Cui, H and Li, X}, title = {Trp-574-Leu and the novel Pro-197-His/Leu mutations contribute to penoxsulam resistance in Echinochloa crus-galli (L.) P. Beauv.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1488976}, pmid = {39654963}, issn = {1664-462X}, abstract = {Recently, due to the widespread use of the acetolactate synthase (ALS)-inhibiting herbicide penoxsulam in paddy fields in China, Echinochloa crus-galli (L.) P. Beauv. has become a problematic grass weed that is frequently not controlled, posing a threat to weed management and rice yield. There are many reports on target-site mutations of ALS inhibiting herbicides; however, the detailed penoxsulam resistance mechanism in E. crus-galli remains to be determined. Greenhouse and laboratory studies were conducted to characterize target-site resistance mechanisms in JL-R, AH-R, and HLJ-R suspected resistant populations of E. crus-galli survived the field-recommended dose of penoxsulam. The whole-plant dose-response testing of E. crus-galli to penoxsulam confirmed the evolution of moderate-level resistance in two populations, JL-R (9.88-fold) and HLJ-R (8.66-fold), and a high-level resistance in AH-R (59.71-fold) population. ALS gene sequencing identified specific mutations in resistant populations, including Pro-197-His in ALS1 for JL-R, Trp-574-Leu in ALS1 for AH-R, and Pro-197-Leu in ALS2 for HLJ-R. In vitro ALS activity assays demonstrated a significantly higher activity in AH-R compared to the susceptible population (YN-S). Molecular docking studies revealed that Trp-574-Leu mutation primarily reduced the enzyme's ability to bind to the triazole-pyrimidine ring of penoxsulam due to decreased π-π stacking interactions, while Pro-197-His/Leu mutations impaired binding to the benzene ring by altering hydrogen bonds and hydrophobic interactions. Additionally, the Pro-197-His/Leu amino acid residue changes resulted in alterations in the shape of the active channel, impeding the efficient entry of penoxsulam into the binding site in the ALS protein. The three mutant ALS proteins expressed via the Bac-to-Bac baculovirus system exhibited notably lower activity inhibition rates than the non-mutant ALS proteins to penoxsulam, indicating all three ALS mutations reduce sensitivity to penoxsulam. This study elucidated the distinct impacts of the Pro-197-His/Leu and Trp-574-Leu mutations in E. crus-galli to penoxsulam resistance. Notably, the Trp-574-Leu mutation conferred stronger resistance to penoxsulam compared to the Pro-197-His/Leu mutations in E. crus-galli. The Pro-197-His/Leu mutations were first detected in E. crus-galli conferring penoxsulam resistance. These findings provide deeper insights into the molecular mechanisms underlying target-site resistance to penoxsulam in E. crus-galli.}, }
@article {pmid39654532, year = {2024}, author = {Dave, KD and Oskarsson, B and Yersak, J and Krauss, R and Heiman-Patterson, T and Lomen-Hoerth, C and Selig, WKD and Halpern Paul, I and Schaeffer, M and Garcia-Trujillo, B and Waldo, D and Thakur, N and Babu, S}, title = {Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2432034}, pmid = {39654532}, issn = {2167-9223}, abstract = {Objectives: To evaluate neurologists and other clinicians' contributions to U.S. ALS diagnostic timelines. Background: Over the past two decades, the average time to ALS diagnosis in the U.S. has remained unchanged at 12 months. ALS patients see 3-4 clinicians prior to referral to an ALS specialist for diagnosis confirmation and/or treatment initiation. There is an urgent need to identify where delays occur, so that targeted clinician awareness may be raised about early suspicion and referrals. Methods: Review of Medicare claims database for health care utilization patterns by ALS beneficiaries during diagnostic journey. Survey of typical clinic wait times for new consultations reported by 75-78 ALS Certified Treatment Centers of Excellence (2019-2021). Results: During 2011-2021, 78,520 Medicare beneficiaries were diagnosed with ALS (T0). The mean (median) timelines between first neurologist ambulatory visit and T0, is 16.5 (11.0) months; mean ± SD for ALS/neuromuscular providers being 9.6 ± 12.6 months versus 16.7 ± 17.5 months for non-neuromuscular neurologists. During the 12-months preceding T0, an ALS patient undergoes median(max) 1.5(4.0) brain-MRIs, 1.6(6.0) spine-MRIs, and 1.3(4.0) electromyography studies. Greater than 75% of ALS centers consistently report ≤ 4 week wait times for new ALS consults. This study introduces "thinkALS," an easy-to-use clinical diagnostic and referral guide for non-ALS neurologists to tackle this challenge. Conclusions: This study is the first to provide metrics on how non-neuromuscular/ALS specialists contribute to ALS diagnostic timelines in the U.S.}, }
@article {pmid39651269, year = {2024}, author = {O'Neill, K and Shaw, R and Bolger, I and ,  and Tam, O and Phatnani, H and Hammell, MG}, title = {ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.19.603731}, pmid = {39651269}, issn = {2692-8205}, support = {R01 NS116350/NS/NINDS NIH HHS/United States ; R01 NS118183/NS/NINDS NIH HHS/United States ; R01 NS118570/NS/NINDS NIH HHS/United States ; RF1 NS118570/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this general heterogeneity, several common factors have been identified. For example, nearly all patients show pathological accumulations of phosphorylated TDP-43 protein in affected regions of the motor cortex and spinal cord. Moreover, large patient cohort studies have revealed that most patient samples can be grouped into a small number of ALS subtypes, as defined by their transcriptomic profiles. These ALS molecular subtypes can be grouped by whether postmortem motor cortex samples display signatures of: mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated transposable element de-silencing (ALS-TE). In this study, we have built a deep layer ALS neural network classifier (DANcer) that has learned to accurately assign patient samples to these ALS subtypes, and which can be run on either bulk or single-cell datasets. Upon applying this classifier to an expanded ALS patient cohort from the NYGC ALS Consortium, we show that ALS Molecular Subtypes are robust across clinical centers, with no new subtypes appearing in a cohort that has quadrupled in size. Signatures from two of these molecular subtypes strongly correlate with disease duration: ALS-TE signatures in cortex and ALS-Glia signatures in spinal cord, revealing molecular correlates of clinical features. Finally, we use single nucleus RNA sequencing to reveal the cell type-specific contributions to ALS subtype, as determined by our single-cell classifier (scDANCer). Single-cell transcriptomes reveal that ALS molecular subtypes are recapitulated in neurons and glia, with both ALS-wide shared alterations in each cell type as well as ALS subtype-specific alterations. In summary, ALS molecular subtypes: (1) are robust across large cohorts of sporadic and familial ALS patient samples, (2) represent a combination of cellular, genetic, and pathological features, and (3) correlate with clinical features of ALS.}, }
@article {pmid39651224, year = {2024}, author = {Kodavati, M and Maloji Rao, VH and Mitra, J and Hegde, ML}, title = {Selective Inhibition of Cytosolic PARylation via PARG99: A Targeted Approach for Mitigating FUS-associated Neurodegeneration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.25.625276}, pmid = {39651224}, issn = {2692-8205}, abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are characterized by complex etiologies, often involving disruptions in functions of RNA/DNA binding proteins (RDBPs) such as FUS and TDP-43. The cytosolic mislocalization and aggregation of these proteins are linked to accumulation of unresolved stress granules (SGs), which exacerbate the disease progression. Poly-ADP-ribose polymerase (PARP)-mediated PARylation plays a critical role in this pathological cascade, making it a potential target for intervention. However, conventional PARP inhibitors are limited by their detrimental effects on DNA repair pathways, which are already compromised in ALS. To address this limitation, we investigated a strategy focused on targeting the cytosolic compartment by expressing the cytosol-specific, natural PAR- glycohydrolase (PARG) isoform, PARG99. Using ALS patient derived FUS mutant induced pluripotent cells (iPSCs) and differentiated neurons, we observed elevated levels of FUS in insoluble fractions in mutant cells compared to mutation-corrected isogenic lines. The insoluble FUS as well as TDP-43 levels increased further in sodium arsenite-treated or oxidatively stressed cells, correlating with accumulation of unresolved SGs. Notably, both PARG99 and PARP inhibitors reduced SG formation and insoluble FUS levels, however, PARG99 treated cells exhibited significantly lower DNA damage markers and improved viability under oxidative and arsenite stress. This study highlights the potential of PARG99 as a cytosol-specific intervention to mitigate FUS-associated toxicity while preserving critical nuclear DNA repair mechanisms, offering a promising strategy for addressing the underlying pathology of ALS and potentially other SG-associated neurodegenerative diseases.}, }
@article {pmid39651197, year = {2024}, author = {Grant, OA and Iacoangeli, A and Zwamborn, RAJ and van Rheenen, W and Byrne, R and Van Eijk, KR and Kenna, K and van Vugt, JJFA and Cooper-Knock, J and Kenna, B and Vural, A and Topp, S and Campos, Y and Weber, M and Smith, B and Dobson, R and van Es, MA and Vourc'h, P and Corcia, P and de Carvalho, M and Gotkine, M and Panades, MP and Mora, JS and Mill, J and Garton, F and McRae, A and Wray, NR and Shaw, PJ and Landers, JE and Glass, JD and Shaw, CE and Basak, N and Hardiman, O and Van Damme, P and McLaughlin, RL and van den Berg, LH and Veldink, JH and Al-Chalabi, A and Al Khleifat, A}, title = {Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.22.624866}, pmid = {39651197}, issn = {2692-8205}, abstract = {Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3'UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.}, }
@article {pmid39651147, year = {2024}, author = {Fleming, AC and Rao, NR and Wright, M and Savas, JN and Kiskinis, E}, title = {The ALS-associated co-chaperone DNAJC7 mediates neuroprotection against proteotoxic stress by modulating HSF1 activity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.12.01.626216}, pmid = {39651147}, issn = {2692-8205}, abstract = {The degeneration of neurons in patients with amyotrophic lateral sclerosis (ALS) is commonly associated with accumulation of misfolded, insoluble proteins. Heat shock proteins (HSPs) are central regulators of protein homeostasis as they fold newly synthesized proteins and refold damaged proteins. Heterozygous loss-of- function mutations in the DNAJC7 gene that encodes an HSP co-chaperone were recently identified as a cause for rare forms of ALS, yet the mechanisms underlying pathogenesis remain unclear. Using mass spectrometry, we found that the DNAJC7 interactome in human motor neurons (MNs) is enriched for RNA binding proteins (RBPs) and stress response chaperones. MNs generated from iPSCs with the ALS-associated mutation R156X in DNAJC7 exhibit increased insolubility of its client RBP HNRNPU and associated RNA metabolism alterations. Additionally, DNAJC7 haploinsufficiency renders MNs increasingly susceptible to proteotoxic stress and cell death as a result of an ablated HSF1 stress response pathway. Critically, expression of HSF1 in mutant DNAJC7 MNs is sufficient to rescue their sensitivity to proteotoxic stress, while postmortem ALS patient cortical neurons exhibit a reduction in the expression of HSF1 pathway genes. Taken together, our work identifies DNAJC7 as a crucial mediator of HNRNPU function and stress response pathways in human MNs and highlights HSF1 as a therapeutic target in ALS.}, }
@article {pmid39650285, year = {2024}, author = {Hu, Y and Deeba, E and Kläppe, U and Öijerstedt, L and Andersson, J and Ruffin, N and Piehl, F and Ingre, C and Fang, F and Seitz, C}, title = {Immune cells and the trajectories of depression, anxiety, and cognitive function among people with amyotrophic lateral sclerosis.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {42}, number = {}, pages = {100907}, pmid = {39650285}, issn = {2666-3546}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) represents a complex syndrome characterized by motor, psychiatric, and cognitive symptoms, where associations between cellular immune features and non-motor manifestations remain unknown.<br><br>METHODS: In this cohort study, we enrolled 250 incident people with ALS (pwALS) assessed with the Hospital Anxiety and Depression Scale, and 226 pwALS with the Montreal Cognitive Assessment, including 218 overlapping pwALS. All individuals were diagnosed between January 2015 and January 2023 in Stockholm, Sweden. We applied joint latent class models to delineate distinct trajectories of anxiety, depression, and cognition, incorporating survival outcomes. A majority of the pwALS had data on leukocyte counts and flow cytometric analyses using a comprehensive T cell panel. We then used immune cell subtypes measured at diagnosis to predict trajectories of these outcomes following ALS diagnosis.<br><br>RESULTS: We identified two distinct trajectories for anxiety, depression, and cognitive function following ALS diagnosis. PwALS with longer survival displayed more stable trajectories, while those with shorter survival showed decreasing anxiety symptom, increasing depressive symptom, and declining cognitive function. Higher count of leukocytes at the time of ALS diagnosis tended to associate with anxiety and depression trajectories related to shorter survival. Among T cell subpopulations, several CD8[+] T cell subsets were associated with a stable trajectory of depressive symptom, and, in turn, better survival.<br><br>CONCLUSION: ALS-associated psychiatric and cognitive trajectories vary significantly between pwALS with different prognosis. Certain T cell subsets measured at diagnosis might be indicative of depression trajectories post-diagnosis.}, }
@article {pmid39649550, year = {2024}, author = {Han, S and Li, RH and Gao, P}, title = {Gut microbiota participates and remodels host metabolism: From treating patients to treating their gut flora.}, journal = {World journal of gastroenterology}, volume = {30}, number = {45}, pages = {4839-4843}, pmid = {39649550}, issn = {2219-2840}, mesh = {Humans ; *Gastrointestinal Microbiome ; Animals ; Uric Acid/blood/metabolism ; Hyperuricemia/microbiology/drug therapy/blood/metabolism ; Metabolomics/methods ; Feces/microbiology ; }, abstract = {In this editorial, we comment on Liu et al's article published in the recent issue of the World Journal of Gastroenterology. Biochemically and pathologically, Liu et al proved that the urate-lowering activity of leech total protein (LTP) was mainly attributed to the rectification of gut microbiota. Specifically, we noticed the change in Bacteroides and Akkermansia after LTP administration. Both bacteria have been reported to alleviate metabolic dysfunction-associated steatohepatitis and other chronic metabolic diseases. LTP was administrated through intragastric manners. Most possibly, LTP would be digested by the gut microbiota further. The anti-hyperuricemia effects should, to the most possible extent, be exerted by the peptides or their secondary metabolic products. Human gut microbiota communicates with other organs through metabolites generated by the microbes or co-metabolized with the host. Whether the anti-hyperuricemia effect could be partially ascribed to the microbiota metabolites also deserves to be discussed. Although metabolomics analysis was performed for serum samples, fecal metabolomics was highly advocated which could facilitate exact mechanism explanation. This study implied that gut microbiota contains many unexplored targets with different therapeutic potentials. It is foreseeable that utilizing these targets can avoid the impairment or side effects of directly using human targets to some extent.}, }
@article {pmid39649175, year = {2024}, author = {Harvey, C and Nowak, A and Zhang, S and Moll, T and Weimer, AK and Barcons, AM and Dos Santos Souza, C and Ferraiuolo, L and Kenna, K and Zaitlen, N and Caggiano, C and Shaw, PJ and Snyder, MP and Mill, J and Hannon, E and Cooper-Knock, J}, title = {Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39649175}, issn = {2693-5015}, support = {R01 HL101388/HL/NHLBI NIH HHS/United States ; P50 HL083800/HL/NHLBI NIH HHS/United States ; P30 DK116074/DK/NIDDK NIH HHS/United States ; R01 HL122939/HL/NHLBI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection of WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.}, }
@article {pmid39647703, year = {2025}, author = {Watters, JJ and Bell, MC and Que, SKT}, title = {Regarding response to Watters et al's "Educational intervention targeting primary care residents improves skin cancer recognition in patients with skin of color".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e105-e106}, doi = {10.1016/j.jaad.2024.11.051}, pmid = {39647703}, issn = {1097-6787}, }
@article {pmid39645528, year = {2024}, author = {Ríos-López, AL and Garza-Velásquez, MF and González, GM and Becerril-García, MA and Flores-Maldonado, O}, title = {Prevalence, virulence factors and antifungal susceptibility of oral isolates of Candida albicans from patients with cystic fibrosis in Mexico.}, journal = {Revista iberoamericana de micologia}, volume = {41}, number = {2-3}, pages = {31-36}, doi = {10.1016/j.riam.2024.09.001}, pmid = {39645528}, issn = {2173-9188}, mesh = {Humans ; *Cystic Fibrosis/microbiology/complications ; *Virulence Factors/genetics ; *Candida albicans/drug effects/isolation &amp; purification/genetics ; Mexico/epidemiology ; *Antifungal Agents/pharmacology ; *Microbial Sensitivity Tests ; Female ; Male ; Adult ; Young Adult ; Adolescent ; *Candidiasis, Oral/microbiology/epidemiology ; Prevalence ; Child ; Drug Resistance, Fungal ; Biofilms/growth &amp; development ; Mouth/microbiology ; Child, Preschool ; }, abstract = {BACKGROUND: Candida species are frequently isolated from the oral cavity of patients with cystic fibrosis. However, the information on the role of Candida in cystic fibrosis is scarce.<br><br>AIMS: This study aimed to evaluate the prevalence, virulence profile and antifungal susceptibility of oral isolates of Candida albicans recovered from patients with cystic fibrosis.<br><br>METHODS: Oropharyngeal swab samples were collected from sixty-five cystic fibrosis patients and sixty-five healthy individuals. Candida isolates were identified by MALDI-TOF VITEK-MS. Proteinase, phospholipase and esterase activity, biofilm production and level expression of ALS, SAP and PLB genes in C. albicans were evaluated. Minimal inhibitory concentration values were determined by means of an antifungal susceptibility test.<br><br>RESULTS: Oral Candida colonization in cystic fibrosis patients was 66.15%, while in healthy individuals was 36.92%. C. albicans was the most frequently isolated species. C. albicans strains from cystic fibrosis patients were high producers of protease and biofilm, and had higher expression levels of adhesin and protease-associated genes in comparison with healthy subjects. Among the C. albicans strains isolated from cystic fibrosis patients, 18.91% were resistant to itraconazole, while 16.21% exhibited resistance to ketoconazole and fluconazole, and only one strain was resistant to voriconazole.<br><br>CONCLUSIONS: This work represents a surveillance study on virulence patterns and antifungal susceptibility of Candida from the oropharyngeal tract in cystic fibrosis.}, }
@article {pmid39645221, year = {2025}, author = {Bajpai, A and Bharathi, V and Patel, BK}, title = {Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.}, journal = {European journal of pharmacology}, volume = {987}, number = {}, pages = {177187}, doi = {10.1016/j.ejphar.2024.177187}, pmid = {39645221}, issn = {1879-0712}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; *Antioxidants/pharmacology/therapeutic use ; *Huntington Disease/metabolism/drug therapy/pathology/genetics ; Molecular Targeted Therapy/methods ; Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; }, abstract = {Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.}, }
@article {pmid39645085, year = {2025}, author = {Ediriweera, GR and Sivaram, AJ and Cowin, G and Brown, ML and McAlary, L and Lum, JS and Fletcher, NL and Robinson, L and Simpson, JD and Chen, L and Wasielewska, JM and Byrne, E and Finnie, JW and Manavis, J and White, AR and Yerbury, JJ and Thurecht, KJ and Vine, KL}, title = {Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {221-235}, doi = {10.1016/j.jconrel.2024.11.074}, pmid = {39645085}, issn = {1873-4995}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/therapy ; *Oligonucleotides, Antisense/administration &amp; dosage ; *Superoxide Dismutase-1/genetics ; *Brain/metabolism ; *Mice, Inbred C57BL ; *Nanoparticles/administration &amp; dosage/chemistry ; *Mice, Transgenic ; Blood-Brain Barrier/metabolism ; Lipids/chemistry/administration &amp; dosage ; Male ; Motor Neurons/metabolism ; Mice ; Microbubbles ; Liposomes ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.}, }
@article {pmid39645043, year = {2025}, author = {Needle, C and Brinks, A and Shapiro, J and Lo Sicco, K}, title = {Response to Chen et al's "Emergence of Janus kinase inhibitors led to increase in proportion of severe alopecia areata patients receiving treatment: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e119-e120}, doi = {10.1016/j.jaad.2024.10.118}, pmid = {39645043}, issn = {1097-6787}, }
@article {pmid39644980, year = {2025}, author = {Guerra San Juan, I and Brunner, JW and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {Neurobiology of disease}, volume = {204}, number = {}, pages = {106759}, doi = {10.1016/j.nbd.2024.106759}, pmid = {39644980}, issn = {1095-953X}, mesh = {*Kinesins/metabolism/genetics ; *Axonal Transport/physiology ; Humans ; *Mitochondria/metabolism ; *Motor Neurons/metabolism ; *Axons/metabolism ; PTB-Associated Splicing Factor/metabolism ; Nerve Regeneration/physiology ; Cells, Cultured ; Neuronal Outgrowth/physiology ; }, abstract = {Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro. KIF5A deficiency caused reduced neurite complexity in young neurons (DIV14) and defects in axonal regeneration. KIF5A deficiency did not affect neurofilament transport but impaired mitochondrial motility and anterograde speed at DIV42. Notably, KIF5A deficiency strongly reduced anterograde transport of splicing factor proline/glutamine-rich (SFPQ)-associated RNA granules in DIV42 axons. Hence, KIF5A plays a critical role in promoting axonal regrowth after injury and in driving the anterograde transport of mitochondria and especially SFPQ-associated RNA granules in mature neurons.}, }
@article {pmid39644798, year = {2025}, author = {Toko, M and Ohshita, T and Nakamori, M and Ueno, H and Akiyama, Y and Maruyama, H}, title = {Myelin measurement in amyotrophic lateral sclerosis with synthetic MRI: A potential diagnostic and predictive method.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123337}, doi = {10.1016/j.jns.2024.123337}, pmid = {39644798}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Male ; Female ; *Myelin Sheath/pathology ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; Adult ; }, abstract = {BACKGROUND: Myelin damage has recently been highlighted as a major causative factor of amyotrophic lateral sclerosis (ALS). Although myelin damage has been pathologically identified in ALS, it has not been clinically evaluated. This study aimed to quantify myelin volume using synthetic MRI to evaluate myelin damage in patients with ALS, and determine its association with clinical parameters.<br><br>METHODS: We evaluated patients with ALS (n&#xa0;=&#xa0;35) and individuals (n&#xa0;=&#xa0;16) without intracranial disease using synthetic magnetic resonance imaging (MRI) and measured total myelin volume (TMV), myelin fraction (MYF), and myelin partial volume (VMY) in the cerebral peduncle and the posterior limb of the internal capsule (PLIC). We also investigated factors associated with acquired quantitative values.<br><br>RESULTS: The TMV was significantly lower in the patients with ALS than in the control group (P&#xa0;=&#xa0;0.045). The TMV (r&#xa0;=&#xa0;0.42, P&#xa0;=&#xa0;0.013) and MYF (r&#xa0;=&#xa0;0.34, P&#xa0;=&#xa0;0.047) significantly correlated with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores in the patients, and MYF was independent of the traditional white matter lesion grading score. The VMY of the PLIC was significantly lower in the ALS than the control group (P&#xa0;=&#xa0;0.018), and the ALS group significantly correlated with ALSFRS-R scores (r&#xa0;=&#xa0;0.36, P&#xa0;=&#xa0;0.033).<br><br>CONCLUSIONS: Myelin damage can be quantified by synthetic MRI as reduced myelin volume, with the possibility of predicting prognoses in patients with ALS. Furthermore, myelin measurements in the PLIC might be a novel diagnostic marker for ALS.}, }
@article {pmid39643934, year = {2025}, author = {Farrokhzad, R and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Insight Into Factors Influencing the Aggregation Process in Wild-Type and P66R Mutant SOD1: Computational and Spectroscopic Approaches.}, journal = {Proteins}, volume = {93}, number = {4}, pages = {885-907}, doi = {10.1002/prot.26765}, pmid = {39643934}, issn = {1097-0134}, mesh = {*Superoxide Dismutase-1/chemistry/genetics/metabolism ; Humans ; *Molecular Dynamics Simulation ; *Hydrophobic and Hydrophilic Interactions ; Protein Aggregates ; Mutation ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Spectroscopy, Fourier Transform Infrared ; Protein Aggregation, Pathological/genetics/metabolism ; Protein Folding ; Thermodynamics ; Protein Conformation, beta-Strand ; Gene Expression ; }, abstract = {Disturbances in metal ion homeostasis associated with amyotrophic lateral sclerosis (ALS) have been described for several years, but the exact mechanism of involvement is not well understood. To elucidate the role of metalation in superoxide dismutase (SOD1) misfolding and aggregation, we comprehensively characterized the structural features (apo/holo forms) of WT-SOD1 and P66R mutant in loop IV. Using computational and experimental methodologies, we assessed the physicochemical properties of these variants and their correlation with protein aggregation at the molecular level. Modifications in apo-SOD1 compared to holo-SOD1 were more pronounced in flexibility, stability, hydrophobicity, and intramolecular interactions, as indicated by molecular dynamics simulations. The enzymatic activities of holo/apo-WT SOD1 were 1.30 and 1.88-fold of the holo/apo P66R mutant, respectively. Under amyloid-inducing conditions, decreased ANS fluorescence intensity in the apo-form relative to the holo-form suggested pre-fibrillar species and amyloid aggregate growth due to occluded hydrophobic pockets. FTIR spectroscopy revealed that apo-WT-SOD1 and apo-P66R exhibited a mixture of parallel and intermolecular β-sheet structures, indicative of aggregation propensity. Aggregate species were identified using TEM, Congo red staining, and ThT/ANS fluorescence spectroscopy. Thermodynamic analyses with GdnHCl demonstrated that metal deficit, mutation, and intramolecular disulfide bond reduction are essential for initiating SOD1 misfolding and aggregation. These disruptions destabilize the dimer-monomer equilibrium, promoting dimer dissociation into monomers and decreasing the thermodynamic stability of SOD1 variants, thus facilitating amyloid/amorphous aggregate formation. Our findings offer novel insights into protein aggregation mechanisms in disease pathology and highlight potential therapeutic strategies against toxic protein aggregation, including SOD1.}, }
@article {pmid39643926, year = {2025}, author = {Wang, J and Du, Y and Zhang, L and Deng, Y and Wang, T and Wang, S and Ji, M}, title = {Pro-197-Ser mutation combinations in acetolactate synthase (ALS) homoeologous genes affect ALS inhibitor herbicide resistance levels in Monochoria korsakowii.}, journal = {Pest management science}, volume = {81}, number = {4}, pages = {1894-1902}, doi = {10.1002/ps.8586}, pmid = {39643926}, issn = {1526-4998}, support = {32372594//National Natural Science Foundation of China/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Mutation ; *Plant Proteins/genetics ; Sulfonylurea Compounds/pharmacology ; Nicotinic Acids ; }, abstract = {BACKGROUND: Monochoria korsakowii is a common broadleaf weed found in rice (Oryza sativa) fields. Acetolactate synthase (ALS) inhibitor herbicides are commonly used to control broadleaf weeds in rice fields. However, prolonged herbicide use has exacerbated resistance issues. In this study, we evaluated the resistance to ALS inhibitors in populations where the same mutation occurred separately and simultaneously in the two ALS homoeologous genes (ALS1 and ALS2) and investigated the resistance mechanisms in M. korsakowii.<br><br>RESULTS: Monochoria korsakowii exhibited high resistance to bensulfuron-methyl, low resistance to penoxsulam, and sensitivity to imazethapyr. Three resistant populations were identified: M-1 and M-2, which independently evolved the Pro-197-Ser mutation in ALS1 and ALS2, respectively, and M-3, which harbored this mutation in both ALS1 and ALS2. The sensitivity of ALS isolated from these populations to herbicide inhibition corresponded to the whole-plant resistance levels. Subsequently, we cloned and transformed Pro-197-Ser-mutated ALS1 and ALS2 into Arabidopsis thaliana. The resistance of homozygous A.&#x2009;thaliana to bensulfuron-methyl and penoxsulam aligned with bioassay trends. Furthermore, we measured the ploidy, relative expression, and copy number of ALS1 and ALS2, and found no significant differences, suggesting that the evolution of resistance was primarily attributed to the Pro-197-Ser mutation. Finally, we developed a derived cleaved amplified polymorphic sequence marker for detecting Pro-197-Ser mutation in ALS.<br><br>CONCLUSION: The same mutation occurring separately in homoeologous genes resulted in similar resistance levels, whereas simultaneous mutations in homoeologous genes led to increased resistance levels. &#xa9; 2024 Society of Chemical Industry.}, }
@article {pmid39642451, year = {2025}, author = {He, X}, title = {Hyperspectral Raman imaging with multivariate curve resolution-alternating least square (MCR-ALS) analysis for xylazine-containing drug mixtures.}, journal = {Forensic science international}, volume = {367}, number = {}, pages = {112314}, doi = {10.1016/j.forsciint.2024.112314}, pmid = {39642451}, issn = {1872-6283}, mesh = {*Xylazine ; *Spectrum Analysis, Raman ; Least-Squares Analysis ; Humans ; Multivariate Analysis ; Acetaminophen/analysis ; Dipyrone/analysis ; Mannitol ; Excipients/chemistry ; }, abstract = {Xylazine, increasingly implicated in illicit opioid overdose deaths, poses a significant public health threat due to its synergistic effects with fentanyl and resistance to naloxone reversal. Despite its rising prevalence, xylazine is not classified as a controlled substance, leading to its exclusion from routine forensic screening. This study introduces a novel analytical method combining Raman hyperspectral imaging with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to detect xylazine in drug mixtures containing common excipients such as acetaminophen, dipyrone, and mannitol. Utilizing only non-negativity constraints, MCR-ALS successfully resolved the Raman spectrum of xylazine at levels as low as 5 % without reference spectra. The method demonstrated robust performance, with percent variance explained (R[2]) values of 99.60 %, 99.80 %, and 99.91 % for the drug mixtures containing 25 %, 10 %, and 5 % xylazine, respectively.}, }
@article {pmid39641862, year = {2024}, author = {Zhang, J and Zhang, X and Xiao, B and Ouyang, J and Wang, P and Peng, X}, title = {Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.}, journal = {Neurogenetics}, volume = {26}, number = {1}, pages = {15}, pmid = {39641862}, issn = {1364-6753}, support = {No. YZ2020MS04//President Foundation of The Fifth Affiliated Hospital, Southern Medical University/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/cerebrospinal fluid ; *Metabolomics/methods ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; Multiple Sclerosis/genetics/cerebrospinal fluid ; Alzheimer Disease/genetics/cerebrospinal fluid ; Parkinson Disease/genetics/cerebrospinal fluid ; Polymorphism, Single Nucleotide ; }, abstract = {To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach. Additionally, different GWAS summary data for NDDs were used to validate the initial results and perform sensitivity analyses to enhance the robustness of the findings. Finally, reverse MR analyses were conducted to assess the possibility of reverse causation. Combining results from the initial and replication phases of MR analysis, we identified potential causal relationships between various CSF metabolites and different NDDs. Specifically, we found potential causal relationships between five CSF metabolites and AD, six CSF metabolites and MS, and thirteen CSF metabolites and ALS. Further sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis indicated causal effects of AD on glucuronate and ALS on acetylcarnitine (C2). Our study, through genetic means, demonstrates close causal associations between the specific types of CSF metabolites and the risk of NDDS (AD, PD, MS, and ALS), providing useful guidance for future clinical researches.}, }
@article {pmid39641521, year = {2025}, author = {Manera, U and Callegaro, S and Canosa, A and Palumbo, F and Grassano, M and Bombaci, A and Dagliati, A and Bosoni, P and Daviddi, M and Casale, F and Cabras, S and Matteoni, E and De Marchi, F and Mazzini, L and Moglia, C and Vasta, R and Calvo, A and Chiò, A}, title = {Croplands proximity is associated with amyotrophic lateral sclerosis incidence and age at onset.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16464}, pmid = {39641521}, issn = {1468-1331}, support = {//Dipartimenti di Eccellenza/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; 259867//Seventh Framework Programme/ ; 2017SNW5MB//Ministero dell'Universit&#xe0; e della Ricerca/ ; RF-2016-02362405//Ministero della Salute/ ; GA101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology ; Humans ; Incidence ; *Age of Onset ; Female ; Male ; Middle Aged ; Aged ; *Crops, Agricultural ; Adult ; Registries ; Italy/epidemiology ; Risk Factors ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from an intricate interplay between genetics and environmental factors. Many studies have explored living in rural areas as a possible risk factor for ALS, without focusing simultaneously on incidence, age at onset and phenotypic features.<br><br>OBJECTIVE: To evaluate the effect of croplands residential proximity on ALS incidence and phenotype, focusing on age of onset, site of onset and progression rate.<br><br>METHODS: The address history of ALS patients belonging to the population-based Piemonte and Valle d'Aosta registry (PARALS), diagnosed between 2007 and 2014, was obtained for the 20&#x2009;years prior to the onset date. The smoothed ALS incidence per year (im) was compared with the percentage of area covered by each crop for each municipality. A proximity score was calculated for each cropland by geolocation, measuring the percentage of area surrounding patients' residence for variable radii, and was used to compare croplands exposure and phenotype.<br><br>RESULTS: We observed an increased ALS incidence in the municipalities with a higher percentage of area covered by arable crops (R&#x2009;=&#x2009;0.191, p&#x2009;<&#x2009;0.001). Age at onset was significantly lower in those patients who lived near arable crops, with a median anticipation ranging from 1.8&#x2009;to 3.4&#x2009;years; using historical data, a significant anticipation was found also for patients living near vineyards.<br><br>DISCUSSION: Our study proved a direct association between arable crops and ALS risk and an inverse association between arable crops and vineyards proximity and age at onset, suggesting the possible causative role of specific environmental contaminants.}, }
@article {pmid39640847, year = {2024}, author = {Raineri, D and De Marchi, F and Vilardo, B and Barbero Mazzucca, C and Scotti, L and Kustrimovic, N and Mazzini, L and Cappellano, G and Chiocchetti, A}, title = {Circulating GLAST[+] EVs are increased in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular biosciences}, volume = {11}, number = {}, pages = {1507498}, pmid = {39640847}, issn = {2296-889X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, hallmarked by the gradual deterioration of motor neurons, culminating in muscle weakness and fatal paralysis. The exact etiology of ALS remains elusive, and there is a critical need for reliable biomarkers to aid in diagnosis and monitoring of disease progression. Extracellular vesicles (EVs) have emerged as promising candidates for biomarker discovery in neurodegenerative diseases such as ALS, giving access to pathologically relevant tissues otherwise typically challenging or invasive to sample. Indeed, EVs can derive by many cell types within the central nervous system, cross the blood-brain barrier and reach the blood, where they can be easily measured. One of the central mechanisms implicated in ALS pathology is glutamate excitotoxicity, which involves excessive glutamate accumulation due to impaired uptake by astrocytes and other glial cells, leading to neuronal damage. GLAST is a key glutamate transporter responsible for maintaining extracellular gluta-mate levels, and its dysregulation is thought to contribute significantly to ALS development and associated neuropathogenesis. Here, we applied a quick and validated method, to evaluate GLAST[+] EVs in ALS patients' plasma and age-matched healthy controls. We found an increase in GLAST[+] EVs that holds promise for uncovering novel diagnostic and therapeutic avenues in ALS research.}, }
@article {pmid39640633, year = {2024}, author = {Nikafshan Rad, H and Su, Z and Trinh, A and Hakim Newton, MA and Shamsani, J and Nygc Als Consortium,  and Karim, A and Sattar, A}, title = {Amyotrophic lateral sclerosis diagnosis using machine learning and multi-omic data integration.}, journal = {Heliyon}, volume = {10}, number = {20}, pages = {e38583}, pmid = {39640633}, issn = {2405-8440}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a complex and rare neurodegenerative disorder characterized by significant genetic, molecular, and clinical heterogeneity. Despite numerous endeavors to discover the genetic factors underlying ALS, a significant number of these factors remain unknown. This knowledge gap highlights the necessity for personalized medicine approaches that can provide more comprehensive information for the purposes of diagnosis, prognosis, and treatment of ALS. This work utilizes an innovative approach by employing a machine learning-facilitated, multi-omic model to develop a more comprehensive knowledge of ALS. Through unsupervised clustering on gene expression profiles, 9,847 genes associated with ALS pathways are isolated and integrated with 7,699 genes containing rare, presumed pathogenic genomic variants, leading to a comprehensive amalgamation of 17,546 genes. Subsequently, a Variational Autoencoder is applied to distil complex biomedical information from these genes, culminating in the creation of the proposed Multi-Omics for ALS (MOALS) model, which has been designed to expose intricate genotype-phenotype interconnections within the dataset. Our meticulous investigation elucidates several pivotal ALS signaling pathways and demonstrates that MOALS is a superior model, outclassing other machine learning models based on single omic approaches such as SNV and RNA expression, enhancing accuracy by 1.7 percent and 6.2 percent, respectively. The findings of this study suggest that analyzing the relationships within biological systems can provide heuristic insights into the biological mechanisms that help to make highly accurate ALS diagnosis tools and achieve more interpretable results.}, }
@article {pmid39639468, year = {2024}, author = {Arango-Cortes, ML and Giraldo-Cadavid, LF and Latorre Quintana, M and Forero-Cubides, JD and Gonzalez-Bermejo, J}, title = {Diaphragm pacing compared with mechanical ventilation in patients with chronic respiratory failure caused by diaphragmatic dysfunction: a systematic review and meta-analysis.}, journal = {Expert review of respiratory medicine}, volume = {18}, number = {12}, pages = {1101-1111}, doi = {10.1080/17476348.2024.2421846}, pmid = {39639468}, issn = {1747-6356}, mesh = {Humans ; Chronic Disease/therapy ; *Diaphragm/physiopathology ; *Electric Stimulation Therapy/methods/statistics &amp; numerical data ; Length of Stay/statistics &amp; numerical data ; Quality of Life ; *Respiration, Artificial/adverse effects/methods/statistics &amp; numerical data ; *Respiratory Paralysis/etiology/mortality/physiopathology/therapy ; Spinal Cord Injuries/complications/mortality/physiopathology/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: The effectiveness of diaphragmatic electrical stimulation (DES) compared to mechanical ventilation (MV) in improving clinical outcomes such as quality-of-life (QOL) and hospital stay remains inconsistent.<br><br>METHODS: We conducted a systematic review and meta-analysis by searching PubMed, Scopus, Google Scholar, LILACS, and IEEE Xplore. We included comparative studies (randomized controlled trials and observational studies) of DES administered via the phrenic nerve or intramuscular electrodes, compared with MV in adults with diaphragmatic paralysis or paresis. Two authors independently extracted data and assessed bias, with discrepancies resolved by a senior author. Results were pooled using the inverse variance method.<br><br>RESULTS: Out of 1,290 articles, nine were included in the systematic review, totaling 852 subjects. In spinal cord injury (SCI), one study reported lower mortality with DES, while three found no difference compared to MV. In these patients, DES was associated with shorter hospital stay, similar QOL, and heterogeneous results on respiratory infections. In amyotrophic lateral sclerosis (ALS), DES was associated with higher mortality and similar QOL compared to MV. Most SCI studies had a serious risk of bias.<br><br>CONCLUSION: DES shows potential in reducing hospital stay and respiratory infections in SCI but is associated with higher mortality in ALS.}, }
@article {pmid39638345, year = {2025}, author = {Webster, CP and Hall, B and Crossley, OM and Dauletalina, D and King, M and Lin, YH and Castelli, LM and Yang, ZL and Coldicott, I and Kyrgiou-Balli, E and Higginbottom, A and Ferraiuolo, L and De Vos, KJ and Hautbergue, GM and Shaw, PJ and West, RJ and Azzouz, M}, title = {RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.}, journal = {Life science alliance}, volume = {8}, number = {2}, pages = {}, pmid = {39638345}, issn = {2575-1077}, support = {MR/V000470/1/MRC_/Medical Research Council/United Kingdom ; MR/V030140/1/MRC_/Medical Research Council/United Kingdom ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Humans ; Mice ; *Disease Models, Animal ; *Dipeptides/metabolism ; *ATPases Associated with Diverse Cellular Activities/metabolism/genetics ; *DNA Helicases/genetics/metabolism ; *Mice, Transgenic ; DNA Repeat Expansion/genetics ; Carrier Proteins/metabolism/genetics ; Motor Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; }, abstract = {A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD.}, }
@article {pmid39638270, year = {2025}, author = {Ruzzante, B and Fruzzetti, F and Cattaneo, M and Lauria Pinter, G and Marcuzzo, S and Candiani, G and Bono, N}, title = {Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos.}, journal = {International journal of pharmaceutics}, volume = {669}, number = {}, pages = {125008}, doi = {10.1016/j.ijpharm.2024.125008}, pmid = {39638270}, issn = {1873-3476}, mesh = {*Osmotic Pressure ; Humans ; *Cell Survival/drug effects ; Nanoparticles/administration &amp; dosage/chemistry ; Drug Delivery Systems/methods ; Fibroblasts/drug effects/metabolism ; Animals ; Cell Size ; Cell Line ; Cells, Cultured ; }, abstract = {Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery. In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake. Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions. In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.}, }
@article {pmid39637982, year = {2024}, author = {Vallée, S and Deneux, V and Funaro, D and Marcoux, D and Powell, J and Hatami, A and Coulombe, J and Piram, M and McCuaig, CC}, title = {Long-term evolution of prepubertal-onset anogenital lichen sclerosus: A 35-year retrospective and cross-sectional study from a single tertiary care maternal and pediatric center.}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaad.2024.09.086}, pmid = {39637982}, issn = {1097-6787}, abstract = {BACKGROUND: Anogenital lichen sclerosus (ALS) in children may persist after puberty with potential clinical repercussions.<br><br>OBJECTIVE: The purpose of this study was to evaluate postpubertal evolution of girls with ALS diagnosed in the prepubertal period based on physical examination, the persistence of functional symptoms, and the effect on quality of life.<br><br>METHODS: We retrospectively reviewed 65 cases of girls with prepubertal-onset ALS. Onset, signs/symptoms, photos, evolution, and treatment were collected from the medical records. Subsequently, 30 of these 65 patients were assessed for persistence of signs/symptoms by physical examination and/or standardized questionnaire.<br><br>RESULTS: Signs of active disease after puberty based on physical examination were present in 92% (N&#xa0;=&#xa0;23) of examined patients. A high proportion of cases with persistent ALS after puberty were asymptomatic (47%, N&#xa0;=&#xa0;14).<br><br>LIMITATIONS: This is a single-center retrospective study with a limited number of patients. Half of our original cohort could not be reached or declined a follow-up visit.<br><br>CONCLUSION: Prepubertal lichen sclerosus is a chronic condition that can be asymptomatic after puberty despite continued disease activity. We recommend long-term follow-up of patients with prepubertal ALS to prevent associated morbidity.}, }
@article {pmid39636751, year = {2025}, author = {Desai, AB and Agarwal, A and Mohamed, AS and Mohamed, KH and Middlebrooks, EH and Bhatt, AA and Gupta, V and Kumar, N and Sechi, E and Flanagan, EP and López Chiriboga, S}, title = {Motor Neuron Diseases and Central Nervous System Tractopathies: Clinical-Radiologic Correlation and Diagnostic Approach.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {45}, number = {1}, pages = {e240067}, doi = {10.1148/rg.240067}, pmid = {39636751}, issn = {1527-1323}, mesh = {Humans ; *Motor Neuron Disease/diagnostic imaging ; Diagnosis, Differential ; Magnetic Resonance Imaging/methods ; Pyramidal Tracts/diagnostic imaging ; }, abstract = {White matter tracts within the central nervous system are organized into ascending and descending pathways that transmit sensory input and motor output, respectively. Tractopathy, or damage to these tracts, can impair sensory or motor functions. Motor neuron diseases are pathologic processes affecting the upper or lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of acquired motor neuron disease. Traditionally, ALS has affected upper and lower motor neurons of the extremities, torso, and head and neck. There are several ALS variants, some of which affect only the upper motor neurons (eg, primary lateral sclerosis), lower motor neurons (eg, progressive muscular atrophy), or motor neurons of the head and neck (eg, progressive bulbar palsy). Characteristic imaging features of ALS include abnormal T2 hyperintensity within the brain along the corticospinal tract, as well as cortical susceptibility signal intensity along the precentral gyrus, termed the "motor band" sign. Spinal muscular atrophy is a less common primary motor neuron disease and appears on images as atrophy of the anterior horn of the spinal cord, as well as proximal muscle atrophy. In addition to pure motor neuron diseases, there are numerous toxic and metabolic conditions, genetic disorders, infectious diseases, and immune-mediated disorders that can secondarily affect the corticospinal tracts (corticospinal tractopathies), producing symptoms of upper motor neuron injury. These tractopathies are visible at MRI as T2-hyperintense lesions along varying segments of the corticospinal tract. A comprehensive diagnostic approach that integrates clinical symptoms with radiologic and laboratory findings is crucial to distinguish among these varied conditions. [©]RSNA, 2024 Supplemental material is available for this article.}, }
@article {pmid39636698, year = {2024}, author = {Nona, RJ and Henderson, RD and Mccombe, PA}, title = {Routine blood biochemical biomarkers in amyotrophic lateral sclerosis: Systematic review and cohort analysis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/21678421.2024.2435976}, pmid = {39636698}, issn = {2167-9223}, abstract = {Introduction: Blood biochemical biomarkers, including urate, creatinine, albumin, and creatine kinase, have been shown to be useful in ALS. To provide further information about the roles of these four biomarkers roles we performed a systematic review. In addition, we also performed a new study of the role of these biomarkers in predicting survival, using data from our local ALS cohort. Methods: (1) Using established databases and other sources, we searched for papers about the use of urate, creatinine, albumin, and creatine kinase as biomarkers in ALS. Included articles were reviewed for information about biomarker levels in ALS and controls, association with markers of functional decline, and survival. (2) For our local ALS cohort, we performed survival analysis, Cox-proportionate-hazard ratio and ROC curves to investigate the use of these biomarkers in predicting survival. Results: (1) For systematic review, 104 papers were included. There was some variability in the findings. For urate, there was evidence of decreased levels in ALS, with higher levels associated ith longer survival. For creatinine, there was evidence of decreased levels in ALS, and higher levels correlated with longer survival. For albumin, some reports of reduced levels in ALS, but no consistent association with survival. For creatine kinase, some reports of increased levels in ALS, with inconsistent association with survival. (2) For the local ALS cohort there was evidence that urate and creatinine were associated with survival, but no significant association with survival. There was less evidence for albumin and CK. Discussion: This study provides support for further studies of these readily available biochemical measurement as bioamerkers in ALS.}, }
@article {pmid39635310, year = {2024}, author = {Yuan, J and Zhang, YJ and Wen, W and Liu, XC and Chen, FL and Yang, Y}, title = {Afferent loop syndrome of a patient with recurrent fever: A case report.}, journal = {World journal of radiology}, volume = {16}, number = {11}, pages = {678-682}, pmid = {39635310}, issn = {1949-8470}, abstract = {BACKGROUND: Afferent loop syndrome (ALS) is a rare complication, Aoki et al reported that the incidence of distal gastrectomy in Billroth-II is 0.3%-1.0%. The clinical manifestations of ALS are atypical, which can manifest as severe abdominal pain, vomiting, obstructive jaundice, malnutrition, etc.<br><br>CASE SUMMARY: The patient was a 58-year-old man who complained of recurrent high fever for more than 1 week. Laboratory tests showed an increase in neutrophil ratio, procalcitonin, C-reactive protein, and abnormal liver function. Enhanced computed tomography scan of the abdomen showed small intestinal obstruction between the anastomosis of the gastrojejunum, bile duct, and pancreaticoduodenum. Gastroscopy revealed significant narrowing of the lumen 15 cm from the anastomosis into the afferent loop. After performing balloon dilation and placement of the nutrition tube, the patient did not experience further fever.<br><br>CONCLUSION: ALS is relatively rare after pancreaticoduodenectomy, and the treatment depends on the nature of the obstructive lesion. The traditional treatment method is surgery, and in recent years, endoscopy has provided a new treatment method for ALS.}, }
@article {pmid39634573, year = {2024}, author = {Braimah, RO and Taiwo, AO and Olasoji, HO and Legbo, JN and Amundson, M and Ibikunle, AA and Suleiman, IK and Bala, M and Ile-Ogedengbe, BO}, title = {Braimah-Taiwo et al New Classification System and Treatment Algorithm of Mandibulo-Maxillary Synostosis Related to Noma. Field Experience From Noma Children Hospital Sokoto, Nigeria.}, journal = {Craniomaxillofacial trauma &amp; reconstruction}, volume = {17}, number = {4}, pages = {279-290}, pmid = {39634573}, issn = {1943-3875}, abstract = {STUDY DESIGN: This was a retrospective study at Noma Children Hospital, Sokoto, Nigeria, from January 2018 to December 2021.<br><br>OBJECTIVE: The main objective of this appraisal was to present Braimah-Taiwo et al's new classification system for mandibulo-maxillary synostosis secondary to noma and also to provide a guide to their treatment.<br><br>METHODS: Noma with mandibulo-maxillary synostosis was the main inclusion criteria. Excluded were cases of acute noma and noma without mandibulo-maxillary synostosis. Data retrieved include demographics of patients and extent of bony ankylosis and mandibulo-maxillary synostosis.<br><br>RESULTS: A total of 64 patients (30 (46.9%) males and 34 (53.1%) females) were managed. Ages ranged from 6 to 40 years with mean &#xb1; SD (18.2 &#xb1; 7.6) years. Regarding the new classification system of mandibulo-maxillary synostosis, 6 (9.4%) patients presented with Type 1 (Mild joint obliteration)&#xb1;Soft tissue scarring, 24 (37.5%) presented with Type II (Total joint obliteration)&#xb1;Soft tissue scarring, 21 (32.8%) presented with Type III (Coronoid, zygoma and maxilla) &#xb1;Soft tissue scarring, 4 (6.3%) presented with Type IV (Condyle, glenoid fossa, coronoid, sigmoid notch and zygoma) &#xb1;Soft tissue scarring, 7 (10.9%) presented with Type V (Condyle, glenoid fossa, coronoid, sigmoid notch, zygoma and pterygo-maxilla) &#xb1;Soft tissue scarring, while 2 (3.1%) patients presented with Type VI (condyle, glenoid fossa, coronoid, sigmoid notch, zygoma, pterygo-maxilla and the orbit) &#xb1;Soft tissue scarring.<br><br>CONCLUSIONS: Pattern of tissue destruction in noma patients is complex involving both soft and hard tissues. This new classification will guide surgeons in the effective management of these patients.}, }
@article {pmid39633896, year = {2024}, author = {Bhaskaran, S and Piekarz, KM and Brown, J and Yang, B and Ocañas, SR and Wren, JD and Georgescu, C and Bottoms, C and Murphy, A and Thomason, J and Saunders, D and Smith, N and Towner, R and Van Remmen, H}, title = {The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1505369}, pmid = {39633896}, issn = {1662-4548}, abstract = {Our study investigated the therapeutic potential of OKN-007 in the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS). The impact of OKN-007, known for its antioxidant, anti-inflammatory, and neuroprotective properties, was tested at two doses (150 mg/kg and 300 mg/kg) at onset and late-stage disease. Results demonstrated a significant delay in disease progression at both doses, with treated mice showing a slower advance to early disease stages compared to untreated controls. Motor neuron counts in the lumbar spinal cord were notably higher in OKN-007 treated mice at the time of disease onset, suggesting neuroprotection. Additionally, OKN-007 reduced microglial activation and preserved reduced neuromuscular junction fragmentation, although it did not significantly alter the increase in astrocyte number or the decline in hindlimb muscle mass. MR spectroscopy (MRS) revealed improved spinal cord perfusion and normalized myo-inositol levels in treated mice, supporting reduced neuroinflammation. While the expression of several proteins associated with inflammation is increased in spinal cord extracts from G93A mice, OKN-007 dampened the expression of IL-1β, IL-1ra and IL-1α. Despite its promising effects on early-stage disease progression, in general, the beneficial effects of OKN-007 diminished over longer treatment durations. Further, we found no improvement in muscle atrophy or weakness phenotypes in OKN-007 treated G93A mice, and no effect on mitochondrial function or lifespan. Overall, our findings suggest that OKN-007 holds potential as a disease-modifying treatment for ALS, although further research is needed to optimize dosing regimens and understand its long-term effects.}, }
@article {pmid39633494, year = {2024}, author = {Ko, VI and Ong, K and Kwon, DY and Li, X and Pietrasiewicz, A and Harvey, JS and Lulla, M and Bhat, G and Cleveland, DW and Ravits, JM}, title = {CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {187}, pmid = {39633494}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Phosphorylation ; *DNA-Binding Proteins/metabolism/genetics ; *Casein Kinase Idelta/metabolism/genetics ; *Casein Kinase 1 epsilon/metabolism/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Motor Neurons/metabolism/pathology/drug effects ; Mice, Inbred C57BL ; Male ; Mice, Knockout ; }, abstract = {Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.}, }
@article {pmid39631325, year = {2024}, author = {Zhang, Y and Liu, Q and Xie, H and Zhang, W and Lin, X and Zhang, H and Yu, H and Ma, Y and Zhang, C and Geng, H and Shi, N and Cui, L and Li, B and Li, YF}, title = {Fecal microbiota transplantation as an effective way in treating methylmercury-poisoned rats.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177850}, doi = {10.1016/j.scitotenv.2024.177850}, pmid = {39631325}, issn = {1879-1026}, mesh = {Animals ; *Methylmercury Compounds/metabolism ; *Fecal Microbiota Transplantation ; Rats ; *Gastrointestinal Microbiome ; Male ; Feces/microbiology ; }, abstract = {Methylmercury (MeHg) can cause devastating neurotoxicity in animals and human beings. Gut microbiota dysbiosis has been found in MeHg-poisoned animals. Fecal microbiota transplantation (FMT) has been shown to improve clinical outcomes in a variety of diseases such as epilepsy, amyotrophic lateral sclerosis (ALS) and autism. The aim of this study was to investigate the effects of FMT on MeHg-poisoned rats. FMT treatment was applied to MeHg-poisoned rats for 14 days. The neurobehavior, weight changes, dopamine (DA), the total Hg and MeHg level were evaluated. Besides, the gut microbiota and metabolites change in feces were also checked. It was found that FMT helped weight gain, alleviated the neurological disorders, enhanced fecal mercury excretion and MeHg demethylation, reconstructed gut microbiome and promoted the production of gut-brain axis related-metabolites in MeHg-poisoned rats. This study elaborates on the therapeutic efficacy of FMT in treating of MeHg-poisoned rats, which sheds lights on the treatment of neurological diseases like Minamata Disease and even Parkinson's Disease.}, }
@article {pmid39630626, year = {2024}, author = {Szeky, B and Jurakova, V and Fouskova, E and Feher, A and Zana, M and Karl, VR and Farkas, J and Bodi-Jakus, M and Zapletalova, M and Pandey, S and Kucera, R and Lochman, J and Dinnyes, A}, title = {Efficient derivation of functional astrocytes from human induced pluripotent stem cells (hiPSCs).}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0313514}, pmid = {39630626}, issn = {1932-6203}, mesh = {*Astrocytes/cytology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Cell Differentiation ; *S100 Calcium Binding Protein beta Subunit/metabolism ; Cytokines/metabolism ; Aquaporin 4/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Cells, Cultured ; }, abstract = {Astrocytes are specialized glial cell types of the central nervous system (CNS) with remarkably high abundance, morphological and functional diversity. Astrocytes maintain neural metabolic support, synapse regulation, blood-brain barrier integrity and immunological homeostasis through intricate interactions with other cells, including neurons, microglia, pericytes and lymphocytes. Due to their extensive intercellular crosstalks, astrocytes are also implicated in the pathogenesis of CNS disorders, such as ALS (amyotrophic lateral sclerosis), Parkinson's disease and Alzheimer's disease. Despite the critical importance of astrocytes in neurodegeneration and neuroinflammation are recognized, the lack of suitable in vitro systems limits their availability for modeling human brain pathologies. Here, we report the time-efficient, reproducible generation of astrocytes from human induced pluripotent stem cells (hiPSCs). Our hiPSC-derived astrocytes expressed characteristic astrocyte markers, such as GFAP, S100b, ALDH1L1 and AQP4. Furthermore, hiPSC-derived astrocytes displayed spontaneous calcium transients and responded to inflammatory stimuli by the secretion of type A1 and type A2 astrocyte-related cytokines.}, }
@article {pmid39630042, year = {2024}, author = {Zinman, L and Duni, E and Abrahao, A}, title = {Rethinking Drug Reimbursement Criteria in Amyotrophic Lateral Sclerosis.}, journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques}, volume = {51}, number = {5}, pages = {606-607}, doi = {10.1017/cjn.2023.320}, pmid = {39630042}, issn = {0317-1671}, }
@article {pmid39629626, year = {2025}, author = {Boutin, RCT and Shobeirian, F and Adam, S and Lehman, A and Salvarinova, R and Friedman, JM}, title = {Immune Dysregulation in a Child With SOD1-Related Neurological Disease.}, journal = {American journal of medical genetics. Part A}, volume = {197}, number = {4}, pages = {e63949}, doi = {10.1002/ajmg.a.63949}, pmid = {39629626}, issn = {1552-4833}, support = {//Mining for Miracles (BCCH Foundation)/ ; //Genome British Columbia/ ; }, mesh = {Humans ; Male ; *Superoxide Dismutase-1/genetics ; *Homozygote ; Young Adult ; Child ; Nervous System Diseases/genetics/pathology ; Phenotype ; Mutation/genetics ; Quadriplegia/genetics/pathology ; }, abstract = {Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS.}, }
@article {pmid39628898, year = {2024}, author = {Stansberry, WM and Fiur, NC and Robins, MM and Pierchala, BA}, title = {Analysis of translatomic changes in the Ubqln2[P497S] model of ALS reveals that motor neurons express muscle-associated genes in non-disease states.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1491415}, pmid = {39628898}, issn = {1664-2295}, support = {T32 AG071444/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressively worsening motor symptoms that lead to eventual fatal paralysis. The number of gene mutations associated with ALS have increased dramatically in recent years, suggesting heterogeneity in the etiology of ALS and the need to develop new models of the disease that encompass these pathologies. In 2011, mutations in the UBQLN2 gene were identified in families with both ALS and frontotemporal dementia (FTD) and have since been linked to ubiquitinated TDP43 inclusion pathology. The involvement of UBQLN2 in ubiquitination and proteasome function suggests an important role in proteostasis, which is reported to be impaired in ALS.<br><br>METHODS: A UBQLN2 mouse model was generated for the P497S mutation and recapitulates some of the motor symptoms of ALS. We utilized ribosomal profiling followed by mRNA sequencing of associated transcripts to characterize gene expression changes of motor neurons in the Ubqln2[P497S] model and evaluated ALS phenotypes in these animals.<br><br>RESULTS: At 12 months of age, we observed reduced motor neuron survival and neuromuscular junction denervation in these mice that translated into motor deficits observed in locomotor behavioral trials. The sequencing of motor neuron transcripts revealed that Wnt pathways and muscle-related transcripts were downregulated in Ubqln2[P497S] mice, while metabolic pathways were upregulated.<br><br>DISCUSSION: Surprisingly, genes often reported to be muscle-specific, such as Desmin and Acta1, were expressed in motor neurons and were dramatically downregulated in symptomatic Ubqln2[P497S] mice. The expression of muscle transcripts by motor neurons suggests their potentially supportive role in skeletal muscle maintenance.}, }
@article {pmid39628659, year = {2024}, author = {Ye, Q and Li, X and Gao, W and Gao, J and Zheng, L and Zhang, M and Yang, F and Li, H}, title = {Role of Rho-associated kinases and their inhibitor fasudil in neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1481983}, pmid = {39628659}, issn = {1662-4548}, abstract = {Neurodegenerative diseases (NDDs) are prevalent in the elderly. The pathogenesis of NDDs is complex, and currently, there is no cure available. With the increase in aging population, over 20 million people are affected by common NDDs alone (Alzheimer's disease and Parkinson's disease). Therefore, NDDs have profound negative impacts on patients, their families, and society, making them a major global health concern. Rho-associated kinases (ROCKs) belong to the serine/threonine protein kinases family, which modulate diverse cellular processes (e.g., apoptosis). ROCKs may elevate the risk of various NDDs (including Huntington's disease, Parkinson's disease, and Alzheimer's disease) by disrupting synaptic plasticity and promoting inflammatory responses. Therefore, ROCK inhibitors have been regarded as ideal therapies for NDDs in recent years. Fasudil, one of the classic ROCK inhibitor, is a potential drug for treating NDDs, as it repairs nerve damage and promotes axonal regeneration. Thus, the current review summarizes the relationship between ROCKs and NDDs and the mechanism by which fasudil inhibits ROCKs to provide new ideas for the treatment of NDDs.}, }
@article {pmid39627937, year = {2024}, author = {Gielas, AM}, title = {Wounds and Vulnerabilities. The Participation of Special Operations Forces in Experimental Brain-Computer Interface Research.}, journal = {Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees}, volume = {}, number = {}, pages = {1-22}, doi = {10.1017/S096318012400063X}, pmid = {39627937}, issn = {1469-2147}, abstract = {Brain-computer interfaces (BCIs) exemplify a dual-use neurotechnology with significant potential in both civilian and military contexts. While BCIs hold promise for treating neurological conditions such as spinal cord injuries and amyotrophic lateral sclerosis in the future, military decisionmakers in countries such as the United States and China also see their potential to enhance combat capabilities. Some predict that U.S. Special Operations Forces (SOF) will be early adopters of BCI enhancements. This article argues for a shift in focus: the U.S. Special Operations Command (SOCOM) should pursue translational research of medical BCIs for treating severely injured or ill SOF personnel. After two decades of continuous military engagement and on-going high-risk operations, SOF personnel face unique injury patterns, both physical and psychological, which BCI technology could help address. The article identifies six key medical applications of BCIs that could benefit wounded SOF members and discusses the ethical implications of involving SOF personnel in translational research related to these applications. Ultimately, the article challenges the traditional civilian-military divide in neurotechnology, arguing that by collaborating more closely with military stakeholders, scientists can not only help individuals with medical needs, including servicemembers, but also play a role in shaping the future military applications of BCI technology.}, }
@article {pmid39627617, year = {2024}, author = {Wiersema, AF and Rennenberg, A and Smith, G and Varderidou-Minasian, S and Pasterkamp, RJ}, title = {Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {479}, pmid = {39627617}, issn = {1420-9071}, support = {XS grant//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; GoALS//Stichting ALS Nederland/ ; TOTALS//Stichting ALS Nederland/ ; MUSALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; MAXOMOD//E-rare3/ ; INTEGRALS//Rare-3/ ; TRIAGE//JPND/ ; }, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Biomarkers/analysis/metabolism ; *Cell Communication ; *Extracellular Vesicles/metabolism ; MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/metabolism/pathology ; Parkinson Disease/metabolism/pathology ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.}, }
@article {pmid39624969, year = {2024}, author = {Yuan, D and Jiang, S and Xu, R}, title = {Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2399962}, pmid = {39624969}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy/epidemiology/genetics ; Humans ; Prognosis ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.}, }
@article {pmid39624674, year = {2024}, author = {Nakamura, K and Fujita, K and Suzuki, M and Kunugi, A and Hirozane, Y and Kunikata, T and Takahashi, B and Narazaki, G and Kondo, H and Haji, S and Hirai, K and Izumi, Y}, title = {Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1418320}, pmid = {39624674}, issn = {1664-2295}, abstract = {BACKGROUND: The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS.<br><br>METHODS: We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6&#x2009;months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses.<br><br>RESULTS: In total, 26 proteins changed significantly (p&#x2009;<&#x2009;0.05 and q&#x2009;<&#x2009;0.10), with levels varying within a large dynamic range (fold change of >1.5 or&#x2009;<&#x2009;0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate.<br><br>CONCLUSION: This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.}, }
@article {pmid39623504, year = {2024}, author = {Gupta, R and Bhandari, M and Grover, A and Al-Shehari, T and Kadrie, M and Alfakih, T and Alsalman, H}, title = {Predictive modeling of ALS progression: an XGBoost approach using clinical features.}, journal = {BioData mining}, volume = {17}, number = {1}, pages = {54}, pmid = {39623504}, issn = {1756-0381}, support = {RSP2024R244//King Saud University/ ; }, abstract = {This research presents a predictive model aimed at estimating the progression of Amyotrophic Lateral Sclerosis (ALS) based on clinical features collected from a dataset of 50 patients. Important features included evaluations of speech, mobility, and respiratory function. We utilized an XGBoost regression model to forecast scores on the ALS Functional Rating Scale (ALSFRS-R), achieving a training mean squared error (MSE) of 0.1651 and a testing MSE of 0.0073, with R[2] values of 0.9800 for training and 0.9993 for testing. The model demonstrates high accuracy, providing a useful tool for clinicians to track disease progression and enhance patient management and treatment strategies.}, }
@article {pmid39623474, year = {2024}, author = {Hoyle, AC and Stevenson, R and Leonhardt, M and Gillett, T and Martinez-Hernandez, U and Gompertz, N and Clarke, C and Cazzola, D and Metcalfe, BW}, title = {Exploring the 'EarSwitch' concept: a novel ear based control method for assistive technology.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {210}, pmid = {39623474}, issn = {1743-0003}, mesh = {Humans ; Female ; Male ; Adult ; Middle Aged ; *Self-Help Devices ; Aged ; Tensor Tympani/physiology ; Young Adult ; Nervous System Diseases/rehabilitation ; Adolescent ; Motor Neuron Disease/rehabilitation ; Communication Devices for People with Disabilities ; Muscle Contraction/physiology ; Multiple Sclerosis/rehabilitation ; }, abstract = {BACKGROUND: Loss of communication with loved ones and carers is one of the most isolating and debilitating effects of many neurological disorders. Assistive technology (AT) supports individuals with communication, but the acceptability of AT solutions is highly variable. In this paper a novel ear based control method of AT, the concept of 'EarSwitch', is presented. This new approach is based on detecting ear rumbling, which is the voluntary contraction of the tensor tympani muscle (TTM), resulting in observable movement of the eardrum and a dull rumbling sound. 'EarSwitch' has the potential to be a discreet method that can complement existing AT control methods. However, only a subset of the population can ear rumble and little is known about the ability of rumbling in populations with neurological disorders.<br><br>METHODS: To explore the viability of the 'EarSwitch' concept as an AT control method we conducted in-depth online surveys with (N=1853) respondents from the general population and (N=170) respondents with self-declared neurological disorders including Motor Neurone Disease (MND) and Multiple Sclerosis (MS).This is the largest ever study to explore ear rumbling and the first to explore whether rumbling is preserved among individuals with neurological disorders. In addition, we validated rumbling, and investigated usability of the 'EarSwitch' concept as a control input, using in-person otoscopic examination with a subset of participants.<br><br>RESULTS: A significant proportion of the population with neurological disorders could benefit from 'EarSwitch' controllable AT. The upper bound prevalence of the ability to rumble without accompanying movements was 55% in the general population, 38% in the neurological population, and 20% of participants with MND (N=95) reported this ability. During the validation procedure, participants achieved high accuracy in self-reporting the ability to rumble (80%) and proved concept of using the 'EarSwitch' method to control a basic interface.<br><br>DISCUSSION: 'EarSwitch' is a potential new AT control method control, either by itself or as a supplement to other existing methods. Results demonstrate self-reported ear rumbling is present among patients with different neurological disorders, including MND. Further research should explore how well the ability to rumble is preserved in different types and stages of neurological disorders.}, }
@article {pmid39622292, year = {2025}, author = {Ojo, O and Boateng, J and Pacella, R and Hanrahan, A and Essex, R and Dibley, L}, title = {Factors Influencing the Care and Management of Diabetic Foot Ulcers: A Scoping Review.}, journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists}, volume = {31}, number = {3}, pages = {380-389}, doi = {10.1016/j.eprac.2024.11.010}, pmid = {39622292}, issn = {1530-891X}, mesh = {Humans ; *Diabetic Foot/therapy ; Patient Education as Topic ; Health Knowledge, Attitudes, Practice ; Health Personnel ; Communication ; Disease Management ; }, abstract = {OBJECTIVE: The objective of this scoping review is to explore the experiences of patients' and healthcare practitioners on the factors that influence the care and management of diabetes-related foot ulcers (DFUs).<br><br>METHODS: Levac et&#xa0;al's 6-stage framework and the Preferred Reporting Items for Systematic Review and Meta-analysis extension for scoping reviews, guided the review. The SPIDER tool was used to define key elements of the review question. Searches for relevant articles were conducted in electronic databases (PUBMED, CINAHL, AMED, Embase, Cochrane Database of Systematic Reviews, and PsycINFO), Google Scholar, and hand searches of reference lists.<br><br>RESULTS: Eight articles met the inclusion criteria and were included in the review. Three themes were identified: Communication and Education about DFUs; Challenges of managing DFUs; and Barriers to treatment and management. The themes are presented as a narrative synthesis.<br><br>CONCLUSION: Inadequate knowledge of diabetic foot care by patients and inconsistent communication by healthcare professionals were primary factors affecting the effective management of diabetes-related foot ulcers. Consistent, patient-focused education that is supported by knowledgeable health care professionals should form the foundation of effective diabetic foot ulcer care.}, }
@article {pmid39621905, year = {2024}, author = {Van Nerom, M and Ahmed, J and Lazar, T and Meszaros, A and Galand, Q and De Malsche, W and Van Lindt, J and Pancsa, R and Maes, D and Tompa, P}, title = {C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2402847121}, pmid = {39621905}, issn = {1091-6490}, support = {952334//EC | Horizon 2020 Framework Programme (H2020)/ ; 778247//EC | Horizon 2020 Framework Programme (H2020)/ ; K124670//National Research, Development and Innovation Office/ ; K131702//National Research, Development and Innovation Office/ ; SRP51//Vrije Universiteit Brussel (VUB)/ ; A0-2004-070//European Space Agency (ESA)/ ; FWOSB77//Fonds Wetenschappelijk Onderzoek (FWO)/ ; 11D2522N//Fonds Wetenschappelijk Onderzoek (FWO)/ ; HBC.2022.0194//Agentschap Innoveren en Ondernemen (VLAIO)/ ; FK-142285//National Research, Development and Innovation Office/ ; BO/00174/22//Magyar Tudom&#xe1;nyos Akad&#xe9;mia (MTA)/ ; 184018//Tempus K&#xf6;zalap&#xed;tv&#xe1;ny (TPF)/ ; }, mesh = {*RNA Recognition Motif Proteins/metabolism/genetics/chemistry ; *Poly-ADP-Ribose Binding Proteins/metabolism/genetics/chemistry ; Humans ; *C9orf72 Protein/genetics/metabolism ; *RNA Helicases/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Dipeptides/metabolism/chemistry ; *DNA Helicases/metabolism/genetics ; *Arginine/metabolism/chemistry ; *Nucleophosmin/genetics ; Frontotemporal Dementia/metabolism/genetics/pathology ; Stress Granules/metabolism ; DNA-Binding Proteins/metabolism/genetics/chemistry ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism/genetics ; Protein Binding ; Phase Separation ; }, abstract = {The toxic effects of C9orf72-derived arginine-rich dipeptide repeats (R-DPRs) on cellular stress granules in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia remain unclear at the molecular level. Stress granules are formed through the switch of Ras GTPase-activating protein-binding protein 1 (G3BP1) by RNA from a closed inactive state to an open activated state, driving the formation of the organelle by liquid-liquid phase separation (LLPS). We show that R-DPRs bind G3BP1 a thousand times stronger than RNA and initiate LLPS much more effectively. Their pathogenic effect is underscored by the slow transition of R-DPR-G3BP1 droplets to aggregated, ThS-positive states that can recruit ALS-linked proteins hnRNPA1, hnRNPA2, and TDP-43. Deletion constructs and molecular simulations show that R-DPR binding and LLPS are mediated via the negatively charged intrinsically disordered region 1 (IDR1) of the protein, allosterically regulated by its positively charged IDR3. Bioinformatic analyses point to the strong mechanistic parallels of these effects with the interaction of R-DPRs with nucleolar nucleophosmin 1 (NPM1) and underscore that R-DPRs interact with many other similar nucleolar and stress-granule proteins, extending the underlying mechanism of R-DPR toxicity in cells. Our results also highlight characteristic differences between the two R-DPRs, poly-GR and poly-PR, and suggest that the primary pathological target of poly-GR is not NPM1 in nucleoli, but G3BP1 in stress granules in affected cells.}, }
@article {pmid39621705, year = {2024}, author = {Foldvari, KM and Stolee, P and Neiterman, E and Boscart, V and Tong, C}, title = {"…but I know something's not right here": Exploring the diagnosis and disclosure experiences of persons living with ALS.}, journal = {PloS one}, volume = {19}, number = {12}, pages = {e0301249}, pmid = {39621705}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/diagnosis ; Female ; Male ; Middle Aged ; Aged ; *Caregivers/psychology ; Disclosure ; Focus Groups ; Truth Disclosure ; }, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), an incurable motor neuron disease, primarily affects those between the ages of 60-79, and has an approximate post-diagnosis life-expectancy of only two to five years. The condition has an unpredictable but ultimately terminal trajectory that poses challenges for patients, caregivers and healthcare providers. While the diagnosis and disclosure are critical periods for intervention and support, knowledge regarding the relational, communicational and psychodynamic forces that occur within the process of diagnostic disclosure is relatively limited.<br><br>OBJECTIVES: The purpose of this study was to explore the experiences of persons living with ALS in the diagnosis and disclosure of the condition, with the support of their caregivers.<br><br>METHODS: We conducted a focus group and in-depth individual interviews with people living with ALS (n = 9), and caregivers (n = 9). The interviews were transcribed, cleaned, and anonymized, and then entered into NVivo 11 for thematic analysis.<br><br>RESULTS: Participants discussed the diagnostic process, including inklings and subtle changes prior to diagnosis, attempts at self-diagnosis, and the lengthy assessment process. Time was also a consideration in the diagnostic disclosure process, in which participants shared how the disclosure was the product of longstanding conversations with their care providers. It was described as rarely a shock to finally have confirmation. Participants shared their information seeking strategies and needs for a diagnosis that, for them, typically came with insufficient information on the disease, prognosis, and next steps.<br><br>SIGNIFICANCE: This project serves as a step in bridging the relevant gaps in our knowledge and understanding towards improved person-centered care practices in the diagnosis and disclosure of ALS.}, }
@article {pmid39621188, year = {2025}, author = {Gerometta, M and Henderson, RD and Friend, R and Cooper, LT and Zhao, J and Boyd, AW and Bartlett, PF}, title = {Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study.}, journal = {Clinical drug investigation}, volume = {45}, number = {1}, pages = {17-28}, pmid = {39621188}, issn = {1179-1918}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Middle Aged ; Adult ; Aged ; Healthy Volunteers ; Dose-Response Relationship, Drug ; Young Adult ; }, abstract = {BACKGROUND: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life.<br><br>OBJECTIVE: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis.<br><br>METHODS: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity.<br><br>RESULTS: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (&#xb1; 22.8) h in healthy volunteers (n = 20) and 74.4 (&#xb1; 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (&#xb1; 26.6) to 101.1 (&#xb1; 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R.<br><br>CONCLUSIONS: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort.<br><br>CLINICAL TRIAL REGISTRATION: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021).}, }
@article {pmid39621126, year = {2024}, author = {Mikhailova, MM and Klein, OI and Patsaev, TD and Panteleyev, AA}, title = {Co-culture of postnatal mouse spinal cord and skeletal muscle explants as an experimental model of neuromuscular interactions.}, journal = {Histochemistry and cell biology}, volume = {163}, number = {1}, pages = {15}, pmid = {39621126}, issn = {1432-119X}, support = {1&#x43f;.2.3//National Research Center "Kurchatov Institute"/ ; 1&#x43f;.2.3//National Research Center "Kurchatov Institute"/ ; 1&#x43f;.2.3//National Research Center "Kurchatov Institute"/ ; 1&#x43f;.2.3//National Research Center "Kurchatov Institute"/ ; }, mesh = {Animals ; Mice ; *Muscle, Skeletal/metabolism ; *Coculture Techniques ; *Spinal Cord/metabolism ; Mice, Inbred C57BL ; Animals, Newborn ; }, abstract = {The intercommunication between nerves and muscles plays an important role in the functioning of our body, and its failure leads to severe neuromuscular disorders such as spinal muscular atrophy and amyotrophic lateral sclerosis. Understanding the cellular and molecular mechanisms underlying nerve-muscle interactions and mediating their mutual influence is an integral part of strategies aimed at curing neuromuscular diseases. Here, we propose a novel ex vivo experimental model for the spinal cord (SC) and skeletal muscle interactions which for the first time utilizes only fully formed (but not yet quite functional) postnatal tissues. The model represents an organotypic co-culture comprising a longitudinal slice of the mouse postnatal SC and an extensor digitorum longus (EDL) muscle explant placed in the "damage zone" of transversally dissected longitudinal slice of the SC. Using this model, we have shown that SC tissue stimulates muscle contractions and reduces the area occupied by acetylcholine receptors on muscle surface. In turn, EDL muscles stimulate the growth of SC-derived neurites. Thus, our organotypic model allows one to assess the mutual influence of neurons and muscles in a nearly natural setting which maintains the architecture and cellular composition of intact tissues. Therefore, this model may provide an effective platform for studying molecular and cellular mechanisms linked to defective neuromuscular interactions in associated pathologies.}, }
@article {pmid39620262, year = {2025}, author = {Chen, Y and Sun, S and Yun, Y and Sun, X and Xin, J and Shao, K and Lin, P and Yu, D and Yan, C and Liu, S}, title = {Connectivity-based striatal subregion microstructural changes in sporadic amyotrophic lateral sclerosis patients: Relation to motor disability, cognitive deficits, and serum biomarkers.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16577}, pmid = {39620262}, issn = {1468-1331}, support = {2020M672067//China Postdoctoral Science Foundation/ ; NSFC82001354//National Natural Science Foundation of China/ ; NSFC82471395//National Natural Science Foundation of China/ ; ZR2023LSW020//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/etiology/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Corpus Striatum/diagnostic imaging/pathology ; Adult ; Neurofilament Proteins/blood ; Diffusion Tensor Imaging ; Diffusion Magnetic Resonance Imaging ; }, abstract = {BACKGROUND AND PURPOSE: To date, no previous studies have used multishell diffusion MRI to identify striatal microstructural damage in vivo in amyotrophic lateral sclerosis (ALS) patients. Thus, in the present study, we aimed to comprehensively explore connectivity-based selective striatal subregion microstructural damage in sporadic ALS patients and its associations with motor disability, cognitive deficits, and serum biomarkers.<br><br>METHODS: In this retrospective study, 79 ALS patients and 53 healthy controls (HCs) who underwent clinical assessment, serum neurofilament light (NfL) measurement, genetic testing, and multishell diffusion MRI scanning were included. Using a probabilistic tractography approach, the striatum was segmented into six subregions based on their corticostriatal connectivity. Three neurite orientation dispersion and density imaging (NODDI) parameters, the neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), of the connectivity-based striatal subregions were measured.<br><br>RESULTS: Compared with HCs, ALS patients had a significantly lower NDI in the bilateral motor and right frontal subregions, a significantly lower ODI in the right motor and frontal subregions, and a significantly higher ISO in the bilateral motor and frontal subregions of the striatum after familywise error (p&#x2009;<&#x2009;0.05). Moreover, striatal subregion microstructural damage was significantly correlated with motor disabilities, cognitive deficits, and serum NfL levels in ALS patients (p&#x2009;=&#x2009;0.020-0.002).<br><br>CONCLUSIONS: Our study provides clear evidence demonstrating that connectivity-based selective striatal subregion microstructural damage is a definite feature of sporadic ALS patients and suggesting that striatal damage may play an important role in motor disability and cognitive deficits in ALS patients.}, }
@article {pmid39617896, year = {2024}, author = {Feng, R and Zhu, Q and Wang, A and Wang, H and Wang, J and Chen, P and Zhang, R and Liang, D and Teng, J and Ma, M and Ding, X and Wang, X}, title = {Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.}, journal = {BMC medicine}, volume = {22}, number = {1}, pages = {566}, pmid = {39617896}, issn = {1741-7015}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Fecal Microbiota Transplantation/methods ; Double-Blind Method ; Female ; Male ; Middle Aged ; Aged ; Gastrointestinal Microbiome/physiology ; Treatment Outcome ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients.<br><br>METHODS: Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6&#xa0;months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n&#x2009;=&#x2009;14) or a mixture of 0.9% saline and food coloring (E150c) as sham transplantation (placebo, n&#x2009;=&#x2009;13). The primary outcome measured the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to week 35. Secondary outcomes included changes in gastrointestinal and respiratory functions, muscle strength, autonomic function, cognition, quality of life, intestinal microbiome composition, and plasm neurofilament light chain protein (NFL). Efficacy and safety outcomes were assessed in the intention-to-treat population.<br><br>RESULTS: A total of 27 randomized patients (47% women; mean age, 67.2&#xa0;years), 24 participants completed the entire study. Notably, ALSFRS-R score changes exhibited no significant differences between FMT (6.1 [SD, 3.11]) and placebo (6.41[SD, 2.73]) groups from baseline to week 35. Secondary efficacy outcomes, encompassing respiratory function, muscle strength, autonomic function, cognition, quality of life, and plasm NFL, showed no significant differences. Nevertheless, the FMT group exhibited improvements in constipation, depression, and anxiety symptoms. FMT induced a shift in gut&#xa0;microbiome community composition, marked by increased abundance of Bifidobacterium, which persisted until week 15 (95% CI, 0.04 to 0.28; p&#x2009;=&#x2009;0.01). Gastrointestinal adverse events were the primary manifestations of FMT-related side effects.<br><br>CONCLUSIONS: In this clinical trial involving 27 sporadic ALS patients, FMT did not&#xa0;significantly slow the decline in ALSFRS-R score. Larger multicenter trials&#xa0;are needed to confirm the efficacy of FMT in sporadic ALS patients and to explore the underlying biological mechanisms.<br><br>TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR 2200064504.}, }
@article {pmid39617118, year = {2025}, author = {Liang, YF and Niu, ZX and Wu, ZW and Zhang, QY and Zhao, XY and Chao, LL and Li, H and Gao, WY}, title = {Catalytic insights of acetolactate synthases from different bacteria.}, journal = {Archives of biochemistry and biophysics}, volume = {764}, number = {}, pages = {110248}, doi = {10.1016/j.abb.2024.110248}, pmid = {39617118}, issn = {1096-0384}, mesh = {*Acetolactate Synthase/metabolism/genetics/chemistry ; *Bacillus subtilis/enzymology/genetics ; *Molecular Docking Simulation ; *Bacterial Proteins/metabolism/genetics/chemistry ; Substrate Specificity ; Klebsiella pneumoniae/enzymology/genetics ; Amino Acid Sequence ; Pyruvic Acid/metabolism ; Catalytic Domain ; }, abstract = {Acetolactate synthase (ALS) is an essential enzyme involved in the biosynthesis of platform chemicals acetoin and 2,3-butanediol in several microorganisms. In this study, we investigated the catalytic differences among three bacterial ALSs involved in the ligation of two molecules of pyruvate or 2-ketobutyrate. Based on the findings, we predicted three amino acid residues in each enzyme that caused a discrepancy in accordance with the multi-sequence alignment and molecular docking experiments: I398, A402, and T480 in Bacillus subtilis ALS; V400, Y404, and S482 in Listeria seleigeri serovar 1/2b ALS; and M394, H398, and G476 in Klebsiella pneumoniae ALS. Subsequently, we mutually mutated the residues in the three ALSs. The data obtained confirmed our inference that these three residues in each enzyme are truly correlated with substrate recognition, particularly in recognizing compounds that are larger than pyruvate, such as 2-ketobutyrate, benzaldehyde, and nitrosobenzene. This study further clarifies the biochemical traits of ALSs derived from various bacteria and expands the scope of ALS research.}, }
@article {pmid39616922, year = {2024}, author = {Santurtún, A and Medín, P and Riancho, JA and Santiago-Setién, M and Ortiz, F and López de Munain, A and Almendra, R and Riancho, J}, title = {Temporo-spatial analysis of amyotrophic lateral sclerosis in Spain: Altitude and land use as new determinants of the disease.}, journal = {The Science of the total environment}, volume = {957}, number = {}, pages = {177796}, doi = {10.1016/j.scitotenv.2024.177796}, pmid = {39616922}, issn = {1879-1026}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Humans ; Male ; Female ; *Altitude ; Spatio-Temporal Analysis ; Middle Aged ; Aged ; Incidence ; Adult ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Currently, ALS is conceived as the result of the interaction between genetics, environmental factors, and aging. This study analyzed the spatial and temporal patterns of ALS in Spain, delving into the potential relationships between altitude, land cover, and this disease.<br><br>METHODOLOGY: ALS death data were collected over a 19-year period, including information on sex, age and municipality of residence. The standardized mortality rate was calculated for each municipality of residencia, and Anselin's local Moran's I statistic was used to identify clusters of high and low incidence. Altitude data were sourced from the Copernicus Land Monitoring Services, while land cover data came from CORINE satellite images and national agricultural statistics.<br><br>RESULTS: The average annual incidence of ALS deaths among adults was 2.5 per 100,000 people. Higher mortality rates were noted in males (2.8) than in females (2.3), with both sexes exhibiting a rising mortality trend in a temporal analysis. Cluster analysis revealed that high mortality areas were mostly located in the North and Northeast of the country. Municipalities in these clusters had significantly lower median altitudes and larger areas of Permanently Irrigated Arable Land and Broad-Leaved Forest.<br><br>CONCLUSION: This study provides new evidence about the increase in ALS cases in European countries during the last decades, reporting for the first time altitude and certain agricultural land uses as potential geographic determinants of the disease.}, }
@article {pmid39616446, year = {2024}, author = {Rutkove, SB and McIlduff, CE and Stommel, E and Levy, S and Smith, C and Gutierrez, H and Verga, S and Samaan, S and Yator, C and Nanda, A and Sonbas-Cobb, B and Capella, T and Pastel, L and Doussan, A and Phipps, K and Murphy, E and Halter, R}, title = {Thoracic electrical impedance tomography for assessing progression of pulmonary dysfunction in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2434174}, pmid = {39616446}, issn = {2167-9223}, support = {R21 NS118434/NS/NINDS NIH HHS/United States ; }, abstract = {Objective: We compared thoracic electrical impedance tomography (EIT) with slow vital capacity (SVC) to determine if EIT could monitor pulmonary function in ALS patients longitudinally. Methods: Of 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) initially enrolled in the Pulmonary Function via Impedance Tomography (PuFIT) study, 22 ALS and 20 HCs returned for a follow-up visit ∼3.9 months later. All participants had thoracic EIT measurements performed simultaneously with standard SVC in upright and supine positions at both visits. EIT data from each measurement were summarized as a single parameter, the impedance-SVC (zSVC), representing an averaged impedance change across both lungs. We assessed alterations over time for both cohorts of participants. Results: Sufficient quality EIT and SVC data were available for 18 of the patients with ALS and 19 HCs. Over time, mean upright SVC significantly declined by 5% in the ALS group and did not change in the healthy group. Supine SVC showed no change in either group. Although mean trajectories of zSVC mirrored mean SVC trajectories in both participant cohorts, changes in zSVC in ALS patients did not reach significance, due to greater variability in the repeated measures. Conclusion: Despite strong cross-sectional correlations to SVC, EIT did not detect a decline in pulmonary function over approximately four months. Increased variability in EIT data explains the lack of sensitivity to change. Technological improvements and special care with electrode placement will be needed for EIT to reach its full potential in longitudinal assessment of pulmonary function in ALS.}, }
@article {pmid39615150, year = {2025}, author = {Garbey, M and Lesport, Q and Öztosun, G and Ghodasara, V and Kaminski, HJ and Bayat, E}, title = {Improving care for amyotrophic lateral sclerosis with artificial intelligence and affective computing.}, journal = {Journal of the neurological sciences}, volume = {468}, number = {}, pages = {123328}, doi = {10.1016/j.jns.2024.123328}, pmid = {39615150}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/psychology ; Male ; Female ; Middle Aged ; Aged ; *Artificial Intelligence ; *Natural Language Processing ; *Emotions/physiology ; Speech/physiology ; Oximetry ; Adult ; }, abstract = {BACKGROUND: Patients with ALS often face difficulties expressing emotions due to impairments in facial expression, speech, body language, and cognitive function. This study aimed to develop non-invasive AI tools to detect and quantify emotional responsiveness in ALS patients, providing objective insights. Improved understanding of emotional responses could enhance patient-provider communication, telemedicine effectiveness, and clinical trial outcome measures.<br><br>METHODS: In this preliminary exploratory study, fourteen patients with ALS had audio recordings performed during routine clinic visits while wearing a wireless pulse oximeter. Emotion-triggering questions related to symptom progression, breathing, mobility, feeding tube, and financial burden were randomly asked. The same questions were posed in separate psychiatric evaluations. Natural language processing (NLP) was used to analyze transcriptions, topic classifications, sentiment, and emotional states, combining pulse and speech data. AI-generated reports summarized the findings.<br><br>RESULTS: Pulse alterations consistent with emotional arousal were identified, with longer consultations and positive communication reducing pulse fluctuations. Financial concerns triggered the strongest emotional response, while discussions about breathing, mobility, and feeding tube increased anxiety. AI-generated reports prioritized patient concerns and streamlined documentation for providers.<br><br>CONCLUSIONS: This study introduces a novel approach to linking pulse and speech analysis to evaluate emotional responses in ALS patients. AI and affective computing provide valuable insights into emotional responses and disease progression, with potential applications for other neurological disorders. This approach could augment clinical trial outcomes by offering a more comprehensive view of patient well-being.}, }
@article {pmid39614020, year = {2025}, author = {Shi, DL and Grifone, R and Zhang, X and Li, H}, title = {Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, function and regeneration.}, journal = {Journal of muscle research and cell motility}, volume = {46}, number = {1}, pages = {53-65}, pmid = {39614020}, issn = {1573-2657}, support = {23545//the French Muscular Dystrophy Association/ ; }, mesh = {Humans ; *RNA-Binding Proteins/metabolism/genetics ; *Muscle, Skeletal/metabolism ; Animals ; *Muscle Development/physiology ; *Regeneration/physiology ; *Myocardium/metabolism ; }, abstract = {RNA-binding proteins are critically involved in the post-transcriptional control of gene expression during embryonic development and in adult life, contributing to regulating cell differentiation and maintaining tissue homeostasis. Compared to the relatively well documented functions of transcription factors, the regulatory roles of RNA-binding proteins in muscle development and function remain largely elusive. However, deficiency of many RNA-binding proteins has been associated with muscular defects, neuromuscular disorders and heart diseases, such as myotonic dystrophy, amyotrophic lateral sclerosis, and cardiomyopathy. Rbm24 is highly conserved among vertebrates and is one of the best characterized RNA-binding proteins with crucial implication in the myogenic and cardiomyogenic programs. It presents the distinctive particularity of displaying highly restricted expression in both skeletal and cardiac muscles, with changes in subcellular localization during the process of differentiation. Functional analyses using different vertebrate models have clearly demonstrated its requirement for skeletal muscle differentiation and regeneration as well as for myocardium organization and cardiac function, by regulating the expression of both common and distinct target genes in these tissues. The challenge remains to decipher the dynamic feature of post-transcriptional circuits regulated by Rbm24 during skeletal myogenesis, cardiomyogenesis, and muscle repair. This review discusses current understanding of its function in striated muscles and its possible implication in human disease, with the aim of identifying research gaps for future investigation.}, }
@article {pmid39612826, year = {2025}, author = {Xu, H and Cheng, J and Leng, Q and Cao, R and Su, W and Sun, L and Xue, F and Han, Y and Wu, R}, title = {Characterization of acetolactate synthase genes and resistance mechanisms of multiple herbicide resistant Lolium multiflorum.}, journal = {Plant physiology and biochemistry : PPB}, volume = {219}, number = {}, pages = {109324}, doi = {10.1016/j.plaphy.2024.109324}, pmid = {39612826}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Plant Proteins/genetics/metabolism ; *Lolium/genetics/enzymology/drug effects ; Imidazoles/pharmacology ; Genes, Plant ; }, abstract = {Combining imidazolinone-tolerant wheat with imazamox presents an effective solution to combat weed resistance. However, Lolium multiflorum, a troublesome resistant weed infesting wheat fields, may have developed resistance to imazamox, and the potential resistance mechanisms are intriguing. In this study, we explored the susceptibility of L. multiflorum to imazamox and investigated the resistance mechanisms, including the contribution of the target enzyme acetolactate synthase (ALS) to resistance and the presence of non-target-site resistance (NTSR). Eight L. multiflorum populations suspected of being resistant to imazamox were collected, and six populations exhibited resistance, ranging from 2.45-fold to 16.32-fold. The LmALS1 gene from susceptible population D3 plants and multiple copies of the LmALS gene (LmALS1, LmALS2, LmALS2α, LmALS3, LmALS3α, LmALS3β) from resistant populations D5 and D8 plants were separately amplified. Two mutations (Pro/Gln197 to Thr, Trp574 to Leu) were found in LmALS1 in the resistant populations. Compared to D3, LmALS1 was overexpressed in D5 but not in D8. The presence of LmALS1 mutants (LmALS1-Thr197 and LmALS1- Leu574), along with LmALS2, LmALS3, and their subunits, contribute to the resistance phenotype by increasing bonding energies, weakening hydrogen bonds, or decreasing protein binding pocket volumes and surface area. Additionally, D5 and D8 populations exhibited multiple resistance (>40-fold) to three other ALS inhibitors: pyroxsulam, flucarbazone-sodium, and mesosulfuron-methyl. Pre-treatment with malathion and 4-chloro-7-nitrobenzoxadiazole (cytochrome P450 monooxygenase and glutathione S-transferase inhibitors respectively) reversed the resistance of the D8 population and partially reversed the resistance of the D5 population to imazamox. This study characterizes ALS genes and extends our knowledge into the ALS resistance mechanisms involved in L. multiflorum. It also deepens our understanding of the complex diversification resistance mechanisms, thereby facilitating advances in weed resistance management strategies in wheat fields.}, }
@article {pmid39612643, year = {2024}, author = {Egorov, VV and Grudinina, NA and Polyakov, DS and Zabrodskaya, YA and Gavrilova, NV and Shavlovsky, MM}, title = {Spontaneous formation of different forms of alpha-synuclein fibrils from a recombinant protein.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151068}, doi = {10.1016/j.bbrc.2024.151068}, pmid = {39612643}, issn = {1090-2104}, mesh = {*alpha-Synuclein/metabolism/chemistry ; *Recombinant Proteins/chemistry/metabolism/genetics ; Humans ; *Amyloid/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Conformation ; }, abstract = {Alpha-synuclein is a protein, the conformational changes of which lead to the development of such socially significant diseases as Parkinson's disease and amyotrophic lateral sclerosis. The methods for differential diagnostics of these diseases based on the use of alpha-synuclein in a non-native conformation obtained from patients as a seed for inducing fibrillogenesis and studying the morphology of the resulting amyloid-like fibrils were described in a number of studies. The authors associate such properties of the seed with the presence of post-translational modifications in the protein obtained from patients. At the same time, the production of fibrils differing in morphology from recombinant alpha-synuclein under various conditions of fibrillogenesis is also described. In this work, we show that the formation of morphologically distinct fibril types from recombinant alpha-synuclein lacking post-translational modifications is possible under the same conditions, and that spontaneously arising different fibril types, when used as a seed for fibrillogenesis, lead to the formation of recombinant protein fibrils morphological similar to the parental seed. The results of the work can be used both in studying the fundamental mechanisms of conformation transfer and in developing test systems for synucleinopathies.}, }
@article {pmid39611550, year = {2024}, author = {Veyrat-Durebex, C and Osman, S and Al Ojaimi, Y and Gosset, P and Dupuy, C and Lefevre, A and Emond, P and Vourc'h, P and Corcia, P and Mereghetti, L and Kempf, F and Raoul, C and Blasco, H}, title = {Gut metabolomic and microbiota analyses in ALS mice reveal specific metabolites despite the absence of significant gut dysbiosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/21678421.2024.2433578}, pmid = {39611550}, issn = {2167-9223}, abstract = {OBJECTIVE: Over the past years, interest in the role of gut microbiota in neurodegenerative diseases has emerged. Despite numerous publications over the past decade, both in human and pre-clinical studies, there is no clear consensus on the microbiota's role or involvement in ALS. Few studies on mouse models of ALS highlighted a correlation between specific bacteria species and the prognostic or severity of the disease. Still these results lack reproducibility and remain controverted. In this article we present a study of fecal microbiota in the SOD1[G93A] mouse model associated with a metabolomic analysis of cecum content, compared to controls.<br><br>METHODS: Intestinal metabolomic profile and fecal microbiota were assessed in two cohorts of SOD[G93A] mice compared to wildtype controls at the terminal stage of the ALS disease.<br><br>RESULTS: Results showed a significant difference in metabolomic profile in SOD1[G93A] mice compared to controls but without a marked change in composition and diversity of fecal microbiota. Nevertheless, we observed an increase of Lachnospiraceae family, which are butyrate-producer bacteria, in SOD1[G93A] mice. Moreover, some metabolites with significantly different intestinal concentrations are partially produced and linked with intestinal bacteria, such as riboflavin, hippurate, and N-acetylputrescine, leaving us convinced of the interest in looking further into the role of the microbiota in ALS.<br><br>CONCLUSIONS: Despite an alteration of the intestinal metabolome in SOD1[G93A] mice, microbiota data did not show significant changes, underlying the need for further research.}, }
@article {pmid39611310, year = {2025}, author = {Diaz, F and Thornton, JS and Wastling, SS and Asaab, A and Morrow, JM and Zafeiropoulos, N and Bresee, C and Allred, P and Avalos, P and Lewis, RA and Baloh, RH and Svendsen, CN}, title = {Longitudinal Quantitative MRI Provides Responsive Outcome Measures for Early and Late Muscle Changes in ALS.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {2}, pages = {171-182}, doi = {10.1002/mus.28306}, pmid = {39611310}, issn = {1097-4598}, support = {CLIN2-09284//This study was supported with funding from The California Institute of Regenerative Medicine./ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; *Disease Progression ; Longitudinal Studies ; *Magnetic Resonance Imaging ; Muscle Strength/physiology ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Outcome Assessment, Health Care ; Clinical Trials, Phase I as Topic ; }, abstract = {INTRODUCTION/AIMS: Studies have demonstrated the potential of muscle MRIs to measure disease progression in ALS. However, the responsiveness and utility of quantitative muscle MRIs in an ALS clinical trial remain unknown. This study aimed to determine the responsiveness of quantitative muscle MRIs to measure disease progression in ALS.<br><br>METHODS: Longitudinal quantitative muscle MRIs were obtained in an ALS study that delivered human neural progenitor cells to the spinal cord (NCT02943850). Participants underwent MRIs at baseline, 1, 3, 6, 9, and 12&#x2009;months. MRI measures included fat fraction (ff), water T2 (T 2m), cross-sectional area (CSA), and remaining muscle area (RMA). Non-MRI measures included strength via Accurate Test of Limb Isometric Strength (ATLIS) and the ALSFRS-R. Standardized response means (SRM) were calculated at 1, 3, 6, and 12&#x2009;months.<br><br>RESULTS: Significant increases in muscle FF and decreases in CSA and RMA were seen as early as 1&#x2009;month from baseline. At 6&#x2009;months, the most responsive measures were muscle FF (SRMthigh&#x2009;=&#x2009;1.85, SRMcalf&#x2009;=&#x2009;1.39), T 2m (SRMthigh&#x2009;=&#x2009;1.2, SRMcalf&#x2009;=&#x2009;1.71), CSA (SRMthigh&#x2009;=&#x2009;-1.58, SRMcalf&#x2009;=&#x2009;-1.14), RMA (SRMthigh&#x2009;=&#x2009;-1.77, SRMcalf&#x2009;=&#x2009;-1.28), and strength tested via ATLIS (SRMknee extension&#x2009;=&#x2009;-1.79, SRMknee flexion&#x2009;=&#x2009;-1.3). The ALSFRS-R was the least responsive at 6&#x2009;months (SRM&#x2009;=&#x2009;-0.85). Muscle FF and T 2m correlated with ALSFRS-R leg subscores and MRI measures demonstrated varying degrees of correlation with strength.<br><br>DISCUSSION: High responsiveness and low variability make quantitative muscle MRI a novel and complementary outcome measure for ALS clinical trials.}, }
@article {pmid39611137, year = {2024}, author = {Valančius, D and Burnytė, B and Masaitienė, R and Morkūnienė, A and Klimašauskienė, A}, title = {Rapidly Progressing and Early-Onset Forms of Amyotrophic Lateral Sclerosis Caused by a Novel SOD1 Variant in a Lithuanian Family.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200217}, pmid = {39611137}, issn = {2376-7839}, abstract = {OBJECTIVES: To describe a novel familial variant of superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS) in a Lithuanian family, highlighting its variable progression and implications for treatment inclusion criteria.<br><br>METHODS: This study presents the clinical and genetic findings of a family with the novel SOD1 variant, including one member diagnosed with early-onset ALS (onset <40 years) and one with a particularly rapidly progressing course of ALS.<br><br>RESULTS: The SOD1 variant NM_000454.5:c.446T>C, NP_000445.1:p.(Val149Ala) was identified in affected family members and 4 asymptomatic members aged 32-56 years. We present detailed disease course of the affected family members obtained during follow-up. Clinically, this variant is associated with variable disease progression, with the time from symptom onset to death ranging from 5 to 77 months.<br><br>DISCUSSION: The novel SOD1 variant p.Val149Ala in this Lithuanian family causes ALS of variable onset and course, including a case of early-onset ALS and one case of rapidly progressing ALS, necessitating recognition by the scientific community and development of tailored therapeutic approaches.}, }
@article {pmid39610104, year = {2025}, author = {Bar Avi, O and Perlson, E}, title = {Navigating the pathways: TAR-DNA-binding-protein-43 aggregation, axonal transport, and local synthesis in amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {10}, pages = {2921-2922}, pmid = {39610104}, issn = {1673-5374}, }
@article {pmid39608855, year = {2024}, author = {Budworth, L and Wilson, B and Sutton-Klein, J and Basu, S and O'Keeffe, C and Mason, SM and Ang, A and Anne-Wilson, S and Reynard, K and Croft, S and Shah, AD and Bank, S and Conner, M and Lawton, R}, title = {Is emergency doctors' tolerance of clinical uncertainty on a novel measure associated with doctor well-being, healthcare resource use and patient outcomes?.}, journal = {Emergency medicine journal : EMJ}, volume = {42}, number = {1}, pages = {}, pmid = {39608855}, issn = {1472-0213}, abstract = {INTRODUCTION: Emergency doctors routinely face uncertainty-they work with limited patient information, under tight time constraints and receive minimal post-discharge feedback. While higher uncertainty tolerance (UT) among staff is linked with reduced resource use and improved well-being in various specialties, its impact in emergency settings is underexplored. We aimed to develop a UT measure and assess associations with doctor-related factors (eg, experience), patient outcomes (eg, reattendance) and resource use (eg, episode costs).<br><br>METHODS: From May 2021 to February 2022, emergency doctors (specialty trainee 3 and above) from five Yorkshire (UK) departments completed an online questionnaire. This included a novel UT measure-an adapted Physicians' Reaction to Uncertainty scale collaboratively modified within our team according to Hillen et al's (2017) UT model. The questionnaire also included well-being-related measures (eg, Brief Resilience Scale) and assessed factors like doctors' seniority. Patient encounters involving prespecified 'uncertainty-inducing' problems (eg, headache) were analysed. Multilevel regression explored associations between doctor-level factors, resource use and patient outcomes.<br><br>RESULTS: 39 doctors were matched with 384 patients. The UT measure demonstrated high reliability (Cronbach's &#x3b1;=0.92) and higher UT was significantly associated with better psychological well-being including greater resilience (Pearson's r=0.56; 95%&#x2009;CI=0.30&#x2009;to 0.74) and lower burnout (eg, Cohen's d=-2.98; -4.62 to -1.33; mean UT difference for 'no' vs 'moderate/high' burnout). UT was not significantly associated with resource use (eg, episode costs: &#x3b2;=-0.07; -0.32 to 0.18) or patient outcomes including 30-day readmission (eg, OR=0.82; 0.28 to 2.35).<br><br>CONCLUSIONS: We developed a reliable UT measure for emergency medicine. While higher UT was linked to doctor well-being, its impact on resource use and patient outcomes remains unclear. Further measure validation and additional research including intervention trials are necessary to confirm these findings and explore the implications of UT in emergency practice.}, }
@article {pmid39608699, year = {2025}, author = {Kale, MB and Wankhede, NL and Bishoyi, AK and Ballal, S and Kalia, R and Arya, R and Kumar, S and Khalid, M and Gulati, M and Umare, M and Taksande, BG and Upaganlawar, AB and Umekar, MJ and Kopalli, SR and Fareed, M and Koppula, S}, title = {Emerging biophysical techniques for probing synaptic transmission in neurodegenerative disorders.}, journal = {Neuroscience}, volume = {565}, number = {}, pages = {63-79}, doi = {10.1016/j.neuroscience.2024.11.055}, pmid = {39608699}, issn = {1873-7544}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Synaptic Transmission/physiology ; Animals ; Synapses/metabolism/pathology/physiology ; }, abstract = {Plethora of research has shed light on the critical role of synaptic dysfunction in various neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Synapses, the fundamental units for neural communication in the brain, are highly vulnerable to pathological conditions and are central to the progression of neurological diseases. The presynaptic terminal, a key component of synapses responsible for neurotransmitter release and synaptic communication, undergoes structural and functional alterations in these disorders. Understanding synaptic transmission abnormalities is crucial for unravelling the pathophysiological mechanisms underlying neurodegeneration. In the quest to probe synaptic transmission in NDDs, emerging biophysical techniques play a pivotal role. These advanced methods offer insights into the structural and functional changes occurring at nerve terminals in conditions like AD, PD, HD &amp; ALS. By investigating synaptic plasticity and alterations in neurotransmitter release dynamics, researchers can uncover valuable information about disease progression and potential therapeutic targets. The review articles highlighted provide a comprehensive overview of how synaptic vulnerability and pathology are shared mechanisms across a spectrum of neurological disorders. In major neurodegenerative diseases, synaptic dysfunction is a common thread linking these conditions. The intricate molecular machinery involved in neurotransmitter release, synaptic vesicle dynamics, and presynaptic protein regulation are key areas of focus for understanding synaptic alterations in neurodegenerative diseases.}, }
@article {pmid39608571, year = {2025}, author = {Diggins, L and Ross, D and Bhanot, S and Corallo, R and Daley, R and Patel, K and Lewis, O and Donahue, S and Thaddeus, J and Hiers, L and Syed, C and Eagerton, D and Mohanty, BK}, title = {CD spectra reveal the state of G-quadruplexes and i-motifs in repeated and other DNA sequences.}, journal = {Biophysical reports}, volume = {5}, number = {1}, pages = {100187}, pmid = {39608571}, issn = {2667-0747}, mesh = {*G-Quadruplexes ; *Circular Dichroism ; Hydrogen-Ion Concentration ; DNA/chemistry/genetics ; Nucleotide Motifs/genetics ; Base Sequence ; Temperature ; Humans ; DNA-Binding Proteins/chemistry/metabolism/genetics ; }, abstract = {The B-DNA of the genome contains numerous sequences that can form various noncanonical structures including G-quadruplex (G4), formed by two or more stacks of four guanine residues in a plane, and intercalating motif (i-motif [iM]) formed by alternately arranged C-C[+] pairs. One of the easy yet sensitive methods to study G4s and iMs is circular dichroism (CD) spectroscopy, which generates characteristic G4 and iM peaks. We have analyzed and compared the effects of various environmental factors including pH, buffer composition, temperature, flanking sequences, complimentary DNA strands, and single-stranded DNA binding protein (SSB) on the CD patterns of G4s and iMs generated by two groups of DNA molecules, one containing tandem repeats of GGGGCC and CCCCGG from the C9ORF72 gene associated with amyotrophic lateral sclerosis and frontotemporal dementia, and the second containing polyG/polyC clusters from oncogene promoter-proximal regions without such tandem repeats. Changes in pH caused drastic changes in CCCCGG-iM and GGGGCC-G4 and the changes were dependent on repeat numbers and G-C basepairing. In contrast, with the DNA sequences from the promoter-proximal regions of oncogenes, iMs disassembled upon pH changes with the peak slowly shifting to lower wavelength but the G4s did not show significant change. Complementary DNA strands and flanking DNA sequences also regulate G4 and iM formation. The SSB disassembled both G4s and iMs formed by almost all sequences suggesting an in vivo role for SSBs in the disassembly of G4s and iMs during DNA replication and other DNA transactions.}, }
@article {pmid39606446, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39606446}, issn = {2693-5015}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, }
@article {pmid39606178, year = {2024}, author = {Tröger, J and Dörr, F and Schwed, L and Linz, N and König, A and Thies, T and Barbe, MT and Orozco-Arroyave, JR and Rusz, J}, title = {Corrigendum: An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1488178}, doi = {10.3389/fdgth.2024.1488178}, pmid = {39606178}, issn = {2673-253X}, abstract = {[This corrects the article DOI: 10.3389/fdgth.2024.1440986.].}, }
@article {pmid39605661, year = {2024}, author = {Zimyanin, V and Dash, BP and Großmann, D and Simolka, T and Glaß, H and Verma, R and Khatri, V and Deppmann, C and Zunder, E and Redemann, S and Hermann, A}, title = {Axonal transcriptome reveals upregulation of PLK1 as a protective mechanism in response to increased DNA damage in FUS [P525L] spinal motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.20.624439}, pmid = {39605661}, issn = {2692-8205}, support = {R01 NS091617/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the gene FUSED IN SARCOMA (FUS) are among the most frequently occurring genetic forms of amyotrophic lateral sclerosis (ALS). Early pathogenesis of FUS -ALS involves impaired DNA damage response and axonal degeneration. However, it is still poorly understood how these gene mutations lead to selective spinal motor neuron (MN) degeneration and how nuclear and axonal phenotypes are linked. To specifically address this, we applied a compartment specific RNA-sequencing approach using microfluidic chambers to generate axonal as well as somatodendritic compartment-specific profiles from isogenic induced pluripotent stem cells (iPSCs)-derived MNs. We demonstrate high purity of axonal and soma fractions and show that the axonal transcriptome is unique and distinct from that of somas including significantly fewer number of transcripts. Functional enrichment analysis revealed that differentially expressed genes (DEGs) in axons were mainly enriched in key pathways like RNA metabolism and DNA damage, complementing our knowledge of early phenotypes in ALS pathogenesis and known functions of FUS. In addition, we demonstrate a strong enrichment for cell cycle associated genes including significant upregulation of polo-like kinase 1 (PLK1) in FUS [P525L] mutant MNs. PLK1 was increased upon DNA damage induction and PLK1 inhibition further increased the number of DNA damage foci in etoposide-treated cells, an effect that was diminished in case of FUS mutant MNs. In contrast, inhibition of PLK1 increased late apoptotic or necrosis-induced neuronal cell death in mutant neurons. Taken together, our findings provide insights into compartment-specific transcriptomics in human FUS -ALS MNs and we propose that specific upregulation of PLK1 might represent an early event in the pathogenesis of ALS, possibly modulating DNA damage response and other associated pathways.}, }
@article {pmid40098659, year = {2023}, author = {Serrano-Giraldo, J and Becerra-Muñoz, MP and Tijaro-Santos, JA and Zarante, I}, title = {[Current situation of rare diseases in Bogotá: Notification to Sivigila from 2019 to 2022].}, journal = {Revista de salud publica (Bogota, Colombia)}, volume = {25}, number = {4}, pages = {107594}, pmid = {40098659}, issn = {2539-3596}, abstract = {OBJECTIVE: To analyze the reports of orphan diseases in Bogotá, in order to describe the epidemiological profile, based on the cases reported to the Public Health System (Sivigila), from January 2019 to March 2022.<br><br>METHODS: A descriptive and cross-sectional study was carried out in which the cases reported to Sivigila in Bogot&#xe1; were analyzed in the period between January 2019 and March 2022. Absolute and relative frequencies, frequency distribution and prevalences and averages of different variables were calculated. notified in the notification sheets.<br><br>RESULTS: From January 2019 to March 2022, 10,399 patients with orphan diseases have been notified to Sivigila in Bogot&#xe1;, of which 56.25% (5,849) are female and 43.75% (4,550) are female. male sex. 87.10% (9,060) of the cases belong to the contributory regime. The town with the highest number of reports was Suba with 15.85% (1,294). The most reported orphan diseases were: multiple sclerosis with 13.1% (1,363), amyotrophic lateral sclerosis with 4.04% (421) and Guillain-Barre syndrome with 3.6% (374). A patient with an orphan disease in Bogot&#xe1; takes 61.3 months on average from the beginning of their symptoms to obtaining a diagnosis (SD 101.9).<br><br>CONCLUSIONS: From the notification to Sivigila in Bogot&#xe1;, compared to the global prevalence, there is an under-registration of patients with orphan diseases and the delay in the diagnosis of these diseases is evident.}, }
@article {pmid39872952, year = {2023}, author = {Wang, J and Zhou, XF and Wang, YJ}, title = {Continuous antioxidant drug exposure: a bridge from ideal world to real world of therapy for amyotrophic lateral sclerosis.}, journal = {Life medicine}, volume = {2}, number = {1}, pages = {lnac042}, pmid = {39872952}, issn = {2755-1733}, }
@article {pmid39605556, year = {2024}, author = {Singer-Clark, T and Hou, X and Card, NS and Wairagkar, M and Iacobacci, C and Peracha, H and Hochberg, LR and Stavisky, SD and Brandman, DM}, title = {Speech motor cortex enables BCI cursor control and click.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39605556}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; }, abstract = {Decoding neural activity from ventral (speech) motor cortex is known to enable high-performance speech brain-computer interface (BCI) control. It was previously unknown whether this brain area could also enable computer control via neural cursor and click, as is typically associated with dorsal (arm and hand) motor cortex. We recruited a clinical trial participant with ALS and implanted intracortical microelectrode arrays in ventral precentral gyrus (vPCG), which the participant used to operate a speech BCI in a prior study. We developed a cursor BCI driven by the participant's vPCG neural activity, and evaluated performance on a series of target selection tasks. The reported vPCG cursor BCI enabled rapidly-calibrating (40 seconds), accurate (2.90 bits per second) cursor control and click. The participant also used the BCI to control his own personal computer independently. These results suggest that placing electrodes in vPCG to optimize for speech decoding may also be a viable strategy for building a multi-modal BCI which enables both speech-based communication and computer control via cursor and click.}, }
@article {pmid39605399, year = {2024}, author = {Tuddenham, JF and Fujita, M and Khairallah, A and Harbison, C and Flowers, XE and Coronas-Samano, G and Maniatis, S and Daly, A and Schneider, JA and Teich, AF and Vonsattel, JPG and Sims, PA and Elyaman, W and Bradshaw, EM and Phatnani, H and Shneider, N and Bennett, DA and De Jager, PL and Przedborski, S and Menon, V and Olah, M}, title = {Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.11.12.623183}, pmid = {39605399}, issn = {2692-8205}, support = {R25 MH129256/MH/NIMH NIH HHS/United States ; }, abstract = {Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.}, }
@article {pmid39605053, year = {2024}, author = {Horiuchi, M and Watanabe, S and Komine, O and Takahashi, E and Kaneko, K and Itohara, S and Shimada, M and Ogi, T and Yamanaka, K}, title = {ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {184}, pmid = {39605053}, issn = {2051-5960}, support = {JP23K06826//Japan Society for the Promotion of Science/ ; JP19KK0214//Japan Society for the Promotion of Science/ ; JP22H00467//Japan Society for the Promotion of Science/ ; JP22ek0109426//Japan Agency for Medical Research and Development/ ; JP24wm0425014//Japan Agency for Medical Research and Development/ ; JP24wm0625301//Japan Agency for Medical Research and Development/ ; }, mesh = {Animals ; *Oligodendroglia/metabolism/pathology ; *DNA-Binding Proteins/metabolism/genetics ; *Mice, Transgenic ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43[M337V] in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43[M337V] and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43[M337V] with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43[M337V]. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43[M337V] overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.}, }
@article {pmid39604641, year = {2025}, author = {Mi, Y and Zhang, P and Hou, X and Ding, Y and Wang, Y and Du, H and Deng, M}, title = {A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {1}, pages = {191-203}, pmid = {39604641}, issn = {2240-2993}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Middle Aged ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; *Disease Progression ; *Pedigree ; Adult ; Aged ; Mutation, Missense/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.}, }
@article {pmid39603574, year = {2024}, author = {Wen, J and Li, Y and Qin, Y and Yan, L and Zhang, K and Li, A and Wang, Z and Yu, F and Lai, J and Yang, W and Liu, YU and Qin, D and Su, H}, title = {Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107518}, doi = {10.1016/j.phrs.2024.107518}, pmid = {39603574}, issn = {1096-1186}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Phenanthridines/pharmacology/therapeutic use ; *Amaryllidaceae Alkaloids/pharmacology/therapeutic use ; *Caenorhabditis elegans/drug effects/metabolism ; *Motor Neurons/drug effects/pathology/metabolism ; Humans ; *Disease Models, Animal ; TDP-43 Proteinopathies/drug therapy/metabolism/pathology ; DNA-Binding Proteins/metabolism/genetics ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; }, abstract = {Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97 % cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43[A315T] in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43[A315T] both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43[A315T]-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.}, }
@article {pmid39603486, year = {2025}, author = {Krus, KL and Benitez, AM and Strickland, A and Milbrandt, J and Bloom, AJ and DiAntonio, A}, title = {Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice.}, journal = {Experimental neurology}, volume = {384}, number = {}, pages = {115068}, doi = {10.1016/j.expneurol.2024.115068}, pmid = {39603486}, issn = {1090-2430}, support = {R01 NS119812/NS/NINDS NIH HHS/United States ; RF1 AG013730/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Stathmin/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Male ; }, abstract = {Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43[Q331K] knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.}, }
@article {pmid39602529, year = {2024}, author = {Jin, S and Tian, Y and Hacker, J and Chen, X and Bertolio, M and Reynolds, C and Jarvis, R and Hu, J and Promes, V and Halim, D and Gao, FB and Yang, Y}, title = {Inflammatory cytokines disrupt astrocyte exosomal HepaCAM-mediated protection against neuronal excitotoxicity in the SOD1G93A ALS model.}, journal = {Science advances}, volume = {10}, number = {48}, pages = {eadq3350}, pmid = {39602529}, issn = {2375-2548}, support = {R37 NS057553/NS/NINDS NIH HHS/United States ; R01 NS101986/NS/NINDS NIH HHS/United States ; R01 AG078728/AG/NIA NIH HHS/United States ; R01 NS118747/NS/NINDS NIH HHS/United States ; R01 NS125490/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *Astrocytes/metabolism ; *Exosomes/metabolism ; Mice ; Humans ; *Cytokines/metabolism ; *Disease Models, Animal ; *Superoxide Dismutase-1/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Mice, Transgenic ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism ; }, abstract = {Astrocyte secreted signals substantially affect disease pathology in neurodegenerative diseases. It remains little understood about how proinflammatory cytokines, such as interleukin-1α/tumor necrosis factor-α/C1q (ITC), often elevated in neurodegenerative diseases, alter astrocyte-secreted signals and their effects in disease pathogenesis. By selectively isolating astrocyte exosomes (A-Exo.) and employing cell type-specific exosome reporter mice, our current study showed that ITC cytokines significantly reduced A-Exo. secretion and decreased spreading of focally labeled A-Exo. in diseased SOD1G93A mice. Our results also found that A-Exo. were minimally associated with misfolded SOD1 and elicited no toxicity to mouse spinal and human iPSC-derived motor neurons. In contrast, A-Exo. were neuroprotective against excitotoxicity, which was completely diminished by ITC cytokines and partially abolished by SOD1G93A expression. Subsequent proteomic characterization of A-Exo. and genetic analysis identified that surface expression of glial-specific HepaCAM preferentially mediates A-Exo's axon protection effect. Together, our study defines a cytokine-induced loss-of-function mechanism of A-Exo. in protecting neurons from excitotoxicity in amyotrophic lateral sclerosis.}, }
@article {pmid39602508, year = {2024}, author = {Lynch, EM and Pittman, S and Daw, J and Ikenaga, C and Chen, S and Dhavale, DD and Jackrel, ME and Ayala, YM and Kotzbauer, P and Ly, CV and Pestronk, A and Lloyd, TE and Weihl, CC}, title = {Seeding-competent TDP-43 persists in human patient and mouse muscle.}, journal = {Science translational medicine}, volume = {16}, number = {775}, pages = {eadp5730}, pmid = {39602508}, issn = {1946-6242}, support = {F32 NS124841/NS/NINDS NIH HHS/United States ; K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; *DNA-Binding Proteins/metabolism ; Mice ; *Muscle, Skeletal/metabolism/pathology ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Myositis, Inclusion Body/metabolism/pathology ; Disease Models, Animal ; }, abstract = {TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.}, }
@article {pmid39601192, year = {2025}, author = {Sørensen, DM and Tankisi, H}, title = {Reliability of MScanFit Motor Unit Number Estimation in the Trapezius Muscle.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {2}, pages = {166-170}, doi = {10.1002/mus.28303}, pmid = {39601192}, issn = {1097-4598}, support = {//Aage &amp; Johanne Louis-Hansens Foundation/ ; //Grosserer L. F. Foghts Foundation/ ; //Dagmar Marshalls Fond/ ; //The Jascha Foundation,/ ; //Lundbeck Foundation/ ; }, mesh = {Humans ; Male ; *Superficial Back Muscles/physiology ; Female ; Reproducibility of Results ; Adult ; *Electromyography/methods ; *Action Potentials/physiology ; Motor Neurons/physiology ; Young Adult ; Middle Aged ; Recruitment, Neurophysiological/physiology ; Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; }, abstract = {INTRODUCTION/AIMS: MScanFit motor unit number estimation (MUNE) is the most recent MUNE method which has shown promising results in extremity muscles, but it has not been applied to bulbar muscles. Bulbar muscles are particularly important in the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to investigate the feasibility and reliability of MScanFit MUNE in the accessory nerve and trapezius muscles.<br><br>METHODS: A total of twenty healthy participants were examined twice within 1-2&#x2009;weeks. We extracted the MScanFit MUNE and size parameter, and compound muscle action potential (CMAP) amplitude values. The reliability of these parameters was assessed using the intra-rater coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland-Altman plots. We also correlated MUNE values with CMAP amplitudes using correlation coefficients.<br><br>RESULTS: Mean MUNE values (Day 1&#x2009;=&#x2009;132.1 and Day 2&#x2009;=&#x2009;137.4), CMAP amplitudes (Day 1&#x2009;=&#x2009;9.71&#x2009;mV and Day 2&#x2009;=&#x2009;10.10&#x2009;mV) and size parameters did not differ between the two sessions (p&#x2009;>&#x2009;0.05). CoV showed excellent reliability for MUNE values, size parameters, and CMAP amplitudes (CoV&#x2009;<&#x2009;7%) whereas ICCs showed moderate reliability for MUNE values (ICC&#x2009;=&#x2009;0.619), poor to moderate reliability for size parameters (between 0.393 and 0.689), and good reliability for CMAP amplitude (ICC&#x2009;=&#x2009;0.864) There was no correlation between MUNE values and CMAP amplitudes.<br><br>DISCUSSION: MScanFit MUNE is applicable and mostly reliable in the trapezius muscle. Further studies in patients are needed to investigate the sensitivity of MScanFit in this muscle in detecting motor unit loss, particularly in ALS.}, }
@article {pmid39598374, year = {2024}, author = {Li, Y and Fu, J and Wang, H}, title = {Advancements in Targeting Ion Channels for the Treatment of Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {11}, pages = {}, pmid = {39598374}, issn = {1424-8247}, support = {2023YFF1205500//National Key Research and Development Program of China/ ; 82471465//NSFC/ ; C2024202005//Distinguished Young Scholars Science Fund of the Natural Science Foundation of Hebei Province/ ; JZX2023002//Technology Project of Hebei Education Department/ ; 22JCQNJC01110//Tianjin Applied Basic Research Project/ ; 236Z2602G, 246Z2605G, 236Z2401G//the central government guides local funds for science and technology development for Hebei Province/ ; NV20230015//The Key Laboratory of Neural and Vascular Biology, Ministry of Education/ ; }, abstract = {Ion channels are integral membrane proteins embedded in biological membranes, and they comprise specific proteins that control the flow of ion transporters in and out of cells, playing crucial roles in the biological functions of different cells. They maintain the homeostasis of water and ion metabolism by facilitating ion transport and participate in the physiological processes of neurons and glial cells by regulating signaling pathways. Neurodegenerative diseases are a group of disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Despite significant progress in understanding the pathophysiological processes of various neurological diseases in recent years, effective treatments for mitigating the damage caused by these diseases remain inadequate. Increasing evidence suggests that ion channels are closely associated with neuroinflammation; oxidative stress; and the characteristic proteins in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, studying the pathogenic mechanisms closely related to ion channels in neurodegenerative diseases can help identify more effective therapeutic targets for treating neurodegenerative diseases. Here, we discuss the progress of research on ion channels in different neurodegenerative diseases and emphasize the feasibility and potential of treating such diseases from the perspective of ion channels.}, }
@article {pmid39598025, year = {2024}, author = {Vacchiano, V and Morabito, F and Bonan, L and Teodorani, L and Faini, C and Rizzo, G and Liguori, R}, title = {Reverse Split Hand as a Neurophysiological Hallmark of Spinal Muscular Atrophy.}, journal = {Journal of clinical medicine}, volume = {13}, number = {22}, pages = {}, pmid = {39598025}, issn = {2077-0383}, abstract = {Objective: Motor unit number estimation (MUNE) methods are crucial for estimating lower motor neuron loss in motor neuron diseases. The MScanFit MUNE (MScanFit) is a novel method that estimates MUNE values from compound motor action potential (CMAP) scans, demonstrating high sensitivity and reproducibility in detecting motor unit loss in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we aimed to characterize the pattern of motor unit loss in the hand intrinsic muscles of SMA patients compared to ALS patients and healthy controls (HC) using MScanFit MUNE. Methods: Patients diagnosed with ALS, adult SMA patients, and HC were prospectively enrolled. MScanFit examinations were performed on the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. To focus on the different patterns of motor neuron degeneration in the intrinsic hand muscles, the ratio of CMAP amplitude of APB to ADM (CMAP ratio) and the ratio of MUNE values of APB to those of the ADM muscle (MUNE ratio) were calculated. Results: The study included 46 ALS patients, 16 SMA patients, and 23 HC. MScanFit MUNE revealed distinct patterns of motor unit degeneration in SMA patients, notably more severe in the ADM than in the APB muscle, indicating a "reverse" split-hand phenomenon. Both CMAP and MUNE ratios demonstrated high diagnostic accuracy in distinguishing ALS from SMA, with the MUNE ratio performing better. Conclusions: MScanFit MUNE is a valuable tool for exploring distinct patterns of motor neuron degeneration in patients with different types of motor neuron diseases.}, }
@article {pmid39596864, year = {2024}, author = {McKenna, MC and Kleinerova, J and Power, A and Garcia-Gallardo, A and Tan, EL and Bede, P}, title = {Quantitative and Computational Spinal Imaging in Neurodegenerative Conditions and Acquired Spinal Disorders: Academic Advances and Clinical Prospects.}, journal = {Biology}, volume = {13}, number = {11}, pages = {}, pmid = {39596864}, issn = {2079-7737}, support = {2023//Spastic Paraplegia Foundation/ ; }, abstract = {Introduction: Quantitative spinal cord imaging has facilitated the objective appraisal of spinal cord pathology in a range of neurological conditions both in the academic and clinical setting. Diverse methodological approaches have been implemented, encompassing a range of morphometric, diffusivity, susceptibility, magnetization transfer, and spectroscopy techniques. Advances have been fueled both by new MRI platforms and acquisition protocols as well as novel analysis pipelines. The quantitative evaluation of specific spinal tracts and grey matter indices has the potential to be used in diagnostic and monitoring applications. The comprehensive characterization of spinal disease burden in pre-symptomatic cohorts, in carriers of specific genetic mutations, and in conditions primarily associated with cerebral disease, has contributed important academic insights. Methods: A narrative review was conducted to examine the clinical and academic role of quantitative spinal cord imaging in a range of neurodegenerative and acquired spinal cord disorders, including hereditary spastic paraparesis, hereditary ataxias, motor neuron diseases, Huntington's disease, and post-infectious or vascular disorders. Results: The clinical utility of specific methods, sample size considerations, academic role of spinal imaging, key radiological findings, and relevant clinical correlates are presented in each disease group. Conclusions: Quantitative spinal cord imaging studies have demonstrated the feasibility to reliably appraise structural, microstructural, diffusivity, and metabolic spinal cord alterations. Despite the notable academic advances, novel acquisition protocols and analysis pipelines are yet to be implemented in the clinical setting.}, }
@article {pmid39596631, year = {2024}, author = {Sneha, NP and Dharshini, SAP and Taguchi, YH and Gromiha, MM}, title = {Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596631}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Transcriptome ; *Spinal Cord/metabolism/pathology ; Frontal Lobe/metabolism/pathology ; Gene Regulatory Networks ; Motor Neurons/metabolism/pathology ; }, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets.<br><br>METHODS: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis.<br><br>RESULTS: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex.<br><br>CONCLUSIONS: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.}, }
@article {pmid39596615, year = {2024}, author = {Papapanagiotou, AP and Anthimidou, EA and Eleftherohorinos, IG and Giantsis, IA}, title = {Comparison of Molecularly Identified Resistant and Susceptible Johnsongrass (Sorghum halepense L.) Populations at ALS Gene, in the Absence and Presence of Field Crops.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596615}, issn = {2073-4425}, mesh = {*Herbicide Resistance/genetics ; *Acetolactate Synthase/genetics ; *Sorghum/genetics/growth &amp; development ; *Herbicides/pharmacology ; Plant Weeds/genetics/growth &amp; development/drug effects ; Plant Proteins/genetics ; Zea mays/genetics/growth &amp; development ; Crops, Agricultural/genetics/growth &amp; development ; Genotype ; Biomass ; Helianthus/genetics/growth &amp; development ; }, abstract = {BACKGROUND/OBJECTIVES: Johnsongrass (Sorghum halepense) is an erect tetraploid, perennial, C4 grass weed species categorized among the world's most noxious weeds due to its high competitive ability against crops and the increased number of field-evolved herbicide-resistant populations. The aim of the present study was to assess the growth rate and performance of resistant (R) johnsongrass genotypes hosting Trp574Leu target-site cross-resistance at ALS gene, inhibiting various herbicides, compared to susceptible (S) conspecific weeds, in the absence and presence of corn or sunflower antagonism.<br><br>METHODS: The aboveground biomass, tiller, and rhizome production ability of one S and one R johnsongrass population with a Trp574-Leu substitution conferring cross-resistance to ALS-inhibiting herbicides were compared under non-competitive conditions. Furthermore, the competitive ability of these two johnsongrass populations against corn or sunflower was determined in a target-neighborhood design.<br><br>RESULTS: The S and R johnsongrass populations displayed similar growth rates concerning aboveground biomass and tiller number, whereas the R population displayed a slightly greater growth rate for rhizome production compared to the S population. Both populations grown with corn produced more aboveground biomass than the ones grown with sunflowers. The aboveground biomass of corn was reduced to a greater extent than sunflower by the presence of both johnsongrass populations, while both crops were affected more by the S than by the R population.<br><br>CONCLUSIONS: Although the inheritance and the genetic background of plant materls were not addressed, the findings of this study indicate clearly that the growth rate and competitive ability of the ALS-resistant johnsongrass population are not associated with the resistance mechanism involved.}, }
@article {pmid39596609, year = {2024}, author = {Luglio, A and Maggi, E and Riviello, FN and Conforti, A and Sorrentino, U and Zuccarello, D}, title = {Hereditary Neuromuscular Disorders in Reproductive Medicine.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596609}, issn = {2073-4425}, support = {PNRR-MR1-2022-12376108//European Union/ ; }, mesh = {Humans ; *Neuromuscular Diseases/genetics/diagnosis ; Female ; Pregnancy ; Reproductive Medicine/methods ; Genetic Testing/methods ; Prenatal Diagnosis ; Preimplantation Diagnosis ; Muscular Atrophy, Spinal/genetics ; Charcot-Marie-Tooth Disease/genetics/diagnosis ; }, abstract = {Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients' quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot-Marie-Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb-Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn.}, }
@article {pmid39596581, year = {2024}, author = {Paubel, A and Marouillat, S and Dangoumau, A and Maurel, C and Haouari, S and Blasco, H and Corcia, P and Laumonnier, F and Andres, CR and Vourc'h, P}, title = {Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, pmid = {39596581}, issn = {2073-4425}, mesh = {Animals ; *Ubiquitin-Conjugating Enzymes/genetics/metabolism ; Mice ; *Neurons/metabolism ; *Neurodevelopmental Disorders/genetics/pathology ; *Neurodegenerative Diseases/genetics ; *Hippocampus/metabolism ; *Cell Differentiation/genetics ; Neurogenesis/genetics ; Cells, Cultured ; N-Methylaspartate/pharmacology/metabolism ; }, abstract = {Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.}, }
@article {pmid39596445, year = {2024}, author = {Jiang, LL and Zhang, XL and Hu, HY}, title = {Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596445}, issn = {1422-0067}, support = {31670782, 31700669//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *DNA-Binding Proteins/metabolism ; *Protein Aggregation, Pathological/metabolism ; Animals ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; Protein Aggregates ; }, abstract = {Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.}, }
@article {pmid39595895, year = {2024}, author = {Pongrácová, E and Buratti, E and Romano, M}, title = {Prion-like Spreading of Disease in TDP-43 Proteinopathies.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595895}, issn = {2076-3425}, abstract = {TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases.}, }
@article {pmid39595845, year = {2024}, author = {Rocha, PS and Bento, N and Svärd, H and Lopes, DM and Hespanhol, S and Folgado, D and Carreiro, AV and de Carvalho, M and Miranda, B}, title = {Voice Assessment in Patients with Amyotrophic Lateral Sclerosis: An Exploratory Study on Associations with Bulbar and Respiratory Function.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595845}, issn = {2076-3425}, support = {PTDC/MEC-NEU/6855/202//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; }, abstract = {BACKGROUND: Speech production is a possible way to monitor bulbar and respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Moreover, the emergence of smartphone-based data collection offers a promising approach to reduce frequent hospital visits and enhance patient outcomes. Here, we studied the relationship between bulbar and respiratory functions with voice characteristics of ALS patients, alongside a speech therapist's evaluation, at the convenience of using a simple smartphone.<br><br>METHODS: For voice assessment, we considered a speech therapist's standardized tool-consensus auditory-perceptual evaluation of voice (CAPE-V); and an acoustic analysis toolbox. The bulbar sub-score of the revised ALS functional rating scale (ALSFRS-R) was used, and pulmonary function measurements included forced vital capacity (FVC%), maximum expiratory pressure (MEP%), and maximum inspiratory pressure (MIP%). Correlation coefficients and both linear and logistic regression models were applied.<br><br>RESULTS: A total of 27 ALS patients (12 males; 61 years mean age; 28 months median disease duration) were included. Patients with significant bulbar dysfunction revealed greater CAPE-V scores in overall severity, roughness, strain, pitch, and loudness. They also presented slower speaking rates, longer pauses, and higher jitter values in acoustic analysis (all p < 0.05). The CAPE-V's overall severity and sub-scores for pitch and loudness demonstrated significant correlations with MIP% and MEP% (all p < 0.05). In contrast, acoustic metrics (speaking rate, absolute energy, shimmer, and harmonic-to-noise ratio) significantly correlated with FVC% (all p < 0.05).<br><br>CONCLUSIONS: The results provide supporting evidence for the use of smartphone-based recordings in ALS patients for CAPE-V and acoustic analysis as reliable correlates of bulbar and respiratory function.}, }
@article {pmid39595818, year = {2024}, author = {Ferullo, L and Risi, B and Caria, F and Olivieri, E and Poli, L and Gazzina, S and Leggio, U and Bertella, E and Giovanelli, G and Labella, B and Padovani, A and Filosto, M}, title = {Gold Coast Criteria in ALS Diagnosis: A Real-World Experience.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595818}, issn = {2076-3425}, abstract = {Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC's specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment.}, }
@article {pmid39595816, year = {2024}, author = {Shandiz, E and Fernandes, GL and Henkin, JS and McCombe, PA and Trajano, GS and Henderson, RD}, title = {Assessing the Effect of Riluzole on Motor Unit Discharge Properties.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595816}, issn = {2076-3425}, abstract = {Background. This study aims to determine if Riluzole usage can change the function and excitability of motor neurons. Methods. The clinical data and indices of motor neuron excitability were assessed using high-density surface EMG parameters from 80 ALS participants. The persistent inward current was assessed using the discharge rate from paired motor units obtained from the tibialis anterior muscle. This enabled the discharge rate at recruitment, peak discharge rates and the hysteresis of the recruitment-derecruitment frequencies (also known as delta F) to be calculated. Limbs were classified according to their strength. Results. No differences in these motor neuron discharge properties were found according to whether Riluzole was used. Conclusions. The possible interpretations of this finding are discussed.}, }
@article {pmid39595812, year = {2024}, author = {Zhang, S and Yang, Y and Lv, X and Zhou, X and Zhao, W and Meng, L and Zhu, S and Zhang, Z and Wang, Y}, title = {Exosome Cargo in Neurodegenerative Diseases: Leveraging Their Intercellular Communication Capabilities for Biomarker Discovery and Therapeutic Delivery.}, journal = {Brain sciences}, volume = {14}, number = {11}, pages = {}, pmid = {39595812}, issn = {2076-3425}, support = {82171871//National Natural Science Foundation of China/ ; BK20230488//Youth Fund Project of the Jiangsu Province Basic Research Program (Natural Science Foundation)/ ; None//Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; }, abstract = {The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.}, }
@article {pmid39595543, year = {2024}, author = {Stoccoro, A and Coppedè, F}, title = {Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases.}, journal = {Biomolecules}, volume = {14}, number = {11}, pages = {}, pmid = {39595543}, issn = {2218-273X}, mesh = {*DNA Methylation/drug effects ; Humans ; *Pesticides/toxicity/adverse effects ; *Neurodegenerative Diseases/genetics/metabolism/chemically induced ; *Epigenesis, Genetic/drug effects ; *Air Pollutants/toxicity/adverse effects ; Environmental Exposure/adverse effects ; Animals ; Metals, Heavy/toxicity/adverse effects ; Metals/toxicity/metabolism/adverse effects ; }, abstract = {Individuals affected by neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are dramatically increasing worldwide. Thus, several efforts are being made to develop strategies for stopping or slowing the spread of these illnesses. Although causative genetic variants linked to the onset of these diseases are known, they can explain only a small portion of cases. The etiopathology underlying the neurodegenerative process in most of the patients is likely due to the interplay between predisposing genetic variants and environmental factors. Epigenetic mechanisms, including DNA methylation, are central candidates in translating the effects of environmental factors in genome modulation, and they play a critical role in the etiology of AD, PD, and ALS. Among the main environmental exposures that have been linked to an increased risk for these diseases, accumulating evidence points to the role of heavy metals, pesticides, and air pollutants. These compounds could trigger neurodegeneration through different mechanisms, mainly neuroinflammation and the induction of oxidative stress. However, increasing evidence suggests that they are also capable of inducing epigenetic alterations in neurons. In this article, we review the available literature linking exposure to metals, pesticides, and air pollutants to DNA methylation changes relevant to neurodegeneration.}, }
@article {pmid39595127, year = {2024}, author = {Cardona, F}, title = {Special Issue "Mechanisms and Novel Therapeutic Approaches for Neurodegenerative Diseases".}, journal = {Biomedicines}, volume = {12}, number = {11}, pages = {}, pmid = {39595127}, issn = {2227-9059}, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are among the major health problems of the elderly, and represent a major global health challenge due to their increasing prevalence and complex pathophysiological mechanisms [...].}, }
@article {pmid39594452, year = {2024}, author = {Dibwe, DF and Oba, S and Monde, S and Hui, SP}, title = {Inhibition of Accumulation of Neutral Lipids and Their Hydroperoxide Species in Hepatocytes by Bioactive Allium sativum Extract.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594452}, issn = {2076-3921}, abstract = {Our ongoing research suggests that extracts from plant-based foods inhibit the accumulation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These findings suggest their potential use in the alleviation of metabolic dysfunction-associated fatty liver disease (MAFLD) and its most severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH). Allium extracts (ALs: AL1-AL9) were used to assess their ability to reduce lipid droplet accumulation (LDA) and oxidized lipid droplet accumulation (oxLDA) by inhibiting neutral lipid accumulation and oxidation in LD. Among the tested Allium extracts, AL1, AL3, and AL6 demonstrated substantial inhibitory effects on the LDA. Furthermore, AL1 extract showed real-time inhibition of LDA in HepG2 cells in DMEM supplemented with oleic acid (OA) within 12 h of treatment. Our lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] species in hepatocytes under OA and linoleic acid loading conditions. These results suggest that Allium-based foods inhibit LD accumulation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolomic analysis of AL1-the bioactive LDAI extract-using both LC-MS/MS and 1D-NMR [[1]H, [13]C, and Dept (135 and 90)] approaches revealed that AL1 contains mainly carbohydrates and glucoside metabolites, including iridoid glucosides, as well as minor amino acids, organosulfur compounds, and organic acids such as the antioxidant ascorbic acid (KA2 = S13), and their derivatives, suggesting that AL1 could be a potential resource for the development of functional foods and in drug discovery targeting MAFLD/MASH and other related diseases.}, }
@article {pmid39593881, year = {2024}, author = {Favier, G and Rocha, DS}, title = {Overview of Tensor-Based Cooperative MIMO Communication Systems-Part 2: Semi-Blind Receivers.}, journal = {Entropy (Basel, Switzerland)}, volume = {26}, number = {11}, pages = {}, pmid = {39593881}, issn = {1099-4300}, abstract = {Cooperative MIMO communication systems play an important role in the development of future sixth-generation (6G) wireless systems incorporating new technologies such as massive MIMO relay systems, dual-polarized antenna arrays, millimeter-wave communications, and, more recently, communications assisted using intelligent reflecting surfaces (IRSs), and unmanned aerial vehicles (UAVs). In a companion paper, we provided an overview of cooperative communication systems from a tensor modeling perspective. The objective of the present paper is to provide a comprehensive tutorial on semi-blind receivers for MIMO one-way two-hop relay systems, allowing the joint estimation of transmitted symbols and individual communication channels with only a few pilot symbols. After a reminder of some tensor prerequisites, we present an overview of tensor models, with a detailed, unified, and original description of two classes of tensor decomposition frequently used in the design of relay systems, namely nested CPD/PARAFAC and nested Tucker decomposition (TD). Some new variants of nested models are introduced. Uniqueness and identifiability conditions, depending on the algorithm used to estimate the parameters of these models, are established. Two families of algorithms are presented: iterative algorithms based on alternating least squares (ALS) and closed-form solutions using Khatri-Rao and Kronecker factorization methods, which consist of SVD-based rank-one matrix or tensor approximations. In a second part of the paper, the overview of cooperative communication systems is completed before presenting several two-hop relay systems using different codings and configurations in terms of relaying protocol (AF/DF) and channel modeling. The aim of this presentation is firstly to show how these choices lead to different nested tensor models for the signals received at destination. Then, by capitalizing on these models and their correspondence with the generic models studied in the first part, we derive semi-blind receivers to jointly estimate the transmitted symbols and the individual communication channels for each relay system considered. In a third part, extensive Monte Carlo simulation results are presented to compare the performance of relay systems and associated semi-blind receivers in terms of the symbol error rate (SER) and channel estimate normalized mean-square error (NMSE). Their computation time is also compared. Finally, some perspectives are drawn for future research work.}, }
@article {pmid39593143, year = {2024}, author = {Clarke, BE and Ziff, OJ and Tyzack, G and Petrić Howe, M and Wang, Y and Klein, P and Smith, CA and Hall, CA and Helmy, A and Howell, M and Kelly, G and Patani, R}, title = {Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {90}, pmid = {39593143}, issn = {1750-1326}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Valosin Containing Protein/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Animals ; *Lysosomes/metabolism ; Mice ; Mutation/genetics ; Phenotype ; Motor Neurons/metabolism/pathology ; Astrocytes/metabolism ; }, abstract = {BACKGROUND: Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood.<br><br>METHODS: Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes.<br><br>RESULTS: Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the&#xa0;inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes.<br><br>CONCLUSIONS: VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other&#xa0;ALS models and post mortem tissue. These phenotypes&#xa0;occur independently of GPNMB. Additionally,&#xa0;VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.}, }
@article {pmid39592088, year = {2025}, author = {Mahakalakar, N and Mohariya, G and Taksande, B and Kotagale, N and Umekar, M and Vinchurney, M}, title = {"Nattokinase as a potential therapeutic agent for preventing blood-brain barrier dysfunction in neurodegenerative disorders".}, journal = {Brain research}, volume = {1849}, number = {}, pages = {149352}, doi = {10.1016/j.brainres.2024.149352}, pmid = {39592088}, issn = {1872-6240}, mesh = {*Blood-Brain Barrier/drug effects/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Humans ; *Subtilisins/metabolism ; *Neuroprotective Agents/pharmacology ; Brain/metabolism/drug effects ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by progressive destruction of neurons and cognitive impairment, and thorough studies have provided evidence that these pathologies have a close relationship to the failure of the blood-brain barrier (BBB). Nattokinase (NK), a protease found in fermented soybeans, has been extensively studied because it displays powerful neuroprotective abilities, which is why current research was reviewed in the present article. It was concluded that there is enough evidence in preclinical studies using experimental animals that NK supplementation can alleviate the condition related to BBB dysfunction, reduce brain inflammation, and improve cognitive ability. Furthermore, the study of NK on the cardiovascular system leads to certain assumptions, which include the impact on vasculature function and the ability to manage blood flow, which is the key feature of BBB integrity. Such assumed mechanisms are fibrinolytic action, anti-inflammatory and antioxidant action, and endothelium function modulation. There are many positive research findings, and it seems that NK may serve as an effective opponent for BBB breakdown; however, a new research level should be taken to disclose the application and therapeutic use of NK in brain neurodegenerative disease.}, }
@article {pmid39592063, year = {2024}, author = {Lorenc, F and Dupuis, L and Cassel, R}, title = {Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {Neurobiology of disease}, volume = {203}, number = {}, pages = {106748}, doi = {10.1016/j.nbd.2024.106748}, pmid = {39592063}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; *Frontotemporal Dementia/pathology/physiopathology ; Humans ; Animals ; *Neurons/pathology ; *Neural Inhibition/physiology ; }, abstract = {Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases. Impaired neuronal excitability, imbalanced excitatory and inhibitory influences, and altered functional connectivity have been reported. These phenomena are likely due to combined alterations in the various cellular components involved in the functioning of neuronal networks. This review focuses on one of these cellular components: inhibitory neurons. We assess the evidence for inhibitory neuron impairments in amyotrophic lateral sclerosis and frontotemporal dementia, as well as the mechanisms leading to the loss of inhibition. We also discuss the contributions of these alterations to symptoms, and the potential therapeutic strategies for targeting inhibitory neuron deficits.}, }
@article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, }
@article {pmid39589985, year = {2024}, author = {Tkachenko, K and González-Saíz, JM and Calvo, AC and Lunetta, C and Osta, R and Pizarro, C}, title = {Comparative Blood Profiling Based on ATR-FTIR Spectroscopy and Chemometrics for Differential Diagnosis of Patients with Amyotrophic Lateral Sclerosis-Pilot Study.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589985}, issn = {2079-6374}, support = {N&#xb7; 801586//European Union's H2020/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/blood ; Humans ; Pilot Projects ; Diagnosis, Differential ; Spectroscopy, Fourier Transform Infrared ; Middle Aged ; Female ; Male ; Aged ; Adult ; Biomarkers/blood ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neurodegenerative disease characterized by poor prognosis. Currently, screening and diagnostic methods for ALS remain challenging, often leading to diagnosis at an advanced stage of the disease. This delay hinders the timely initiation of therapy, negatively impacting patient well-being. Additionally, misdiagnosis with other neurodegenerative disorders that present similar profiles often occurs. Therefore, there is an urgent need for a cost-effective, rapid, and user-friendly tool capable of predicting ALS onset. In this pilot study, we demonstrate that infrared spectroscopy, coupled with chemometric analysis, can effectively identify and predict disease profiles from blood samples drawn from ALS patients. The selected predictive spectral markers, which are used in various discriminant models, achieved an AUROC sensitivity of almost 80% for distinguishing ALS patients from controls. Furthermore, the differentiation of ALS at both the initial and advanced stages from other neurodegenerative disorders showed even higher AUROC values, with sensitivities of 87% (AUROC: 0.70-0.97). These findings highlight the elevated potential of ATR-FTIR spectroscopy for routine clinical screening and early diagnosis of ALS.}, }
@article {pmid39589981, year = {2024}, author = {Mohaček-Grošev, V and Škrabić, M and Gebavi, H and Blažek Bregović, V and Marić, I and Amendola, V and Grdadolnik, J}, title = {Binding of Glutamic Acid to Silver and Gold Nanoparticles Investigated by Surface-Enhanced Raman Spectroscopy.}, journal = {Biosensors}, volume = {14}, number = {11}, pages = {}, pmid = {39589981}, issn = {2079-6374}, support = {croatian-slovenian bilateral project//Ministry of Scirence and Education of the Republic of Croatia/ ; }, mesh = {*Spectrum Analysis, Raman ; *Glutamic Acid/chemistry ; *Silver/chemistry ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; Hydrogen-Ion Concentration ; }, abstract = {Glutamate is the most important excitatory neurotransmitter, which is relevant for the study of several diseases such as amyotrophic lateral sclerosis and Alzheimer. It is the form L-glutamic acid (Glu) takes at physiologically relevant pHs. The surface-enhanced Raman spectra of Glu obtained at pH values ranging from 3.3 to 12 are collected in the presence of silver and gold colloids and on solid substrates. The observed bands are compared with the positions of calculated normal modes for free neutral glutamic acid, glutamic acid monohydrate, glutamic acid bound to gold and silver atoms, and sodium glutamate. Although gold atoms prefer to bind to the NH2 group as compared to carbonyl groups, silver atoms prefer binding to hydroxyl groups more than binding to the amino group. SERS spectra of glutamic acid solutions with a pH value of 12, in which both carboxylic groups are deprotonated, indicate a complexation of the glutamic acid dianion with the sodium cation, which was introduced into the solution to adjust the pH value. Further research towards an optimal substrate is needed.}, }
@article {pmid39589881, year = {2024}, author = {Jean Gregoire, M and Sirtori, R and Donatelli, L and Morgan Potts, E and Collins, A and Zamor, D and Katenka, N and Fallini, C}, title = {Early disruption of the CREB pathway drives dendritic morphological alterations in FTD/ALS cortical neurons.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2406998121}, pmid = {39589881}, issn = {1091-6490}, support = {P20 GM103430/GM/NIGMS NIH HHS/United States ; Early Career Development Award//RI-INBRE/ ; R01NS116143//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM103430//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 NS116143/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Dendrites/metabolism ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Frontotemporal Dementia/metabolism/genetics/pathology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Neurons/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; C9orf72 Protein/genetics/metabolism ; Phosphorylation ; Cerebral Cortex/metabolism/pathology ; }, abstract = {Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and/or motor decline, such as Alzheimer's disease (AD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD/ALS as well. However, the mechanisms behind reduced CREB activity in FTD/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient's postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD/ALS and possibly other neurodegenerative diseases.}, }
@article {pmid39589500, year = {2025}, author = {Apolloni, S and D'Ambrosi, N}, title = {Biochemical dissection of STAT3 signaling in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3229-3230}, pmid = {39589500}, issn = {1673-5374}, }
@article {pmid39589178, year = {2025}, author = {Peng, Y and Zhou, L and Jin, Y and Wu, D and Chen, N and Zhang, C and Liu, H and Li, C and Ning, R and Yang, X and Mao, Q and Liu, J and Zhang, P}, title = {Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {12}, pages = {3349-3369}, pmid = {39589178}, issn = {1673-5374}, abstract = {The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca 2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca 2+ signaling. Conversely, Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca 2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca 2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca 2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca 2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.}, }
@article {pmid39589160, year = {2025}, author = {Wang, Y and Li, D and Xu, K and Wang, G and Zhang, F}, title = {Copper homeostasis and neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3124-3143}, pmid = {39589160}, issn = {1673-5374}, abstract = {Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.}, }
@article {pmid39588282, year = {2024}, author = {Dash, BP and Freischmidt, A and Helferich, AM and Ludolph, AC and Andersen, PM and Weishaupt, JH and Hermann, A}, title = {Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1457704}, pmid = {39588282}, issn = {1662-5102}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.}, }
@article {pmid39587229, year = {2024}, author = {Wang, C and Wang, S and Xue, Y and Zhong, Y and Li, H and Hou, X and Kang, DD and Liu, Z and Tian, M and Wang, L and Cao, D and Yu, Y and Liu, J and Cheng, X and Markovic, T and Hashemi, A and Kopell, BH and Charney, AW and Nestler, EJ and Dong, Y}, title = {Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {39587229}, issn = {1546-1696}, abstract = {Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model.}, }
@article {pmid39585162, year = {2024}, author = {Savvidis, C and Kouroglou, E and Kallistrou, E and Ragia, D and Dionysopoulou, S and Gavriiloglou, G and Tsiama, V and Proikaki, S and Belis, K and Ilias, I}, title = {IGFBP-2 in Critical Illness: A Prognostic Marker in the Growth Hormone/Insulin-like Growth Factor Axis.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {4}, pages = {621-630}, pmid = {39585162}, issn = {1873-149X}, abstract = {Critical illness (CI) triggers complex disruptions in the growth hormone (GH)/insulin-like growth factor (IGF) axis, significantly affecting the dynamics of insulin-like growth-factor-binding proteins (IGFBPs). Among these, IGFBP-2 shows a sustained elevation during CI, which inversely correlates with serum levels of IGF-1, IGFBP-3, and the acid-labile subunit (ALS). Although IGFBP-2 does not directly interact with ALS, it may influence the availability of IGFs by competing with other IGFBPs for binding to IGF-1 and IGF-2. Research suggests that this persistent elevation of IGFBP-2 is largely driven by cytokine activity during CI, reflecting an adaptive response rather than a direct result of GH/IGF axis dysregulation. The clinical importance of IGFBP-2 is emphasized by its correlation with disease severity in conditions like sepsis and coronavirus disease 2019 (COVID-19), where its levels are markedly elevated compared to healthy controls and are similar to those observed in sepsis from various causes. Beyond its role in endocrine regulation, IGFBP-2 appears to play a part in metabolic and inflammatory pathways. Elevated IGFBP-2 levels have been linked to increased mortality and longer hospital stays, indicating its potential utility as a prognostic marker. Furthermore, measuring plasma IGFBP-2 may have other diagnostic applications, aiding in the assessment of CI when traditional biomarkers are inconclusive.}, }
@article {pmid39585060, year = {2024}, author = {Magni, E and Hochsprung, A and Cáceres-Matos, R and Pabón-Carrasco, M and Heredia-Camacho, B and Solís-Marcos, I and Luque-Moreno, C}, title = {Effects of Respiratory Training on Pulmonary Function, Cough, and Functional Independence in Patients with Amyotrophic Lateral Sclerosis.}, journal = {Neurology international}, volume = {16}, number = {6}, pages = {1332-1342}, pmid = {39585060}, issn = {2035-8385}, abstract = {BACKGROUND: Respiratory complications in patients with amyotrophic lateral sclerosis (ALS), due to the involvement of respiratory muscles, are the leading cause of death, and respiratory physiotherapy (RP) focuses on addressing these complications.<br><br>OBJECTIVES: The objective was to evaluate the effectiveness of an RP intervention that combines the four specific techniques (inspiratory muscle training, lung volume recruitment, manually assisted coughing, and diaphragmatic breathing training) in patients with ALS.<br><br>METHODS: A quasi-experimental study was carried out, and a specific RP programme was implemented in 15 patients with ALS (12 sessions, 30 min/session, one session/week, duration of three months), based on directed ventilation techniques, lung volume recruitment, manually assisted coughing, and the use of incentive spirometry and a cough assist device, along with a daily home exercise programme. Respiratory functions were assessed (pre- and post-intervention, with follow-up at three months) using Forced Vital Capacity (FVC) and Peak Expiratory Cough Flow (PECF); functionality was assessed using the Revised ALS Functional Rating Scale (ALSFRS-R) and the Modified Barthel Index by Granger.<br><br>RESULTS: FVC experienced an increase after three months of the intervention initiation (p = 0.30), which was not sustained at the three-month follow-up after the intervention ended. All other variables remained practically constant after treatment, with their values decreasing at follow-up.<br><br>CONCLUSION: A specific RP intervention could have beneficial effects on respiratory functions, potentially preventing pulmonary infections and hospitalisations in patients with ALS. It may improve FVC and help stabilize the patient's functional decline. Considering the progressive and degenerative nature of the disease, this finding could support the usefulness of these techniques in maintaining respiratory function.}, }
@article {pmid39584466, year = {2024}, author = {Daneshpour, A and Rezvanimehr, A and Niktalab, P and Sharif, H and Yazdanpanah, N and Saleki, K and Rezaei, N}, title = {Exploring the role of vault complex in the nervous system: a literature review.}, journal = {Reviews in the neurosciences}, volume = {}, number = {}, pages = {}, pmid = {39584466}, issn = {2191-0200}, abstract = {Vault RNAs (vtRNAs) are a novel group of non-coding RNAs that are involved in various signaling mechanisms. vtRNAs are joined by three proteins major vault protein (MVP), vault poly (ADP-ribose) polymerase (VPARP), and telomerase-associated protein 1 (TEP1) to form the vault complex. In humans, only four vtRNA including vtRNA 1-1, vtRNA 1-2, vtRNA 1-3, vtRNA 2-1) have been discovered. In nerve cells, vtRNA is involved in synapse formation through MAPK signaling. vtRNA travels to the distal area of neurites as a key unit in the vault complex. Moreover, tRNA is detached from the vault complex in the neurite via a mitotic kinase Aurora-A-reliant MVP phosphorylation. Several molecules contribute to the formation of vtRNAs. For instance, SRSF2 and NSUN2 and their attachment to vtRNA1-1 determines the production of small-vtRNAs. Through the same factors, vtRNAs could play a role in neurodevelopmental deficits. Addition the role of vtRNA expression and vault proteins has been recently studied in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as well as brain cancers. While the mechanisms of vtRNA involvement in neurological disorders is not well-demonstrated, we believe this could be related to the impact of vtRNA regulation in autophagy, immunoregulation, RNA stability, cellular stress, apoptosis, and regulation of other epigenetic pathways. The present review captures the state-of-the-art regarding the role of vtRNAs in neurodevelopment, normal nervous system function, and neurological disorders.}, }
@article {pmid39583905, year = {2024}, author = {Townley, MA}, title = {Spinneret spinning field ontogeny and life history observations in the spider Palpimanus uncatus (Araneae: Palpimanidae).}, journal = {The Journal of arachnology}, volume = {52}, number = {1}, pages = {41-70}, pmid = {39583905}, issn = {0161-8202}, support = {P20 GM113131/GM/NIGMS NIH HHS/United States ; }, abstract = {As in other Palpimanidae, two pairs of posterior spinnerets present in typical Araneomorphae are vestigial in Palpimanus uncatus Kulczyński, 1909, with only the anterior lateral spinneret (ALS) pair prominent. Nevertheless, in late juvenile and adult females, spigots appear in the ancestral posterior spinneret region (PS). Consistent with these spigots serving cylindrical silk glands, females construct substantial egg sacs. While juveniles and adults exhibit a compressed PS, in postembryos it is fully extended. Piriform silk gland (PI) spigots form a linear array on ALSs from the 1[st] stadium, increasing in number during ontogeny by addition of PIs of the tartipore-accommodated (T-A) subtype (i.e., functional during proecdyses). The number of T-A PIs added from one stadium to the next and locations occupied by their spigots often exhibit a stereotypic pattern, especially consistent in early instars. The number of non-T-A PIs remains constant through ontogeny from the 1[st] stadium: one per ALS rather than the two per ALS inferred in a few araneoids. The secondary major ampullate silk gland (2° MaA) spigot, primitively uni-shafted among araneomorphs, has become modified into a multi-shafted spigot with extended base, the number of shafts increasing during ontogeny. However, the multiple ducts that connect to the shafts continue to be accommodated during proecdysis by a single enormous tartipore. Sexual dimorphism is present, with late stadium females having greater numbers of T-A PI spigots and 2° MaA spigot shafts. Observations are presented pertaining to feeding behavior, sexual cannibalism (absent), habitat, winter diapause, numbers of molts, and longevity.}, }
@article {pmid39582565, year = {2024}, author = {Byeon, H}, title = {Glymphatic system function in diverse glucose metabolism states.}, journal = {World journal of diabetes}, volume = {15}, number = {11}, pages = {2245-2250}, pmid = {39582565}, issn = {1948-9358}, abstract = {The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications, including glymphatic system dysfunction. The glymphatic system, crucial for brain waste clearance, is implicated in cognitive decline and neurodegenerative diseases like Alzheimer's disease. This letter explores recent research on glymphatic function across different glucose metabolism states. Tian et al's study reveals significant glymphatic dysfunction in type 2 diabetes mellitus patients, evidenced by lower diffusion tensor imaging analysis along perivascular space indices compared to those with normal glucose metabolism and prediabetes. The research also reveals a link between glymphatic dysfunction and cognitive impairment. Additional research underscores the role of glymphatic impairment in neurodegenerative diseases. These findings highlight the importance of integrating glymphatic health into diabetes management and suggest potential biomarkers for early diagnosis and targeted therapeutic interventions.}, }
@article {pmid39581840, year = {2025}, author = {Hannaford, A and Pavey, N and Menon, P and van den Bos, MAJ and Kiernan, MC and Simon, N and Vucic, S}, title = {Muscle ultrasound aids diagnosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {170}, number = {}, pages = {234-243}, doi = {10.1016/j.clinph.2024.11.008}, pmid = {39581840}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/diagnosis ; Male ; Female ; Middle Aged ; *Ultrasonography/methods/standards ; Aged ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Adult ; Cohort Studies ; Prospective Studies ; Fasciculation/diagnostic imaging/physiopathology ; }, abstract = {OBJECTIVE: There is a need for improved diagnostic tools in Amyotrophic Lateral Sclerosis (ALS). Our objective was to assess muscle ultrasound as a diagnostic tool in patients with ALS and determine a simplified screening protocol to aid implementation in clinical practice.<br><br>METHODS: Ultrasound of bulbar and limb muscles was prospectively performed on all patients referred to a single centre with suspected ALS. Clinical measures of disease severity and upper motor neuron impairment were also recorded. Receiver operating characteristic (ROC) curves were calculated to assess the diagnostic utility of muscle ultrasound.<br><br>RESULTS: 94 patients initially suspected of ALS were recruited to this observational cohort study. Forty-four were subsequently diagnosed as ALS and 50 as disease mimics. ALS patients demonstrated a higher frequency and more generalised distribution of fasciculations compared to mimics. A simplified 5 muscle screening protocol exhibited an AUC of 0.94 (95&#xa0;%CI 0.89-0.99) in discriminating ALS from mimics. The presence of&#xa0;&#x2265;&#xa0;3 fasciculating muscles detected using this screening protocol was 89&#xa0;% sensitive and 88&#xa0;% specific for the diagnosis of ALS.<br><br>CONCLUSIONS: Muscle ultrasound, screening as few as 5 muscles, has diagnostic utility in ALS.<br><br>SIGNIFICANCE: Muscle ultrasound enhances clinical diagnosis in ALS.}, }
@article {pmid39581338, year = {2025}, author = {Kokona, B and Cunningham, NR and Quinn, JM and Jacobsen, DR and Garcia, FJ and Galindo, SM and Petrucelli, L and Stafford, WF and Laue, TM and Fairman, R}, title = {Studying C9orf72 dipeptide repeat polypeptide aggregation using an analytical ultracentrifuge equipped with fluorescence detection.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115720}, pmid = {39581338}, issn = {1096-0309}, support = {P40 OD018537/OD/NIH HHS/United States ; R15 NS081681/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *C9orf72 Protein/genetics ; *Caenorhabditis elegans/genetics ; *Dipeptides/chemistry ; Ultracentrifugation ; Drosophila melanogaster/genetics ; Humans ; Protein Aggregates ; Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Peptides/chemistry/genetics/analysis ; Fluorescence ; }, abstract = {Sedimentation velocity, using an analytical ultracentrifuge equipped with fluorescence detection, and electrophoresis methods are used to study aggregation of proteins in transgenic animal model systems. Our previous work validated the power of this approach in an analysis of mutant huntingtin aggregation. We demonstrate that this method can be applied to another neurodegenerative disease studying the aggregation of three dipeptide repeats (DPRs) produced by aberrant translation of mutant c9orf72 containing large G4C2 hexanucleotide repeats. These repeat expansions are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We analyzed the aggregation patterns of (Gly-Pro)47, (Gly-Ala)50, and (Gly-Arg)50 fused to fluorescent proteins in samples prepared from D. melanogaster, and (Gly-Ala)50 in C. elegans, using AU-FDS and SDD-AGE. Results suggest that (GP)47 is largely monomeric. In contrast, (GA)50 forms both intermediate and large-scale aggregates. (GR)50 is partially monomeric with some aggregation noted in SDD-AGE analysis. The aggregation of this DPR is likely to represent co-aggregated states with DNA and/or RNA. The power of these methods is the ability to gather data on aggregation patterns and characteristics in animal model systems, which may then be used to interpret the mitigation of aggregation through genetic or molecular therapeutic interventions.}, }
@article {pmid39580968, year = {2024}, author = {Lewandowski, SA and Kular, L and Jagodic, M}, title = {Epigenetic age acceleration as a biomarker of amyotrophic lateral sclerosis severity?.}, journal = {EBioMedicine}, volume = {110}, number = {}, pages = {105470}, pmid = {39580968}, issn = {2352-3964}, }
@article {pmid39580792, year = {2025}, author = {Kaplan, E and Weissbach, A and Kadmon, G and Nahum, E and Stein, J}, title = {Plasma exchange using peripheral arterial and venous access in the pediatric intensive care unit.}, journal = {Transfusion}, volume = {65}, number = {1}, pages = {152-158}, pmid = {39580792}, issn = {1537-2995}, mesh = {Humans ; *Plasma Exchange/methods/adverse effects ; Retrospective Studies ; *Intensive Care Units, Pediatric ; Child ; Male ; Female ; Child, Preschool ; Infant ; Adolescent ; Catheterization, Peripheral/methods/adverse effects ; Radial Artery ; }, abstract = {OBJECTIVE: Therapeutic plasma exchange (TPE) is a vital therapeutic modality in pediatric intensive care units (PICU) for various indications. Traditionally, pediatric TPE is performed via a large bore, double lumen catheter, whose insertion necessitates deep sedation, and poses risk of hemorrhagic and thrombotic complications. Building on our previous success utilizing percutaneous radial artery catheters (ALs) for apheresis procedures, we present our experience with ALs for TPE procedures in the PICU.<br><br>METHODS: A retrospective cohort study, conducted in the PICU of a tertiary, university affiliated pediatric hospital, including all children aged 19&#x2009;years and younger, who underwent TPE using an AL for vascular access, between 2018 and 2023. TPE procedures were evaluated for utility (the procedure was performed as planned) and safety.<br><br>RESULTS: A total of 72 procedures were performed on 20 children, using ALs for inlet access and peripheral intra-venous catheters for blood return. Procedure success rate was 94%, with AL malfunction causing transient delays in 6%. All were successfully completed following AL replacement. ALs were mostly 20 and 22 gauge, predominantly located in the radial artery. AL gauge did not significantly affect flow rate or procedure duration.<br><br>CONCLUSIONS: Our findings support AL use for vascular access, as a viable alternative to the traditional large bore, double lumen catheters most often used for TPE in children. Benefits of AL use may include a decrease in sedation requirements and a lower risk of vascular complications. Further investigation is warranted, for consideration as routine practice in PICUs.}, }
@article {pmid39579998, year = {2025}, author = {Baroukhian, J and Seiffert-Sinha, K and Sinha, AA}, title = {Response to Kasperkiewicz et al's "Pemphigus following herpes simplex infection: A global comprehensive cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {4}, pages = {e99-e100}, doi = {10.1016/j.jaad.2024.07.1536}, pmid = {39579998}, issn = {1097-6787}, }
@article {pmid39579996, year = {2025}, author = {Watanabe, Y and Yamaguchi, Y}, title = {Regarding response to Yamaguchi et al's "Anti-SS-A antibody is a potential predictor of severe Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e73-e74}, doi = {10.1016/j.jaad.2024.11.030}, pmid = {39579996}, issn = {1097-6787}, }
@article {pmid39579963, year = {2024}, author = {Carracedo, S and Launay, A and Dechelle-Marquet, PA and Faivre, E and Blum, D and Delarasse, C and Boué-Grabot, E}, title = {Purinergic-associated immune responses in neurodegenerative diseases.}, journal = {Progress in neurobiology}, volume = {243}, number = {}, pages = {102693}, doi = {10.1016/j.pneurobio.2024.102693}, pmid = {39579963}, issn = {1873-5118}, mesh = {Humans ; *Neurodegenerative Diseases/immunology/metabolism ; Animals ; *Receptors, Purinergic/metabolism ; }, abstract = {The chronic activation of immune cells can participate in the development of pathological conditions such as neurodegenerative diseases including Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, compelling evidence indicates that purinergic signaling plays a key role in neuro-immune cell functions. The extracellular release of adenosine 5'-triphosphate (ATP), and its breakdown products (ADP and adenosine) provide the versatile basis for complex purinergic signaling through the activation of several families of receptors. G-protein coupled adenosine A2A receptors, ionotropic P2X and G-protein coupled P2Y receptors for ATP and other nucleotides are abundant and widely distributed in neurons, microglia, and astrocytes of the central nervous system as well as in peripheral immune cells. These receptors are strongly linked to inflammation, with a functional interplay that may influence the intricate purinergic signaling involved in inflammatory responses. In the present review, we examine the roles of the purinergic receptors in neuro-immune cell functions with particular emphasis on A2AR, P2X4 and P2X7 and their possible relevance to specific neurodegenerative disorders. Understanding the molecular mechanisms governing purinergic receptor interaction will be crucial for advancing the development of effective immunotherapies targeting neurodegenerative diseases.}, }
@article {pmid39579350, year = {2024}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Protocol for handling and using SOD1 mice for amyotrophic lateral sclerosis pre-clinical studies.}, journal = {STAR protocols}, volume = {5}, number = {4}, pages = {103459}, pmid = {39579350}, issn = {2666-1667}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Superoxide Dismutase-1/genetics/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Female ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that has no proper cure. Pre-clinical studies on ALS mice are an essential milestone toward clinical trials. Here, we present a protocol for handling and using SOD1[G37R] mice for ALS pre-clinical studies. We describe steps for breeding, genotyping, monitoring, and behavioral testing of mice. We then detail procedures for perfusion, organ harvesting, and immunostaining for postmortem analysis. This protocol can be easily modified for other mouse lines. For complete details on the use and execution of this protocol, please refer to Alfahel et al.[1].}, }
@article {pmid39578404, year = {2025}, author = {Phrathep, DD and Abdo, Z and Tadros, M and Lewandowski, E and Evans, J}, title = {The role of osteopathic manipulative treatment for dystonia: a literature review.}, journal = {Journal of osteopathic medicine}, volume = {125}, number = {4}, pages = {203-211}, pmid = {39578404}, issn = {2702-3648}, mesh = {Humans ; *Manipulation, Osteopathic/methods ; *Dystonia/therapy ; }, abstract = {CONTEXT: Dystonia is a movement disorder that causes involuntary muscle contractions leading to abnormal movements and postures, such as twisting. Dystonia is the third most common movement disorder in the United States, with as many as 250,000 people affected. Because of its complexity, dystonia presents a significant challenge in terms of management and treatment. Despite limited research, osteopathic manipulative treatment (OMT) has been considered as an adjunctive treatment due to its inexpensive and noninvasive nature, as opposed to other modalities such as botulinum toxin injections, deep brain stimulation (DBS), and transcranial magnetic stimulation, which are often expensive and inaccessible. OMT treatments performed in case studies and series such as balanced ligamentous tension/articular ligamentous strain (BLT/ALS), muscle energy (ME), high-velocity low-amplitude (HVLA), and myofascial release (MFR) have shown reduction of pain and muscle hypertonicity, including in patients with dystonia.<br><br>OBJECTIVES: The studies reviewed in this paper provide a snapshot of the literature regarding the current evidence of OMT's role for dystonia.<br><br>METHODS: A medical reference librarian conducted a thorough literature search across multiple databases including PubMed and Google Scholar to find articles relevant to the use of OMT for dystonia. The search employed a combination of Medical Subject Headings (MeSH) terms and keywords related to osteopathic medicine and dystonia to ensure precise retrieval of relevant articles within the last 20 years. Despite limited research on the topic, all four relevant reports found in the literature were selected for review.<br><br>RESULTS: Of the four relevant reports, case series and studies highlighted the potential benefits of OMT in managing dystonia, particularly cervical dystonia and foot dystonia. OMT has shown promising results addressing pain, stiffness, and impaired motor function. In cases of foot dystonia in Parkinson's disease, OMT has helped improve gait and reduce pain by targeting somatic dysfunctions (SDs) associated with dystonia, such as abnormalities in foot progression angle (FPA) and musculoskeletal imbalances. Also, OMT has been found to alleviate symptoms of cervical dystonia, including tremors, muscle spasms, and neck stiffness. These interventions performed in case studies and series led to improvements in gait biomechanics in foot dystonia and overall symptom severity in patients with cervical dystonia.<br><br>CONCLUSIONS: Currently, botulinum toxin, oral medications, physical therapy, and rehabilitation are commonly utilized in managing dystonia. The studies reviewed in this paper suggest that these treatments may lead to improvements in pain and muscle hypertonicity in patients with dystonia. It is important to investigate whether factors such as the type of dystonia (eg, focal vs. segmental) and its underlying cause (eg, idiopathic, trauma, infection, autoimmune, medication side effects) influence treatment outcomes. Further research is recommended to explore the role of OMT in managing dystonia.}, }
@article {pmid39578133, year = {2025}, author = {Travaglia, A and Lal, S and Pullagura, SR}, title = {Advancing ALS research: public-private partnerships to accelerate drug and biomarker development.}, journal = {Trends in neurosciences}, volume = {48}, number = {1}, pages = {1-2}, doi = {10.1016/j.tins.2024.10.008}, pmid = {39578133}, issn = {1878-108X}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Public-Private Sector Partnerships ; *Biomarkers ; Drug Development/methods ; Drug Discovery/methods ; Biomedical Research/methods ; Animals ; }, abstract = {Developing effective treatments for amyotrophic lateral sclerosis (ALS) has been hindered by both the complexity of the disease and decentralized research efforts. By fostering collaboration, standardization, and inclusivity, the Accelerating Medicines Partnership® (AMP®) ALS initiative aims to lay the foundation for future discoveries in ALS biomarkers and treatments.}, }
@article {pmid39577830, year = {2024}, author = {Morikawa, K and Izumiya, Y and Takashio, S and Kawano, Y and Oguni, T and Kuyama, N and Oike, F and Yamamoto, M and Tabata, N and Ishii, M and Hanatani, S and Hoshiyama, T and Kanazawa, H and Matsuzawa, Y and Usuku, H and Yamamoto, E and Ueda, M and Tsujita, K}, title = {Early experience with daratumumab-containing regimens in patients with light-chain cardiac amyloidosis.}, journal = {Journal of cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jjcc.2024.11.003}, pmid = {39577830}, issn = {1876-4738}, abstract = {BACKGROUND: Immunoglobulin light-chain (AL) amyloidosis is a lethal condition resulting from misfolded immunoglobulin ALs produced by clonal CD38-positive plasma cells. Treatment with daratumumab, an anti-human CD38 monoclonal antibody, led to higher frequencies of complete hematologic response and better clinical outcomes compared with conventional treatment. This study sought to evaluate the survival benefit of daratumumab-containing regimens in patients with AL cardiac amyloidosis.<br><br>METHODS AND RESULTS: We examined 65 consecutive patients with AL cardiac amyloidosis (mean age: 67.2&#x202f;&#xb1;&#x202f;10.4&#x202f;years, male: 69&#x202f;%) who underwent chemotherapy. We divided patients into a daratumumab group, which used daratumumab-containing regimens before second-line treatment (n&#x202f;=&#x202f;32), and a conventional treatment group (n&#x202f;=&#x202f;33). Compared with the conventional treatment group, the daratumumab group tended to be older, but there were no significant differences between groups in biomarkers and echocardiographic parameters. A total of 26 patients (40&#x202f;%) died (median follow-up duration: 395&#x202f;days). Kaplan-Meier survival analysis showed that the daratumumab group had significantly lower mortality compared with the conventional treatment group (p&#x202f;=&#x202f;0.04; log-rank test). Cox hazard analysis revealed that use of daratumumab-containing regimens was associated with lower mortality after adjustment for the revised Mayo staging of AL amyloidosis (hazard ratio: 0.32; 95&#x202f;% confidence interval: 0.12 to 0.85; p&#x202f;=&#x202f;0.02).<br><br>CONCLUSION: Daratumumab-containing regimens may be associated with improved survival in patients with AL cardiac amyloidosis.}, }
@article {pmid39577774, year = {2025}, author = {Olesen, MA and Villavicencio-Tejo, F and Cuevas-Espinoza, V and Quintanilla, RA}, title = {Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives.}, journal = {Ageing research reviews}, volume = {103}, number = {}, pages = {102594}, doi = {10.1016/j.arr.2024.102594}, pmid = {39577774}, issn = {1872-9649}, mesh = {Humans ; *tau Proteins/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Tauopathies/metabolism/pathology ; Aging/metabolism/pathology ; }, abstract = {Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.}, }
@article {pmid39577687, year = {2025}, author = {Li, Z and Zhang, Y and Li, D and Du, X and Chen, L and Guo, Y}, title = {Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD pathway.}, journal = {Neuroscience}, volume = {564}, number = {}, pages = {202-213}, doi = {10.1016/j.neuroscience.2024.11.053}, pmid = {39577687}, issn = {1873-7544}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Microglia/metabolism ; *Spinal Cord/metabolism/pathology ; *Up-Regulation ; Mice ; *Smad Proteins/metabolism ; *Signal Transduction/physiology ; *Disease Models, Animal ; *Antigens, CD/metabolism ; *Transforming Growth Factor beta/metabolism ; Mice, Transgenic ; Inflammation/metabolism ; Lipopolysaccharides/pharmacology ; Transforming Growth Factor beta1/metabolism ; }, abstract = {CD109 is a multifunctional coreceptor, whose function has been widely studied in tumor progression and metastasis. One of the reported primary roles of CD109 involves down-regulating TGFβ signaling. However, the role of CD109 in central nervous system, especially neurodegenerative disease, is barely known. Here, we examined the expression changes and cellular location of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice, and explored the role and mechanism of CD109 on LPS-treated BV2 microglia and primary microglia derived from SOD1-G93A mice. Our results showed an increased expression of CD109 and TGFβ/SMAD pathway molecules in lumbar spinal cord of SOD1-G93A mice. Further cellular localization analysis demonstrated that proliferating microglia contributed mainly to the upregulation of CD109 and TGFβ1. Moreover, CD109 intervention in vitro partially reduced inflammatory response and TGFβ/SMAD pathway activation in both LPS-treated BV2 microglia and primary SOD1-G93A microglia. Thus, CD109 was involved in pathogenesis of ALS mice, and interventions targeting on CD109 modulation could be a potential therapeutic strategy for ALS.}, }
@article {pmid39577621, year = {2024}, author = {Reiche, L and Plaack, B and Lehmkuhl, M and Weyers, V and Gruchot, J and Picard, D and Perron, H and Remke, M and Knobbe-Thomsen, C and Reifenberger, G and Küry, P and Kremer, D}, title = {HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior.}, journal = {Microbes and infection}, volume = {}, number = {}, pages = {105460}, doi = {10.1016/j.micinf.2024.105460}, pmid = {39577621}, issn = {1769-714X}, abstract = {Gliomas are the most common parenchymal tumors of the central nervous system (CNS). With regard to their still unclear etiology, several recent studies have provided evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to the evolution and progression of many neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and, particularly, multiple sclerosis (MS). In these diseases, HERVs exert effects on cellular processes such as inflammation, proliferation, and migration. In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. Here, we now show that HERV-W ENV is also present in the microglial cells (MG) of the tumor microenvironment (TME) in gliomas. It modulates the behavior of glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secreted cytokines, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties.}, }
@article {pmid39577228, year = {2025}, author = {Sojdeh, S and Safarkhani, M and Daneshgar, H and Aldhaher, A and Heidari, G and Nazarzadeh Zare, E and Iravani, S and Zarrabi, A and Rabiee, N}, title = {Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology's unexplored frontier.}, journal = {European journal of medicinal chemistry}, volume = {282}, number = {}, pages = {117080}, doi = {10.1016/j.ejmech.2024.117080}, pmid = {39577228}, issn = {1768-3254}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/therapy ; Humans ; *Nanotechnology ; Genetic Therapy ; Animals ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {This review explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author's prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.}, }
@article {pmid39577115, year = {2024}, author = {Abdian, S and Fakhri, S and Moradi, SZ and Khirehgesh, MR and Echeverría, J}, title = {Saffron and its major constituents against neurodegenerative diseases: A mechanistic review.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {135}, number = {}, pages = {156097}, doi = {10.1016/j.phymed.2024.156097}, pmid = {39577115}, issn = {1618-095X}, mesh = {Animals ; Humans ; *Carotenoids/pharmacology/therapeutic use ; *Crocus/chemistry ; Cyclohexenes/pharmacology ; Glucosides/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/chemistry/pharmacology ; Phytochemicals/pharmacology ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Terpenes/pharmacology ; Vitamin A/analogs &amp; derivatives ; }, abstract = {BACKGROUND: Neurodegeneration has been recognized as the main pathophysiological alteration in the majority of brain-related diseases. Despite contemporary attempts to provide acceptable medicinal therapies, the conclusion has not been much beneficial. Besides, the complex pathophysiological mechanisms behind neurodegenerative diseases (NDDs) urge the needs for finding novel multi-target agents. Accordingly, saffron with major active constituents and as multi-targeting agents have shown beneficial effects in modulating NDDs with higher efficacy and lower side effects.<br><br>PURPOSE: The present study provides a systematic and comprehensive review of the existing in vitro, in vivo, and clinical data on the effectiveness, and signaling pathways of saffron and its key phytochemical components in the management of NDDs. The need to develop novel saffron delivery systems is also considered.<br><br>METHODS: Studies were identified through a systematic and comprehensive search in Science Direct, PubMed, and Scopus databases through April 30, 2024. The whole saffron major constituents (e.g., saffron, crocin, crocetin, picrocrocin, and safranal) and NDDs (e.g., neuro*, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington*, Parkinson*, Alzheimer*, and brain) were selected as keywords to find related studies. In the systematic analysis, 64 articles were directly included in the current study. Additional reports were added within the comprehensive studies in the review.<br><br>RESULTS: Saffron and its active metabolites crocin, crocetin, safranal, and picrocrocin have shown acceptable efficacy in managing NDDs like Alzheimer's disease, Parkinson's disease, Attention deficit hyperactivity disorder, depression, and other NDDs via modulating apoptotic (e.g., caspases, Bax/Bcl-2, cytochrome c, and death receptors), inflammatory (e.g., NF-&#x3ba;B, IL-1&#x3b2;, IL-6, TNF-&#x3b1;, and COX-2), and oxidative strass (e.g., Nrf2, GSH, GPx, CAT, SOD, MDA, ROS, and nitrite) signaling pathways. The presented in vitro, in vivo, and clinical evidences showed us a better future of controlling NDDs with higher efficacy, while decreasing associated side effects with no significant toxicity. Additionally, employing novel delivery systems could increase the efficacy of saffron phytoconstituents to resolve the issues pharmacokinetic limitations.<br><br>CONCLUSION: Saffron and its major constituents employ anti-inflammatory, anti-apoptotic and antioxidant mechanisms in modulating several dysregulated-signaling pathways in NDDs. However, further research is necessary to elucidate the precise underlying mechanisms in exploring the feasibility of using saffron active compounds against NDDs. More studies should focus on dose-response relationships, long-term effects, highlighting key mechanisms, and designing more well-controlled clinical trials. Additionally, developing stable and cost-benefit novel delivery systems in future works helps to remove the pharmacokinetic limitations of saffron major constituents.}, }
@article {pmid39575748, year = {2024}, author = {Xu, Z and He, S and Begum, MM and Han, X}, title = {Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.}, journal = {Antioxidants &amp; redox signaling}, volume = {41}, number = {16-18}, pages = {1073-1099}, pmid = {39575748}, issn = {1557-7716}, support = {P30 AG013319/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; R01 AG061729/AG/NIA NIH HHS/United States ; R01 AG085545/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Myelin Sheath/metabolism ; *Lipid Metabolism ; Animals ; Lipids ; }, abstract = {Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.}, }
@article {pmid39575564, year = {2025}, author = {Olofsson, J and Bergström, S and Mravinacová, S and Kläppe, U and Öijerstedt, L and Zetterberg, H and Blennow, K and Ingre, C and Nilsson, P and Månberg, A}, title = {Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {113-123}, doi = {10.1080/21678421.2024.2428930}, pmid = {39575564}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Middle Aged ; Aged ; *Biomarkers/cerebrospinal fluid ; Prognosis ; *Disease Progression ; Adult ; Cohort Studies ; Phosphorylation ; }, abstract = {OBJECTIVE: To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH).<br><br>METHOD: CSF levels of NfL, NfM, and pNfH were analyzed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Center in Stockholm, Sweden. NfM levels were analyzed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations.<br><br>RESULT: Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls. Similarly, higher NfM levels were found in fast compared with slow progressing patients for baseline and longitudinal progression when evaluating both total and subscores of ALSFRS-R. These findings were consistent with the results observed for NfL and pNfH. All three proteins, used individually as well as in combination, showed comparable performance when classifying fast vs slow progressing patients (AUCs 0.78-0.85). For all neurofilaments, higher survival probability was observed for patients with low CSF levels.<br><br>CONCLUSION: Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. Additional investigations with independent cohorts and longitudinal studies are needed to further assess the potential added value of NfM.}, }
@article {pmid39574866, year = {2024}, author = {Manohar, R and Yang, FX and Stephen, CD and Schmahmann, JD and Eklund, NM and Gupta, AS}, title = {At-home wearables and machine learning capture motor impairment and progression in adult ataxias.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574866}, support = {R01 NS117826/NS/NINDS NIH HHS/United States ; R01 NS134597/NS/NINDS NIH HHS/United States ; }, abstract = {A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior. Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T). Remotely collected cross-sectional (n = 76) and longitudinal data (n = 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, strongly separated ataxia and control populations, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.}, }
@article {pmid39574800, year = {2024}, author = {Bouajila, N and Domenighetti, C and Aubin, HJ and Naassila, M}, title = {Alcohol consumption and its association with cancer, cardiovascular, liver and brain diseases: a systematic review of Mendelian randomization studies.}, journal = {Frontiers in epidemiology}, volume = {4}, number = {}, pages = {1385064}, pmid = {39574800}, issn = {2674-1199}, abstract = {BACKGROUND: The health effects of alcohol consumption, particularly regarding potential protective benefits of light to moderate intake compared to abstinence, remain a subject of ongoing debate. However, epidemiological studies face limitations due to imprecise exposure measurements and the potential for bias through residual confounding and reverse causation. To address these limitations, we conducted a systematic review of Mendelian Randomization (MR) studies examining the causal relationship between alcohol consumption and cancers, cardiovascular, liver, and neurological diseases.<br><br>METHODOLOGY: We searched PubMed, ScienceDirect and Embase and Europe PMC up to 05/2024 for MR studies investigating the association of genetically predicted alcohol consumption with cancers, cardiovascular, liver and neurological diseases. We assessed methodological quality based on key elements of the MR design a genetic association studies tool.<br><br>RESULTS: We included 70 MR studies that matched our inclusion criteria. Our review showed a significant association of alcohol consumption with multiple cancers such as oral and oropharyngeal, esophageal, colorectal cancers, hepatocellular carcinoma and cutaneous melanoma. While the available studies did not consistently confirm the adverse or protective effects of alcohol on other cancers, such as lung cancer, as suggested by observational studies. Additionally, MR studies confirmed a likely causal effect of alcohol on the risk of hypertension, atrial fibrillation, myocardial infraction and vessels disease. However, there was no evidence to support the protective effects of light to moderate alcohol consumption on cognitive function, Alzheimer's disease, and amyotrophic lateral sclerosis, as reported in observational studies while our review revealed an increased risk of epilepsy and multiple sclerosis. The available studies provided limited results on the link between alcohol consumption and liver disease.<br><br>CONCLUSIONS: Despite the valuable insights into the causal relationship between alcohol consumption and various health outcomes that MR studies provided, it is worth noting that the inconsistent ability of genetic instrumental variables to distinguish between abstainers, light and moderate drinkers makes it difficult to differentiate between U or J-shaped vs. linear relationships between exposure and outcome. Additional research is necessary to establish formal quality assessment tools for MR studies and to conduct more studies in diverse populations, including non-European ancestries.<br><br>www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021246154, Identifier: PROSPERO (CRD42021246154).}, }
@article {pmid39574607, year = {2024}, author = {Fürtjes, AE and Foote, IF and Xia, C and Davies, G and Moodie, J and Taylor, A and Liewald, DC and Redmond, P and Corley, J and McIntosh, AM and Whalley, HC and Maniega, SM and Hernández, MV and Backhouse, E and Ferguson, K and Bastin, ME and Wardlaw, J and de la Fuente, J and Grotzinger, AD and Luciano, M and Hill, WD and Deary, IJ and Tucker-Drob, EM and Cox, SR}, title = {Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574607}, issn = {2692-8205}, support = {R01 AG073593/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 MH120219/MH/NIMH NIH HHS/United States ; MR/M013111/1/MRC_/Medical Research Council/United Kingdom ; P2C HD042849/HD/NICHD NIH HHS/United States ; P30 AG066614/AG/NIA NIH HHS/United States ; U54 MH091657/MH/NIMH NIH HHS/United States ; }, abstract = {A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV~ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h [2] SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h [2] = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.}, }
@article {pmid39574440, year = {2024}, author = {Kaur, N and Verma, AK and Girdhar, M and Kumar, A and Siddiqui, MA and Al-Khedhairy, AA and Malik, T and Mohan, A}, title = {Genome-wide analysis of the Cannabis sativa cytochrome P450 monooxygenase superfamily and uncovering candidate genes for improved herbicide tolerance.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1490036}, pmid = {39574440}, issn = {1664-462X}, abstract = {Cannabis sativa is an economically important crop, yet weed management remains a significant challenge due to limited herbicide options. Cytochrome P450 enzymes play crucial roles in plant metabolism, including herbicide detoxification. This study aimed to identify and characterize the CYP gene family in Cannabis and investigate their potential role in herbicide metabolism. We identified 225 CYP proteins encoded by 221 genes in the Cannabis genome, classified into 9 clans and 47 families. The majority of CsCYPs were predicted to be located in endomembrane system and chromosomal mapping revealed that they were present in all the chromosomes. Motif and gene structure analysis supported the results from phylogenetic analysis. The gene duplication analysis results showed that tandem duplication plays a pivotal role in evolutionary expansion of CsCYP superfamily. Promoter analysis revealed various cis-acting elements involved in stress, light, hormone and development responses. Molecular docking simulations identified several CsCYPs with strong binding affinities to ALS-inhibiting herbicides, particularly bispyribac-sodium, propoxycarbazone-sodium, and pyriftalid. CsCYP_215, CsCYP_213, CsCYP_217 and CsCYP_14 emerged as promising candidates for herbicide metabolism. Analysis of binding site residues revealed the importance of hydrophobic and aromatic interactions in herbicide binding. This study provides the first comprehensive characterization of the CYP gene family in C. sativa and offers new insights into their potential roles in herbicide metabolism. The identification of promising herbicide-metabolizing CYP candidates opens new avenues for developing herbicide-tolerant Cannabis varieties, potentially addressing key challenges in weed management and crop productivity.}, }
@article {pmid39572918, year = {2024}, author = {Changkakoti, L and Rajabalaya, R and David, SR and Balaraman, AK and Sivasubramanian, H and Mukherjee, AK and Bala, A}, title = {Exploration of the Role of Vitamins in Preventing Neurodegenerative Diseases: Comprehensive Review on Preclinical and Clinical Findings.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X327677240902105443}, pmid = {39572918}, issn = {1875-6190}, abstract = {Neurodegenerative diseases (NDDs) are a multifaceted and heterogeneous group of complex diseases. Unfortunately, a cure for these conditions has yet to be found, but there are ways to reduce the risk of developing them. Studies have shown that specific vitamins regulate the brain molecules and signaling pathways, which may help prevent degeneration. This review focuses on examining the role of vitamins in preventing five significant types of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). This review also highlights promising and controversial findings about the potential impact of vitamins on this group of diseases. Several developed countries standardize daily dietary vitamin intake to meet nutrient requirements, improve health, and prevent chronic diseases like NDDs. However, more research is necessary to gain a more comprehensive understanding of their therapeutic benefits, including studies exploring different drug-dose paradigms, diverse humanized animal models, and clinical trials conducted in various locations.}, }
@article {pmid39572390, year = {2024}, author = {Morales, JMN and Alcaraz, MR and Loto, A and Parellada, EA and Tulli, F and Morán Vieyra, FE and Borsarelli, CD}, title = {Chemometric modeling of spectroscopic data for characterizing the visible-light-driven photocatalytic N-dealkylation of rhodamine B on a TiO2 film.}, journal = {Photochemistry and photobiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/php.14043}, pmid = {39572390}, issn = {1751-1097}, support = {PIP-2020-101043CO//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PUE-2018-035//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; PICT-2019-02052//Fondo para la Investigaci&#xf3;n Cient&#xed;fica y Tecnol&#xf3;gica/ ; 23A/254//Universidad Nacional de Santiago del Estero/ ; }, abstract = {The green-light driven photocatalytic N-deethylation reaction of Rhodamine B (RhB) on a TiO2 film was investigated by UV-vis absorption and fluorescence emission spectroscopies, in addition to HPLC and HR-MS, to ascertain the nature of the reaction products. The evolution of the photocatalytic reaction was chemometrically analyzed using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) of the spectroscopic data to obtain the kinetic and spectral decomposition of the RhB derivatives involved in the reaction. This was then compared with the results obtained by standard HPLC analysis. The MCR-ALS analysis yielded satisfactory spectral and kinetic profiles for RhB and the fully deethylated product, Rhodamine 110. However, the spectral profiles for the N-triethyl (3EtRh) and the mixture of the two isomeric N-diethyl (2EtRh) derivatives exhibited some spectral distortions due to significant spectral overlap between these compounds. In contrast to the HPLC analysis, the MCR-ALS could not resolve the N-ethylrhodamine (EtRh) derivative. The deethylation reactions occurred via independent zero-order steps at the surface of TiO2, indicating that the RhB degradation reaction is governed by the adsorption-desorption equilibrium of the dye and derivatives on the photocatalyst surface, thereby enhancing the diffusion of compounds on the surface.}, }
@article {pmid39572211, year = {2025}, author = {Benatar, M and Heiman-Patterson, TD and Cooper-Knock, J and Brickman, D and Casaletto, KB and Goutman, SA and Vinceti, M and Dratch, L and Arias, JJ and Swidler, J and Turner, MR and Shefner, J and Westeneng, HJ and van den Berg, LH and Al-Chalabi, A and , }, title = {Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS/FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334339}, pmid = {39572211}, issn = {1468-330X}, abstract = {There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines.}, }
@article {pmid39572209, year = {2024}, author = {Grassano, M}, title = {Navigating the presymptomatic frontier in genetic ALS and FTD.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334924}, pmid = {39572209}, issn = {1468-330X}, }
@article {pmid39571437, year = {2025}, author = {Parastar, H and Yazdanpanah, H and Weller, P}, title = {Non-targeted volatilomics for the authentication of saffron by gas chromatography-ion mobility spectrometry and multivariate curve resolution.}, journal = {Food chemistry}, volume = {465}, number = {Pt 2}, pages = {142074}, doi = {10.1016/j.foodchem.2024.142074}, pmid = {39571437}, issn = {1873-7072}, mesh = {*Crocus/chemistry ; *Ion Mobility Spectrometry/methods ; Food Contamination/analysis ; Gas Chromatography-Mass Spectrometry ; Volatile Organic Compounds/chemistry/analysis ; Discriminant Analysis ; Multivariate Analysis ; Principal Component Analysis ; Least-Squares Analysis ; Iran ; }, abstract = {In the present contribution, a novel non-targeted volatilomic study based on headspace GC-IMS (HS-GC-IMS) was developed for the authentication and geographical origin discrimination of saffron. In this regard, multivariate curve resolution-alternating least squares (MCR-ALS) was employed to recover the pure GC elution and IMS profiles of saffron metabolites. Iranian saffron samples from seven important areas were analyzed by HS-GC-IMS. The resulting second-order GC-IMS datasets were organized in a augmented matrix and processed using MCR-ALS with various constraints. The MCR-ALS resolved GC profiles were analyzed by different pattern recognition techniques; principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and data driven-soft independent modeling of class analogy (DD-SIMCA). The saffron samples were assigned to their seven geographical origins with an accuracy of 89.0 %. Additionally, four adulterants (style, safflower, madder and calendula) were reliably detected with over 94.0 % accuracy. In this context, GC-IMS substantially outperformed the commonly used FT-NIR spectroscopy approach.}, }
@article {pmid39571211, year = {2025}, author = {Wang, Z and Wu, P and Zhao, Y and Li, X and Kong, D}, title = {Application of excitation-emission matrix fluorescence spectroscopy and chemometrics for quantitative analysis of emulsified oil concentration.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {328}, number = {}, pages = {125423}, doi = {10.1016/j.saa.2024.125423}, pmid = {39571211}, issn = {1873-3557}, abstract = {Emulsified oil concentration is an important index for quantitative analysis of sea surface oil spill pollution, and the development of a fast and effective quantitative analysis method for emulsified oil concentration plays a crucial role in the estimation of oil spill volume and post-spill assessment. A quantitative analysis method for emulsified oil concentration based on excitation-emission matrix (EEM) fluorescence spectroscopy and chemometrics was proposed. Firstly, the EEM fluorescence spectra of two emulsified oils were measured using a FLS1000 fluorescence spectrometer. Then, the measured EEM fluorescence spectra were decomposed by parallel factor analysis (PARAFAC), and several key excitation wavelengths were filtered from the loading matrix obtained from the decomposition. Subsequently, the three-band fluorescence index (TBFI) at these excitation wavelengths was calculated and combined with the optimal band selection algorithm, from which the optimal emission band combinations were selected. Finally, the selected optimal emission bands were combined with partial least squares regression (PLSR) to establish a prediction model for emulsified oil concentration. By comparing the prediction results with those based on PARAFAC-PLSR and multivariate curve resolved-alternating least squares (MCR-ALS)-PLSR models, the TBFI-PLSR model showed the best results in the quantitative analysis of emulsified oil concentration. The coefficient of determination, mean square relative error, and ratio of performance to interquartile distance for the gasoline and diesel fuel emulsion validation sets were 0.93, 3.67%, 4.72, and 0.93, 3.72%, 4.60, respectively.}, }
@article {pmid39570667, year = {2024}, author = {Burks, CA and Brenner, MJ}, title = {Commentary on Von Sneidern et al's "Evaluation and Treatment of Acute Facial Palsy: Opportunities for Optimization at a Single Institution."-Bridging the Gap Between Guidelines and Practice.}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/fpsam.2024.0263}, pmid = {39570667}, issn = {2689-3622}, }
@article {pmid39570437, year = {2025}, author = {Maity, D and Kaundal, RK}, title = {Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {4}, pages = {1661-1686}, pmid = {39570437}, issn = {1590-3478}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Humans ; *MicroRNAs/genetics/metabolism ; *Early Diagnosis ; Biomarkers/metabolism ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron degeneration, leading to muscle weakness and paralysis, with no effective treatments available. Early diagnosis could slow disease progression and optimize treatment. MicroRNAs (miRNAs) are being investigated as potential biomarkers due to their regulatory roles in cellular processes and stability in biofluids. However, variability across studies complicates their diagnostic utility in ALS. This study aims to identify significantly dysregulated miRNAs in ALS through meta-analysis to elucidate disease mechanisms and improve diagnostic strategies.<br><br>METHODS: We systematically searched PubMed, Google Scholar, and the Cochrane Library, following predefined inclusion and exclusion criteria. The primary effect measure was the standardized mean difference (SMD) with a 95% confidence interval, analyzed using a random-effects model. Additionally, we used network pharmacology to examine the targets of dysregulated miRNAs and their roles in ALS pathology.<br><br>RESULTS: Analysing 34 studies, we found significant upregulation of hsa-miR-206, hsa-miR-133b, hsa-miR-23a, and hsa-miR-338-3p, and significant downregulation of hsa-miR-218, hsa-miR-21-5p, and hsa-let-7b-5p in ALS patients. These miRNAs are involved in ALS pathophysiology, including stress granule formation, nuclear pore complex, SMCR8 and Sig1R dysfunction, histone methyltransferase complex alterations, and MAPK signaling perturbation, highlighting their critical role in ALS progression.<br><br>CONCLUSION: This study identifies several dysregulated miRNAs in ALS patients, offering insights into their role in the disease and potential as diagnostic biomarkers. These findings enhance our understanding of ALS mechanisms and may inform future diagnostic strategies. Validating these results and exploring miRNA-based interventions are crucial for improving ALS diagnosis and treatment outcomes.}, }
@article {pmid39569894, year = {2024}, author = {Brannigan, JFM and Liyanage, K and Horsfall, HL and Bashford, L and Muirhead, W and Fry, A}, title = {Brain-computer interfaces patient preferences: a systematic review.}, journal = {Journal of neural engineering}, volume = {21}, number = {6}, pages = {}, doi = {10.1088/1741-2552/ad94a6}, pmid = {39569894}, issn = {1741-2552}, mesh = {*Brain-Computer Interfaces ; Humans ; *Patient Preference ; Adult ; Middle Aged ; Spinal Cord Injuries/rehabilitation/psychology/physiopathology ; Amyotrophic Lateral Sclerosis/psychology/rehabilitation/physiopathology ; }, abstract = {Objective. Brain-computer interfaces (BCIs) have the potential to restore motor capabilities and functional independence in individuals with motor impairments. Despite accelerating advances in the performance of implanted devices, few studies have identified patient preferences underlying device design, and each study typically captures a single aetiology of motor impairment. We aimed to characterise BCI patient preferences in a large cohort across multiple aetiologies.Approach. We performed a systematic review of all published studies reporting patient preferences for BCI devices, including both qualitative and quantitative data. We searched MEDLINE, Embase, and CINAHL from inception to 18 April 2023. Two reviewers independently screened articles and extracted data on demographic information, device use, invasiveness preference, device design, and functional preferences.Main results. From 1316 articles identified, 28 studies met inclusion criteria, capturing preferences from 1701 patients (mean age 42.1-64.3 years). The most represented conditions were amyotrophic lateral sclerosis (n= 15 studies, 53.6%) and spinal cord injury (n= 13 studies 46.4%). Individuals with motor impairments prioritised device accuracy over other design characteristics. In four studies where patients ranked performance characteristics, accuracy was ranked first each time. We found that the speed and accuracy of BCI systems in recent publications exceeds reported patient preferences, however this performance has been achieved with a level of training and setup burden that would not be tolerated by most patients. Preferences varied by disease aetiology and severity; amyotrophic lateral sclerosis patients typically prioritised communication functions, whereas spinal cord injury patients emphasised limb control and sphincteric functions.Significance.Our findings highlight that despite advances in BCI performance exceeding patient expectations, there remains a need to reduce training and setup burdens to enhance usability. Moreover, patient preferences differ across conditions and impairment severities, underscoring the importance of personalised BCI configurations and tailored training regimens to meet individual needs.}, }
@article {pmid39569650, year = {2025}, author = {Luo, S and Wang, X and Ma, B and Liu, D and Li, L and Wang, L and Ding, N and Zou, L and Wang, J and Pan, J and Sang, D and Zhou, H and Qu, H and Lu, Y and Yang, L}, title = {Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.}, journal = {Biomolecules &amp; biomedicine}, volume = {25}, number = {3}, pages = {632-647}, doi = {10.17305/bb.2024.11218}, pmid = {39569650}, issn = {2831-090X}, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism/genetics ; Animals ; *Motor Neurons/drug effects/pathology/metabolism ; *Mice, Transgenic ; Mice ; *Axons/drug effects/pathology ; *Mice, Inbred C57BL ; Disease Models, Animal ; Superoxide Dismutase/metabolism/genetics ; Cell Survival/drug effects ; Spinal Cord/drug effects/pathology/metabolism ; Male ; Apolipoproteins A ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.}, }
@article {pmid39569145, year = {2024}, author = {Mirceta, M and Schmidt, MHM and Shum, N and Prasolava, TK and Meikle, B and Lanni, S and Mohiuddin, M and Mckeever, PM and Zhang, M and Liang, M and van der Werf, I and Scheers, S and Dion, PA and Wang, P and Wilson, MD and Abell, T and Philips, EA and Sznajder, &#x141;J and Swanson, MS and Mehkary, M and Khan, M and Yokoi, K and Jung, C and de Jong, PJ and Freudenreich, CH and McGoldrick, P and Yuen, RKC and Abrahão, A and Keith, J and Zinman, L and Robertson, J and Rogaeva, E and Rouleau, GA and Kooy, RF and Pearson, CE}, title = {C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.26.620312}, pmid = {39569145}, issn = {2692-8205}, abstract = {The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72 Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72 Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show C9orf72 Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of C9orf72 as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. C9orf72 Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one C9orf72 Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72 Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic C9orf72 Exp mice, implicating C9orf72 Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.}, }
@article {pmid39568840, year = {2024}, author = {Souayah, N and Chong, ZZ and Patel, T and Nasar, A and Pahwa, A and W Sander, H}, title = {Regression equation analysis enhances detection of conduction slowing beyond axonal loss in diabetic neuropathy.}, journal = {Heliyon}, volume = {10}, number = {21}, pages = {e39712}, pmid = {39568840}, issn = {2405-8440}, abstract = {OBJECTIVES: To evaluate the utility of regression analysis in the assessment of conduction slowing in diabetic distal symmetrical polyneuropathy (DSP) and in identifying superimposed demyelination beyond fiber loss.<br><br>BACKGROUND: Causes of conduction slowing beyond pure axonal loss has been attributed to an additional demyelinating component. We therefore evaluated the utility of regression analysis in the assessment of conduction slowing in diabetic DSP and in identifying superimposed demyelination beyond fiber loss.<br><br>METHODS: We previously established regression analysis to develop confidence intervals that assess the range of conduction slowing from primary demyelination in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, by using the regression equations, we analyzed conduction slowing in patients with diabetic DSP.<br><br>RESULTS: Mean conduction velocity (CV) was significantly slower in diabetic DSP than in the non-diabetic DSP for all tested nerves. More patients were found to fulfill the regression equation criteria in the diabetic group compared to the non-diabetic group (47.0&#xa0;% vs. 23.3&#xa0;%). The estimated likelihood of having more than two motor nerves with CV slowing in the demyelination range by American Academy of Neurology or regression equations criteria was significantly higher in the diabetic DSP (0.73) compared to non-diabetic DSP (0.52).<br><br>CONCLUSIONS: Conduction slowing in diabetic DSP beyond what is expected exclusively from axonal loss could be identified by regression analysis.}, }
@article {pmid39568376, year = {2024}, author = {Held-Bradford, EC and Sells, M and Longhurst, JK and Doherty, M}, title = {Variation in amyotrophic lateral sclerosis presentation and outcomes based on phenotype and physical therapy movement system diagnosis: a case series.}, journal = {Physiotherapy theory and practice}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/09593985.2024.2430745}, pmid = {39568376}, issn = {1532-5040}, abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease and presentation varies. There is limited description of this variability and how physical therapy (PT) specific movement system diagnoses (MSD) may impact care.<br><br>PURPOSE: The purpose of this case series is to describe the variability of ALS presentation longitudinally across early, middle, and late stages of ALS based on phenotype and MSD.<br><br>METHODS: Four individuals were selected from an ALS clinic chart review representing a unique combination of phenotypes and MSDs (Case 1: bulbar onset force production deficit (FPD), Case 2: bulbar onset fractionated movement deficit (FMD), Case 3: limb onset FPD, Case 4: limb onset FMD). Descriptions of care over 9 years included outcomes of disability (ALS Functional Rating scale-revised), activity (10&#x2009;Meter Walk Test, Five Times Sit to Stand Test, Trunk Impairment Scale-version 2), and impairment (strength and spasticity).<br><br>RESULTS: Persons with ALS were seen every 3 to 6&#x2009;months (10 to 19 visits total). Determination of MSD was hardest to complete in early stage bulbar onset ALS. Patterns of decline through stages varied by MSD and phenotype, most notably in length of time in middle stage. Limb onset FMD had the slowest progression. Falls and fall related injuries were most frequent in limb onset ALS but falls occurred in all cases.<br><br>CONCLUSION: The combination of MSD and phenotype enhanced variability description offers new insights into clinical decision-making in ALS care.}, }
@article {pmid39568060, year = {2024}, author = {Abbas, AEF and Abdelshafi, NA and Gamal, M and Halim, MK and Said, BAM and Naguib, IA and Mansour, MMA and Morshedy, S and Salem, YA}, title = {Simultaneously quantifying a novel five-component anti- migraine formulation containing ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine using UV spectrophotometry and chemometric models.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {233}, pmid = {39568060}, issn = {2661-801X}, support = {TU-DSPP-2024-49//Taif University/ ; }, abstract = {This study presents a new method for simultaneously quantifying a complex anti-migraine formulation containing five components (ergotamine, propyphenazone, caffeine, camylofin, and mecloxamine) using UV spectrophotometry and chemometric models. The formulation presents analytical challenges due to the wide variation in component concentrations (ERG: PRO: CAF: CAM: MEC ratio of 0.075:20:8:5:4) and highly overlapping UV spectra. To create a comprehensive validation dataset, the Kennard-Stone Clustering Algorithm was used to address the limitations of arbitrary data partitioning in chemometric methods. Three different chemometric models were evaluated: Classical Least Squares (CLS), Partial Least Squares (PLS), and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS). Among these, MCR-ALS demonstrated excellent performance, achieving recovery values of 98-102% for all components, accompanied by minimal root mean square errors of calibration (0.072-0.378) and prediction (0.077-0.404). Moreover, the model exhibited high accuracy, with relative errors ranging from 1.936 to 3.121%, bias-corrected mean square errors between 0.074 and 0.389, and a good sensitivity (0.2097-1.2898 μg mL[-1]) for all components. The Elliptical Joint Confidence Region analysis further confirmed the predictive performance of the models, with MCR-ALS consistently showing the smallest ellipses closest to the ideal point (slope = 1, intercept = 0) for most analytes, indicating superior accuracy and precision. The approach's sustainability was rigorously assessed using six advanced metrics, validating its environmental friendliness, economic viability, and practical application. This approach effectively resolves complex pharmaceutical formulations, contributing to sustainable development objectives in quality control processes.}, }
@article {pmid39567497, year = {2024}, author = {Zhu, Z and Song, M and Ren, J and Liang, L and Mao, G and Chen, M}, title = {Copper homeostasis and cuproptosis in central nervous system diseases.}, journal = {Cell death &amp; disease}, volume = {15}, number = {11}, pages = {850}, pmid = {39567497}, issn = {2041-4889}, mesh = {Humans ; *Copper/metabolism ; *Homeostasis ; *Central Nervous System Diseases/metabolism/pathology ; Animals ; }, abstract = {Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.}, }
@article {pmid39567371, year = {2024}, author = {Nuzum, ND and Deady, C and Kittel-Schneider, S and Cryan, JF and O'Mahony, SM and Clarke, G}, title = {More than just a number: the gut microbiota and brain function across the extremes of life.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2418988}, pmid = {39567371}, issn = {1949-0984}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Brain/microbiology ; Animals ; Brain-Gut Axis/physiology ; Alzheimer Disease/microbiology/physiopathology ; Neurodegenerative Diseases/microbiology ; }, abstract = {Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.}, }
@article {pmid39565466, year = {2025}, author = {Crowley, PD and Mira, P and Saleh, OMA}, title = {Minocycline susceptibility in Stenotrophomonas maltophilia: a closer look at institutional data amid CLSI breakpoint revisions.}, journal = {European journal of clinical microbiology &amp; infectious diseases : official publication of the European Society of Clinical Microbiology}, volume = {44}, number = {2}, pages = {459-460}, doi = {10.1007/s10096-024-04995-5}, pmid = {39565466}, issn = {1435-4373}, mesh = {*Stenotrophomonas maltophilia/drug effects/genetics ; *Microbial Sensitivity Tests ; *Anti-Bacterial Agents/pharmacology ; Humans ; *Minocycline/pharmacology ; *Gram-Negative Bacterial Infections/microbiology/drug therapy ; }, abstract = {In this letter we respond Bakthavatchalam et al's brief report on susceptibility of Stenotrophomonas maltophilia to Minocycline in the setting of new susceptibility breakpoints. We outline our institution's experience with this organism and new data of susceptibility with the breakpoint of < 1 mg/L from the past 5 months showing 93.8% of 144 isolates remained susceptible.}, }
@article {pmid39564190, year = {2024}, author = {Cavaliere, F and Hermann, DM and Magliaro, C}, title = {Editorial: Human brain organoids to model neurodegenerative diseases at the BOSS23 Brain Organoid Summer School.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1501036}, doi = {10.3389/fncel.2024.1501036}, pmid = {39564190}, issn = {1662-5102}, }
@article {pmid39564171, year = {2024}, author = {Byeon, H}, title = {Holistic approaches to mitigating psychological distress in gynecological cancer patients.}, journal = {World journal of psychiatry}, volume = {14}, number = {11}, pages = {1766-1771}, pmid = {39564171}, issn = {2220-3206}, abstract = {This article delves into the psychological impact of gynecological malignancies and suggests pathways to improve the quality of life (QoL) for affected patients. Building on Shang et al's comprehensive analysis, this piece integrates insights from various studies to highlight the profound influence of psychological and physical symptoms on patients undergoing treatment for gynecological cancers. The study underscores that anxiety and depression significantly exacerbate the disease's toll. Factors such as physical exercise and digital and interactive health interventions show promise in mitigating these adverse effects. The article emphasizes the necessity for a holistic care approach that addresses both physical and emotional needs. Recommendations include enhanced training for healthcare providers, public awareness campaigns, streamlined diagnostic pathways, and improved access to specialist care. These integrated strategies aim to ensure that women facing gynecological cancers can maintain an optimal QoL through comprehensive and multidisciplinary care models.}, }
@article {pmid39563746, year = {2024}, author = {Moyana, TN}, title = {Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test.}, journal = {World journal of gastroenterology}, volume = {30}, number = {42}, pages = {4576-4582}, pmid = {39563746}, issn = {2219-2840}, mesh = {Humans ; *Alanine Transaminase/blood ; *Biomarkers/blood ; Mass Screening/methods/standards ; Fatty Liver/diagnosis/blood/epidemiology ; Obesity/complications/diagnosis/epidemiology ; Early Diagnosis ; Reference Values ; Male ; Liver/pathology ; Non-alcoholic Fatty Liver Disease/diagnosis/blood/epidemiology ; }, abstract = {The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al's work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.}, }
@article {pmid39563026, year = {2025}, author = {Hawley, ZCE and Pardo, ID and Cao, S and Zavodszky, MI and Casey, F and Ferber, K and Luo, Y and Hana, S and Chen, SK and Doherty, J and Costa, R and Cullen, P and Liu, Y and Carlile, TM and Chowdhury, T and Doyle, B and Clarner, P and Mangaudis, K and Guilmette, E and Bourque, S and Koske, D and Nadella, MVP and Trapa, P and Hawes, ML and Raitcheva, D and Lo, SC}, title = {Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {1}, pages = {215-234}, pmid = {39563026}, issn = {1525-0024}, mesh = {Animals ; *Dependovirus/genetics ; Mice ; *MicroRNAs/genetics ; *Ganglia, Spinal/metabolism ; *Genetic Vectors/administration &amp; dosage/genetics ; *RNA Interference ; Superoxide Dismutase-1/genetics ; Humans ; Neurons/metabolism ; Male ; }, abstract = {Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.}, }
@article {pmid39562997, year = {2024}, author = {Zheng, W and Xia, T and Zhang, X and Han, J and Li, Y and Tian, N and Zheng, G and Wang, J and Peng, Y and Yao, D and Long, F}, title = {Tailoring Multifunctional Amine Salts Based on Anisole Liquid Soaking for Fabricating Efficient and Stable Perovskite Solar Cells.}, journal = {ACS applied materials &amp; interfaces}, volume = {16}, number = {48}, pages = {66643-66654}, doi = {10.1021/acsami.4c12455}, pmid = {39562997}, issn = {1944-8252}, abstract = {The post-treatment based on spin-coating (SC) organic amine salts is commonly used for surface modification of perovskite films to eliminate defects. However, there is still a lack of systematic study and a unified understanding of the functions and mechanisms of different organic amine salts. The SC method is also not conducive to the industrialization of solar cells. In this work, we study three different organic amine salts, and a passivation strategy for perovskite films based on green anisole liquid soaking (ALS) has been developed. Phenylethylammonium iodide (PEAI), diethylamine hydroiodide (DEAI), and guanidine hydroiodide (GAI) organic amine salt passivators are selected to modify perovskite films, and their effect and working mechanism are also systematically estimated. It is found that PEAI passivates shallow-level defects on the surface of perovskite films, while DEAI incorporates into the perovskite lattice to suppress point defects, and GAI eliminates excess PbI2 residuals in perovskite films. These three organic-amine-salt-modified devices achieve enhanced power conversion efficiencies (PCE) of 21.82% (PEAI-ALS), 21.74% (DEAI-ALS), and 22.21% (GAI-ALS), which is much higher than that of the pristine device without treatment (19.95%). The PCE of the PEAI-ALS device retains nearly 94% of the initial efficiency after 1200 h in unpackaged conditions and about 40% ambient humidity, achieving the best stability performance. Particularly, the PEAI-ALS device has the best comprehensive performance in efficiency and stability. And PEAI is estimated by the SC method and ALS method, and it is found that the PEAI-ALS device achieves a higher PCE compared to the PEAI-SC device (21.51%). We believe that the post-treatment based on a combination of appropriate amine salts and ALS enables a universal approach for fabrication of perovskite solar cells with enhanced photovoltaic performance.}, }
@article {pmid39562594, year = {2024}, author = {Tahmasebi, BK and Zand, E and Yousefi, A and Babaei, S and Sadeghpour, A}, title = {Surveillance and mapping of tribenuron-methyl-resistant weeds in wheat fields.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28626}, pmid = {39562594}, issn = {2045-2322}, mesh = {*Plant Weeds/drug effects ; *Triticum/drug effects/genetics/growth &amp; development ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; Iran ; Weed Control/methods ; }, abstract = {Tribenuron-methyl (TBM) is among the herbicides that are widely used for controlling broadleaf weeds in wheat fields in Iran due to its low mammalian toxicity and environmental risk, use at low doses, the broad spectrum of weed control, and low price compared to other herbicides. However, wheat farmers' repeated application and dissatisfaction with the optimal and effective control of the TBM herbicide have led to investigating broadleaf weed resistance in Iranian wheat fields. For this purpose, through a national call in 2018, a total of 240 broadleaf weed populations belonging to 13 species and 7 plant families were collected from 153 wheat fields in 72 counties across 14 provinces suspected to be resistant to the TBM herbicide. Then, a screening test was conducted in a completely randomized design with 5 replications of each biotype using the recommended dose of 25 g a.i. ha[- 1] of TBM in the greenhouse. Overall, the results indicated that 124 (51.7%) of the screened populations were resisted to TBM. Specifically, 44 populations (81%) of Sinapis arvensis L., 18 populations (45%) of Malva neglecta Wallr., 25 populations (45%) of Silybum marianum (L.) Gaertn, 2 populations (66.6%) of Ammi majus L., 1 population (50%) of Rapistrum rugosum L., 3 populations (21%) of Descurainia Sophia (L.) Webb ex Prantl, 9 populations (36%) of Vaccaria hispanica Mill., 8 populations (48%) of Galium aparine L., 9 populations (75%) of Melilotus indicus L. According to the Adkins and Maas evaluation, 4 populations (100%) of Raphanus raphanistrum L. were classified as resistant to TBM. This study is the first comprehensive investigation of broadleaf weed resistance to TBM across Iranian wheat fields, providing crucial insights for future herbicide management strategies. Given the high incidence of resistance, continued use of TBM in Iranian wheat fields may lead to increased yield loss and environmental pollution. Additionally, it is necessary to investigate cross-resistance in resistant populations to other ALS-inhibiting herbicides.}, }
@article {pmid39561111, year = {2024}, author = {Rohrer, C and Palumbo, A and Paul, M and Reese, E and Basu, S}, title = {Neurotransmitters and neural hormone-based probes for quadruplex DNA sequences associated with neurodegenerative diseases.}, journal = {Nucleosides, nucleotides &amp; nucleic acids}, volume = {}, number = {}, pages = {1-24}, doi = {10.1080/15257770.2024.2431145}, pmid = {39561111}, issn = {1532-2335}, abstract = {The potential of neurotransmitters and neural hormones as possible G-quadruplex DNA binders was analyzed using fluorescence spectroscopy, surface-enhanced Raman spectroscopy (SERS), DNA melting analysis, and molecular docking. G-quadruplex sequences, (GGC)3 and G4C2, with roles in Fragile X syndrome and amyotrophic lateral sclerosis (ALS), respectively, were selected, and their interactions with melatonin, serotonin, and gamma-aminobutyric acid (GABA), were studied. Both melatonin and serotonin demonstrated strong interactions with the DNA sequences with hydrogen bonding being the primary mode of interaction, with some non-intercalative interactions involving the π systems. GABA demonstrated much weaker interactions and may not be a suitable candidate as a probe for low concentrations of G-quadruplex DNA.}, }
@article {pmid39560839, year = {2024}, author = {Wu, R and Ramakrishnan, S and Lin, H and Dong, Z and Liu, M and Qiang, L}, title = {Development and validation a novel FEZF2 based fluorescent reporter for corticospinal motor neurons.}, journal = {Metabolic brain disease}, volume = {40}, number = {1}, pages = {17}, pmid = {39560839}, issn = {1573-7365}, support = {R01 NS115977/NS/NINDS NIH HHS/United States ; 4100083087//the CURE program via Drexel University College of Medicine/ ; 32070725//the National Natural Science Foundation/ ; }, mesh = {Animals ; *Motor Neurons/metabolism ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Pyramidal Tracts/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Genes, Reporter ; Cells, Cultured ; DNA-Binding Proteins ; }, abstract = {Corticospinal motor neurons (CSMNs), also named upper motor neurons, are the giant pyramidal neurons called Betz cells. In mammals, the majority of CSMNs reside within layer V of the primary motor cortex, where they extend long axon bundles named the pyramidal tract into the brainstem and the spinal cord to control voluntary movement. CSMN lesions are implicated in a variety of neurodegenerative disorders, such Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and Hereditary Spastic paraplegia. Although FEZF2-CTIP2 genetic axis have been indicated as the cardinal molecular pathway underlying the development of CSMNs, these proteins are transcription factors that are mostly used to label the nuclei of CSMNs in the fixed cells and tissues. Therefore, a fluorescent reporter to mark CSMNs will be invaluable in identifying living CSMNs, including their extended processes, for time-lapse imaging and high-throughput molecular analyses with much more improved specificity. Based on the in-silico analysis, we identified a putative region within the promoter sequence of FEZF2 and assembled it with an indispensable enhancer motif at its downstream of the gene to form a complex promoter that drives the expression of reporter GFP. The plasmid and virus of FEZF2:eGFP reporter constructs were further validated for its use in specifically labeling CSMNs in primary neuronal cultures from the embryonic rat motor cortex, postnatal mouse cortex. This innovative molecular labeling tool has the potential to offer indispensable support in diverse experimental setups, enabling a comprehensive understanding of the susceptibility and specificity of CSMNs in a wide array of neurological disorders.}, }
@article {pmid39559551, year = {2024}, author = {Wang, J and Chi, L and Liu, S and Yin, J and Zhang, Y and Shen, J and Wang, X}, title = {Overlooked role of long capping time and environmental factors in the plateau lake for impairing lanthanum-modified-bentonite's immobilization to phosphate.}, journal = {Water research X}, volume = {25}, number = {}, pages = {100272}, pmid = {39559551}, issn = {2589-9147}, abstract = {Lanthanum-modified-bentonite(LMB) has been applied for eutrophication management as a phosphate(P)-binding agent in many lakes. However, re-eutrophication took place several years or decades later after the first practice of capping due to dynamic environmental factors in the plateau lake. Here, we investigated the effect of long-term capping and integrated environmental factors in the plateau lake including alkalinity, organic matter, disturbance and photodegradation to the LMB immobilization. Long-term LMB immobilization exhibited C accumulation(82.3%), La depletion(53.5%) and lager size effect in the sediment particle, indicating the breakage of La-O-P bonds and the formation of La-O-C bonds over immobilization time. Additionally, pH(8-10) in the plateau lake could enhance the P desorption and decrease P adsorption through electrostatic repulsion enhancement with the zeta potential reduction(7.2 mV). Further disturbance experiment indicated a significant releasing trend of active P and DGT-labile P from the solid phase, pore water to the overlying water after disturbances due to resuspended releasing, particle size and amorphous Fe, Mn and Al's redistribution. Moreover, [31]P NMR and EPR results indicated photodegradation after disturbance converted diester phosphate into orthophosphate with long-term LMB immobilization via the oxidation of ·OH in the sediment of the plateau lake. Therefore, management issues for Xingyun Lake may apply to other plateau lakes with low external P input, intermediate depth and intense disturbance.}, }
@article {pmid39558635, year = {2024}, author = {Pillai, M and Patil, AD and Das, A and Jha, SK}, title = {Pathological Mutations D169G and P112H Electrostatically Aggravate the Amyloidogenicity of the Functional Domain of TDP-43.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {23}, pages = {4267-4283}, doi = {10.1021/acschemneuro.4c00372}, pmid = {39558635}, issn = {1948-7193}, mesh = {Humans ; *DNA-Binding Proteins/genetics/metabolism/chemistry ; *Static Electricity ; *Amyloid/metabolism/genetics ; Mutation ; Protein Domains/genetics ; Hydrogen-Ion Concentration ; Protein Aggregation, Pathological/genetics/metabolism ; }, abstract = {Aggregation of TDP-43 is linked to the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, electrostatic point mutations such as D169G and P112H, located within the highly conserved functional tandem RNA recognition motif (RRM) domains of the TDP-43 protein (TDP-43[tRRM]), have been identified in diseased patients as well. In this study, we address how the electrostatic mutations alter both the native state stability and aggregation propensity of TDP-43[tRRM]. The mutants D169G and P112H show increased chemical stability compared to the TDP-43[tRRM] at physiological pH. However, at low pH, both the mutants undergo a conformational change to form amyloid-like fibrils, though with variable rates─the P112H mutant being substantially faster than the other two sequences (TDP-43[tRRM] and D169G mutant) showing comparable rates. Moreover, among the three sequences, only the P112H mutant undergoes a strong ionic strength-dependent aggregability trend. These observations signify the substantial contribution of the excess charge of the P112H mutant to its unique aggregation process. Complementary simulated observables with atomistic resolution assign the experimentally observed sequence-, pH-, and ionic strength-dependent aggregability pattern to the degree of thermal lability of the mutation site-containing RRM1 domain and its extent of dynamical anticorrelation with the RRM2 domain whose combination eventually dictate the extent of generation of aggregation-prone partially unfolded conformational ensembles. Our choice of a specific charge-modulated pathogenic mutation-based experiment-simulation-combination approach unravels the otherwise hidden residue-wise contribution to the individual steps of this extremely complicated multistep aggregation process.}, }
@article {pmid39557859, year = {2024}, author = {Pamphlett, R and Parkin Kullmann, J}, title = {Early life events may be the first steps on the multistep path to amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28497}, pmid = {39557859}, issn = {2045-2322}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/etiology/genetics ; Humans ; Female ; Male ; Middle Aged ; Risk Factors ; Adult ; Aged ; Case-Control Studies ; Surveys and Questionnaires ; }, abstract = {A combination of multiple genetic and environmental factors appear to be required to trigger the onset of amyotrophic lateral sclerosis (ALS). Early life environmental exposures have been reported to be risk factors for a variety of adult-onset diseases, so we used data from an online international ALS case-control questionnaire to estimate whether any of these could be risk factors for the clinical onset of ALS. Responses were obtained from 1,049 people aged 40 years or more, 568 with ALS and 481 controls. People with ALS were more likely to have been born and lived longer in a country area than in a city area, to have younger parents, and to have lower educational attainment and fewer years of education. No ALS-control differences were found in sibling numbers, birth order, adult height, birth weight, parent smoking, Cesarean delivery, or age of starting smoking. In conclusion, early life events and conditions may be part of a group of polyenvironmental risk factors that act together with polygenetic variants to trigger the onset of ALS. Reducing exposure to adverse environmental factors in early life could help to lower the risk of later developing ALS.}, }
@article {pmid39557152, year = {2025}, author = {Yu, H and Ren, K and Jin, Y and Zhang, L and Liu, H and Huang, Z and Zhang, Z and Chen, X and Yang, Y and Wei, Z}, title = {Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis.}, journal = {Neuropharmacology}, volume = {264}, number = {}, pages = {110217}, doi = {10.1016/j.neuropharm.2024.110217}, pmid = {39557152}, issn = {1873-7064}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; *Neuroinflammatory Diseases/metabolism/immunology/pathology ; Animals ; *Mitochondria/metabolism ; *Alarmins/metabolism ; Inflammasomes/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.}, }
@article {pmid39556975, year = {2024}, author = {Yu, Z and Qi, J and Liu, S and Zhao, X and Huang, H}, title = {Evaluating forest aboveground biomass estimation model using simulated ALS point cloud from an individual-based forest model and 3D radiative transfer model across continents.}, journal = {Journal of environmental management}, volume = {372}, number = {}, pages = {123287}, doi = {10.1016/j.jenvman.2024.123287}, pmid = {39556975}, issn = {1095-8630}, mesh = {*Biomass ; *Forests ; Models, Theoretical ; Computer Simulation ; Trees/growth &amp; development ; Algorithms ; }, abstract = {Area-based approach (ABA) has been widely employed for estimating forest aboveground biomass (AGB) using airborne laser scanning (ALS) data. However, its scalability is limited due to challenges in model generalization across different forest types and regions. The selection of sensitive variables from ALS data is crucial for constructing robust forest AGB estimation models, yet this selection varies significantly among forest types and regions. Traditionally, assessing the influence of variable selection is hindered by the lack of accurate reference forest AGB values. Computer simulation-based method provides a perspective for exploring these challenges. This study employs an individual-based forest growth process model, FORMIND, coupled with a 3D radiative transfer model (RTM), LESS, to evaluate the transferability of ABA-based forest AGB estimation models and the generalization of ALS-derived variables. We used six virtual 3D forest scenes and two real-world forest sites, representing a range of global forest types, along with their simulated ALS data, to develop a forest AGB estimation model using the random forest algorithm, which allowed us to analyze the importance of various variables. We assessed model transferability through cross-comparison. Additionally, we validated the model using field plots and ALS data collected from two distinct regions. The results showed that the canopy surface area and volume extracted using the α-shape algorithm and parameters fitted from the Weibull distribution are vital variables when using ALS for forest AGB estimation across forest types and regions. Incorporating these variables into the model significantly improves the accuracy of forest AGB estimation. The optimized model achieved a R[2] of 0.945, a RMSE of 34.22 t/ha, and a MAE of 20.53 t/ha. Our study not only deepens the understanding of the relationship between forest vertical structural metrics and AGB but also highlights the potential of computer simulation as a tool for refining the estimation of forest structural parameters.}, }
@article {pmid39556393, year = {2024}, author = {Ishii, J and Nishikimi, M and Kikutani, K and Ohki, S and Ota, K and Anzai, T and Takahashi, K and Okubo, M and Ohshimo, S and Iwami, T and Shime, N}, title = {Resuscitation Attempt and Outcomes in Patients With Asystole Out-of-Hospital Cardiac Arrest.}, journal = {JAMA network open}, volume = {7}, number = {11}, pages = {e2445543}, pmid = {39556393}, issn = {2574-3805}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality/epidemiology ; Male ; Female ; Aged ; Middle Aged ; Japan/epidemiology ; *Cardiopulmonary Resuscitation/methods ; *Registries ; *Emergency Medical Services/statistics &amp; numerical data ; Aged, 80 and over ; Advanced Cardiac Life Support/methods ; Prospective Studies ; Epinephrine/therapeutic use/administration &amp; dosage ; Treatment Outcome ; Cohort Studies ; }, abstract = {IMPORTANCE: Little is known about the epidemiology of out-of-hospital cardiac arrest (OHCA) in patients with asystole in countries where prehospital resuscitation is not withheld or terminated.<br><br>OBJECTIVE: To investigate the secular trends in the patient outcomes and advanced life support (ALS) procedures and evaluate the association of ALS procedures with favorable outcomes among patients with OHCA and asystole.<br><br>This cohort study analyzed data from a nationwide prospective OHCA registry in Japan. OHCA occurred from June 1, 2014, to December 31, 2020. Adults with an initial rhythm of asystole and OHCA were included in the analysis, which was conducted between July 29, 2022, and August 24, 2024.<br><br>EXPOSURES: Year of OHCA and prehospital ALS procedures (advanced airway management [AAM] and intravenous epinephrine administration).<br><br>MAIN OUTCOMES AND MEASURES: Trends in prehospital and in-hospital ALS procedures and patient outcomes were described using the Jonckheere-Terpstra trend test for continuous variables and the Cochran-Armitage trend test for categorical variables. The primary outcome was a favorable neurological outcome at 30 days. The secondary outcomes included a favorable neurological outcome at 90 days and survival at 30 and 90 days. Associations between prehospital procedures and outcomes were analyzed using time-dependent propensity score and risk-set matching.<br><br>RESULTS: Of 60&#x202f;349 patients with OHCA, 35&#x202f;843 (59.4%) presented with asystole (median age, 77 [IQR, 64-85] years; 20 573 [57.4%] men). Among these, 33&#x202f;674 patients (93.9%) underwent ALS procedures, with 67 (0.2%) achieving a favorable neurological outcome at 30 days. No significant trends in the outcomes were noted, except for a decline in return of spontaneous circulation (424 of 1848 [22.9%] to 1178 of 5892 [20.0%]; P&#x2009;=&#x2009;.003). Neither AAM (odds ratio [OR], 1.27 [95% CI, 0.76-2.12]; P&#x2009;=&#x2009;.36) nor intravenous epinephrine administration (OR, 0.53 [95% CI, 0.24-1.13]; P&#x2009;=&#x2009;.10) was associated with a favorable neurological outcome at 30 days, although both were associated with survival at 30 days (ORs, 1.45 [95% CI, 1.21-1.74] and 1.81 [95% CI, 1.44-2.27], respectively; P&#x2009;<&#x2009;.001 for both).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of patients with OHCA presenting with asystole, the proportion with a favorable neurological outcome at 30 days was substantially low, and no prehospital ALS procedure was associated with a favorable neurological outcome. These findings suggest that discussions regarding implementation of a termination of resuscitation rule for such patients are warranted.}, }
@article {pmid39556113, year = {2025}, author = {Yeganeh Markid, T and Pourahmadiyan, A and Hamzeh, S and Sharifi-Bonab, M and Asadi, MR and Jalaiei, A and Rezazadeh, M and Ghafouri-Fard, S}, title = {A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {2}, pages = {e16255}, doi = {10.1111/jnc.16255}, pmid = {39556113}, issn = {1471-4159}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Polyadenylation ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.}, }
@article {pmid39553255, year = {2024}, author = {Zeinali, M and Almasi Dooghaee, M and Ziaee, M and Haghi Ashtiani, B}, title = {Evaluation of Relationship Between Laboratory, Electrodiagnostic, and Functional Parameters in Patients With Amyotrophic Lateral Sclerosis; A Cross Sectional Study.}, journal = {Basic and clinical neuroscience}, volume = {15}, number = {4}, pages = {553-560}, pmid = {39553255}, issn = {2008-126X}, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a poor prognosis that leads to limb and or bulbar muscle degeneration. Several demographic and biological factors have prognostic importance, but little data exist on the relationship between clinical, electrodiagnostic, and laboratory markers as predictors of disease progression. We aimed to assess the relationships between different aspects of ALS patients' clinical, electrodiagnostic, and laboratory features and their level of functioning.<br><br>METHODS: We included 27 ALS patients diagnosed within the last two years. A neurology resident conducted clinical assessment and electrodiagnostic studies. The motor unit number index (MUNIX) and compound motor action potential (CMAP) were used to measure motor unit loss. Serum creatinine, urea, albumin, and creatine kinase were measured as laboratory markers. We used the Persian version of the ALS functional rating scale (ALS-FRS) as the main outcome measure. The Pearson correlation coefficient was calculated to assess the correlations using the SPSS software, version 16.<br><br>RESULTS: None of the demographic or laboratory parameters were correlated with ALSFRS. Patients with the onset of disease in the limbs had a higher MUNIX score than those with bulbar onset. Also, increased body mass index (BMI) was associated with lower CMAP and MUNIX scores (P=0.02). Higher serum creatinine levels were significantly associated with higher lower limb MUNIX (P=0.04). Higher lower limb MUNIX was associated with a higher lower limb functional score.<br><br>CONCLUSION: Decreased serum creatinine may indicate lower limb motor unit loss in patients with ALS. Also, MUNIX scores may be used as substitutes for ALS-FRS in ALS trials. Further research is needed to elucidate the clinical application of these findings.}, }
@article {pmid39552508, year = {2025}, author = {Zhong, R and Dionela, DLA and Kim, NH and Harris, EN and Geisler, JG and Wei-LaPierre, L}, title = {Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral Sclerosis Mice.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {542-557}, pmid = {39552508}, issn = {1531-8249}, support = {R56 NS117429/NS/NINDS NIH HHS/United States ; NS99545/NS/NINDS NIH HHS/United States ; R01 NS127858/NS/NINDS NIH HHS/United States ; R21 NS099545/NS/NINDS NIH HHS/United States ; NS117429/NS/NINDS NIH HHS/United States ; NS127858/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/physiopathology ; *2,4-Dinitrophenol/pharmacology ; Mice ; *Muscle, Skeletal/drug effects/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Recovery of Function/drug effects/physiology ; Muscle Contraction/drug effects/physiology ; Male ; Uncoupling Agents/pharmacology ; Motor Neurons/drug effects ; Neuromuscular Junction/drug effects ; }, abstract = {OBJECTIVE: Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.<br><br>METHODS: hSOD1[G93A] mice were treated with 0.5-1.0&#x2009;mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18&#x2009;weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18&#x2009;weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1[G93A] mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.<br><br>RESULTS: DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18&#x2009;weeks old in hSOD1[G93A] mice. Strikingly, symptomatic hSOD1[G93A] mice exhibited a period of recovery in running ability at 20&#x2009;cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.<br><br>INTERPRETATION: Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025;97:542-557.}, }
@article {pmid39552337, year = {2024}, author = {Baindoor, S and Gibriel, HAY and Venø, MT and Su, J and Morrissey, EP and Jirström, E and Woods, I and Kenny, A and Alves, M and Halang, L and Fabbrizio, P and Bilen, M and Engel, T and Hogg, MC and Bendotti, C and Nardo, G and Slack, RS and Kjems, J and Prehn, JHM}, title = {Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration.}, journal = {Disease models &amp; mechanisms}, volume = {17}, number = {11}, pages = {}, pmid = {39552337}, issn = {1754-8411}, support = {17/JPND/3455//Research Ireland/ ; //European Regional Development Fund/ ; //FutureNeuro/ ; //Precision ALS/ ; 18/CRT/6214//Research Ireland Centre for Research Training in Genomics Data Science/ ; //EU Joint Programme - Neurodegenerative Disease Research/ ; CUP E48I20000000007//Regione Lombardia/ ; SG-2018-12366226//Ministero della Salute/ ; //Royal College of Surgeons in Ireland/ ; }, mesh = {Animals ; *Disease Models, Animal ; *RNA, Transfer/genetics/metabolism ; *RNA, Small Untranslated/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Neurodegenerative Diseases/genetics/pathology ; Mice ; Humans ; Mice, Transgenic ; Parkinson Disease/genetics/pathology ; Frontotemporal Dementia/genetics/pathology ; }, abstract = {Transfer RNA-derived small RNAs (tsRNAs) - categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) - are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5' tiRNAs selectively in the two ALS models, lower expression of 3' tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3' tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease.}, }
@article {pmid39551788, year = {2024}, author = {Sadeghdoust, M and Das, A and Kaushik, DK}, title = {Fueling neurodegeneration: metabolic insights into microglia functions.}, journal = {Journal of neuroinflammation}, volume = {21}, number = {1}, pages = {300}, pmid = {39551788}, issn = {1742-2094}, support = {MS220110//U.S. Department of Defense/ ; 916184//Multiple Sclerosis Society of Canada/ ; }, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; }, abstract = {Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.}, }
@article {pmid39551782, year = {2024}, author = {Labrador, L and Rodriguez, L and Beltran, S and Hernandez, F and Gomez, L and Ojeda, P and Bergmann, C and Calegaro-Nassif, M and Kerr, B and Medinas, DB and Manque, P and Woehlbier, U}, title = {Overexpression of autophagy enhancer PACER/RUBCNL in neurons accelerates disease in the SOD1[G93A] ALS mouse model.}, journal = {Biological research}, volume = {57}, number = {1}, pages = {86}, pmid = {39551782}, issn = {0717-6287}, support = {1200459//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 1150743//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 11160288//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 1191538//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 1230905//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; ACT210039//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 11240328//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 1240176//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Autophagy/genetics/physiology ; Mice ; Humans ; Superoxide Dismutase-1/genetics ; Motor Neurons/pathology ; Superoxide Dismutase/genetics ; Neurons/pathology ; Male ; Female ; Autophagy-Related Proteins/genetics/metabolism ; Disease Progression ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1[G93A] ALS mouse model. Unexpectedly, PACER/SOD1[G93A] double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1[G93A] mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.}, }
@article {pmid39551156, year = {2025}, author = {Chen, LC and Martin, A and Senna, MM}, title = {Response to Truel J. et al's "Response to 'Topical tofacitinib for patients with lichen planopilaris and/or frontal fibrosing alopecia'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e69}, doi = {10.1016/j.jaad.2024.11.011}, pmid = {39551156}, issn = {1097-6787}, }
@article {pmid39551139, year = {2024}, author = {Liu, C and Chen, IS and Barri, M and Murrell-Lagnado, R and Kubo, Y}, title = {Structural determinants of M2R involved in inhibition by Sigma-1R.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {108006}, pmid = {39551139}, issn = {1083-351X}, mesh = {*Receptors, sigma/metabolism/genetics ; Humans ; *Sigma-1 Receptor ; HEK293 Cells ; *Receptor, Muscarinic M2/metabolism/genetics ; Animals ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/genetics ; }, abstract = {Sigma-1 receptor (S1R) is a multimodal chaperone protein that is implicated in various pathophysiological conditions including drug addiction, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). S1R interacts with various ion channels and receptors on the endoplasmic reticulum or plasma membrane (PM). It has been reported that S1R colocalizes with the M2-muscarinic acetylcholine receptor (M2R) on the soma of motoneurons, although a functional interaction between these two proteins has not been established. Here, we investigated the regulation of M2R signaling by S1R using electrophysiological recordings of GIRK currents in HEK293T cells. We observed that S1R strongly inhibited M2R-mediated activation of GIRK1/2, but the disease mutant linked to ALS, S1R E102Q, did not. The inhibitory effect of S1R was selective for M2R and wasn't seen when S1R was co-expressed with other Gi/o coupled receptors including M4R. Chimeric and mutant receptors of M2R and M4R were generated and analyzed, and this highlighted Ala401 in the transmembrane 6 domain (TM6) of M2R and Glu172 as well as Glu175 in the extracellular loop 2 regions of M2R, as essential for the inhibition by S1R. Co-immunoprecipitation confirmed the physical interaction between M2R and S1R. Immunocytochemical labeling of M2R and S1R expressed in HeLa cells, HEK293T cells, and cultured hippocampal neurons, showed clear PM expression of M2R throughout the cell which was decreased by coexpression with S1R but was still apparent. Taken together, our results show that S1R interacts with M2R to reduce both its PM expression and function, and this involves TM6 and the extracellular loop 2.}, }
@article {pmid39551138, year = {2024}, author = {Yang, C and Leifer, C and Lammerding, J and Hu, F}, title = {Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {12}, pages = {107999}, pmid = {39551138}, issn = {1083-351X}, support = {R21 AG078741/AG/NIA NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; *Cytosol/metabolism ; Humans ; Animals ; *Homeostasis ; DNA/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Cytoplasm/metabolism ; beta Karyopherins/metabolism/genetics ; Neurons/metabolism/pathology ; Mice ; Cell Nucleus/metabolism ; Oligodeoxyribonucleotides/metabolism ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA binding protein predominantly localized in the nucleus under physiological conditions. TDP-43 proteinopathy, characterized by cytoplasmic aggregation and nuclear loss, is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus it is crucial to understand the molecular mechanism regulating TDP-43 homeostasis. Here, we show that the uptake of oligodeoxynucleotides (ODNs) from the extracellular space induces reversible TDP-43 cytoplasmic puncta formation in both neurons and glia. ODNs facilitate the liquid-liquid phase separation of TDP-43 in vitro. Importantly, persistent accumulation of DNA in the cytoplasm leads to nuclear depletion of TDP-43 and enhanced production of a short isoform of TDP-43 (sTDP-43). In addition, in response to ODN uptake, the nuclear import receptor karyopherin subunit β1 (KPNB1) is sequestered in the cytosolic TDP-43 puncta. ALS-linked Q331K mutation decreases the dynamics of cytoplasmic TDP-43 puncta and increases the levels of sTDP-43. Moreover, the TDP-43 cytoplasmic puncta are induced by DNA damage and by impaired nuclear envelope integrity due to Lamin A/C deficiency. In summary, our data support that abnormal DNA accumulation in the cytoplasm may be one of the key mechanisms leading to TDP-43 proteinopathy and provides novel insights into molecular mechanisms of ALS caused by TDP-43 mutations.}, }
@article {pmid39550606, year = {2024}, author = {Rabadi, MH and Russell, KA and Xu, C}, title = {Analysis of Mortality Causes and Locations in Veterans with ALS: A Decade Review.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {30}, number = {}, pages = {e945816}, pmid = {39550606}, issn = {1643-3750}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; *Veterans ; Male ; Female ; Middle Aged ; Aged ; *Cause of Death ; Retrospective Studies ; United States/epidemiology ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to rapid degeneration of nerves in the brain and spinal cord, with eventual loss of voluntary movements, including breathing. This retrospective study of medical record data from 105 US veterans diagnosed with ALS at the Oklahoma City VA Medical Center between 2010 and 2021 aimed to identify patient demographics, and the causes and places of death for these veterans. MATERIAL AND METHODS Data from 105 US veterans diagnosed with ALS by the El Escorial criteria and supported by neurophysiology testing was reviewed. The information about the place and cause of death was obtained from each patient's care provider and death certificate. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated for the causes of death, by sex, age group, and location of death. RESULTS During the 11-year follow-up period, 80 (76.2%) veterans with ALS died. The mean (SD) follow-up time was 4.53 (4.55) years. Most of the deaths were due to respiratory failure and pneumonia (n=43, mortality rate=9.21 per 100 person-years). Most patients died at home (n=71, 88.7%). The annual crude mortality rate was 16.7 and the all-cause death SMR was 25.63 (95% CI, 20.32-31.55). CONCLUSIONS This study's findings are that in veterans with ALS, the main cause of death is respiratory disease (failure). The main location of death was the home, with their family members. The all-cause mortality rate among veterans with ALS was 26 times greater than for the general Oklahoma population.}, }
@article {pmid39550435, year = {2024}, author = {Wang, Z and Cao, W and Deng, B and Fan, D}, title = {Lower creatinine-to-cystatin c ratio associated with increased risk of incident amyotrophic lateral sclerosis in the prospective UK biobank cohort.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28289}, pmid = {39550435}, issn = {2045-2322}, support = {81873784//National Natural Science Foundation of China/ ; BYSYDL2019002//Peking University Third Hospital/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/blood/epidemiology ; Humans ; Male ; Female ; *Creatinine/blood ; Middle Aged ; United Kingdom/epidemiology ; Aged ; Incidence ; Prospective Studies ; *Cystatin C/blood ; Risk Factors ; *Biological Specimen Banks ; *Biomarkers/blood ; Proportional Hazards Models ; Adult ; UK Biobank ; }, abstract = {Reduced muscle mass has been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, it remains unclear whether decreased muscle mass is a risk factor for ALS or a consequence of motor neuron degeneration. Recently, serum creatinine-to-cystatin C ratio (CCR) have emerged as promising biomarkers for assessing muscle mass. We aimed to explore the association between CCR and the incidence of ALS using data from the UK Biobank. Between 2006 and 2010, 446,945 participants were included in the baseline. CCR was calculated as the ratio of serum creatinine to cystatin C. Cox regression models were used to analyze the relationship between CCR and ALS incidence. Furthermore, subgroup analyses were conducted to investigate potential covariates in these relationships. After adjusting for all covariates, the multivariate Cox regression analysis revealed a significant association between decreased CCR and an increased risk of ALS (hazard ratio (HR) = 0.990, 95% confidence interval (CI): 0.982-0.999, P = 0.026). Participants were stratified into groups based on CCR tertiles. Compared with participants in the highest tertiles of CCR, those in the lowest (HR = 1.388, 95% CI: 1.032-1.866, P = 0.030) and medium tertiles (HR = 1.348, 95% CI: 1.045-1.739, P = 0.021) had an increased risk of ALS incidence. Subgroup analysis showed that the relationship between CCR and ALS incidence was particularly significant among participants aged < 65 years (CCR tertile 1: HR = 1.916, 95% CI: 1.366-2.688, P < 0.001; CCR tertile 2: HR = 1.699, 95% CI: 1.267-2.278, P < 0.001). The present results demonstrate that lower CCR is significantly associated with a higher risk of ALS.}, }
@article {pmid39548852, year = {2025}, author = {Dellar, ER and Vendrell, I and Amein, B and Lester, DG and Edmond, EC and Yoganathan, K and Dharmadasa, T and Sogorb-Esteve, A and Fischer, R and Talbot, K and Rohrer, JD and Turner, MR and Thompson, AG}, title = {Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {449-459}, pmid = {39548852}, issn = {1531-8249}, support = {2018-I2M-2-002//Chinese Academy of Medical Sciences Innovation Fund for Medical Science/ ; Lester/2450/795/MNDA_/Motor Neurone Disease Association/United Kingdom ; Thompson/Jan20/952-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; MR/Y001095/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; Female ; Male ; *Frontotemporal Dementia/cerebrospinal fluid/genetics ; Middle Aged ; Cross-Sectional Studies ; Aged ; *DNA Repeat Expansion/genetics ; *Heterozygote ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/genetics ; Biomarkers/cerebrospinal fluid ; Adult ; Isoenzymes/cerebrospinal fluid/genetics ; }, abstract = {OBJECTIVE: To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.<br><br>METHODS: Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.<br><br>RESULTS: Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value&#x2009;=&#x2009;0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p&#x2009;=&#x2009;0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p&#x2009;=&#x2009;0.007).<br><br>INTERPRETATION: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2025;97:449-459.}, }
@article {pmid39548731, year = {2024}, author = {Shino, Y and Muraki, N and Kobatake, Y and Kamishina, H and Kato, R and Furukawa, Y}, title = {Disulfide-mediated oligomerization of mutant Cu/Zn-superoxide dismutase associated with canine degenerative myelopathy.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5210}, pmid = {39548731}, issn = {1469-896X}, support = {JP21am0101083//Japan Agency for Medical Research and Development/ ; 19H05765//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22H02768//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 22K19389//The Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; 23EXC334//Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences/ ; }, mesh = {Animals ; Dogs ; *Disulfides/chemistry/metabolism ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; Protein Multimerization ; Dog Diseases/genetics ; Spinal Cord Diseases/genetics/metabolism ; Amino Acid Substitution ; Zinc/metabolism/chemistry ; Mutation ; Mutation, Missense ; Copper/metabolism/chemistry ; }, abstract = {A homozygous E40K mutation in the gene coding canine Cu/Zn-superoxide dismutase (cSOD1) causes degenerative myelopathy (DM) in dogs. A pathological hallmark of DM with the cSOD1 mutation is the aggregation of mutant cSOD1 proteins in neurons. The amino acid substitution E40K disrupts a salt bridge between Glu40 and Lys91 and is considered to destabilize the native state of cSOD1; however, the mechanism by which mutant cSOD1 aggregates remains unclear. Here, we show that mutant cSOD1 losing a copper and zinc ion forms oligomers crosslinked via disulfide bonds. The E40K substitution was found to result in the increased solvent exposure of the Cys7 side chain, which then attacked the disulfide bond (Cys57-Cys146) in cSOD1 to form disulfide-linked oligomers. We also successfully prevented the Cys7 exposure and thus the oligomerization of mutant cSOD1 by a fragment antibody that specifically recognizes the region around the mutation site. The fragment antibody covered the β-plug region, reinforcing the interactions compromised by the E40K substitution and thus contributing to the maintenance of the structural integrity of the β-barrel core of cSOD1. Taken together, we propose that the Cys7 exposure in cSOD1 upon the salt bridge disruption plays a central role in the aggregation mechanism of DM-associated mutant cSOD1.}, }
@article {pmid39548508, year = {2024}, author = {Panei, FP and Di Rienzo, L and Zacco, E and Armaos, A and Tartaglia, GG and Ruocco, G and Milanetti, E}, title = {Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {12}, pages = {e5201}, pmid = {39548508}, issn = {1469-896X}, support = {855923//ERC-2019-Synergy Grant (ASTRA, 855923)/ ; ivBM4PAP,101098989//EIC-2022-PathfinderOpen/ ; CN00000041//National Center for Gene Therapy and Drugs Based on RNA Technology/ ; CUPj33C22001130001//Potenziamento Strutture di Ricerca e Creazione di Campioni Nazionali Di R&amp;S/ ; }, mesh = {*Aptamers, Nucleotide/chemistry/metabolism ; *Molecular Dynamics Simulation ; Humans ; *DNA-Binding Proteins/chemistry/metabolism ; *Protein Binding ; RNA/chemistry/metabolism ; Molecular Docking Simulation ; }, abstract = {Investigating the binding between proteins and aptamers, such as peptides or RNA molecules, is of crucial importance both for understanding the molecular mechanisms that regulate cellular activities and for therapeutic applications in several pathologies. Here, a new computational procedure, employing mainly docking, clustering analysis, and molecular dynamics simulations, was designed to estimate the binding affinities between a protein and some RNA aptamers, through the investigation of the dynamical behavior of the predicted molecular complex. Using the state-of-the-art software catRAPID, we computationally designed a set of RNA aptamers interacting with the TAR DNA-binding protein 43 (TDP-43), a protein associated with several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We thus devised a computational protocol to predict the RNA-protein molecular complex, so that the structural and dynamical behavior of such a complex can be investigated through extensive molecular dynamics simulation. We hypothesized that the coordinated and synchronized motion of the protein-binding residues, when in contact with RNA molecule, is a critical requisite in order to have a stable binding. Indeed, we calculated the motion covariance exhibited by the interface residues during molecular dynamics simulation: we tested the results against experimental measurements of binding affinity (in this case, the dissociation constant) for six RNA molecules, resulting in a linear correlation of about 0.9. Our findings suggest that the synchronized movement of interface residues plays a pivotal role in ensuring the stability within RNA-protein complexes, moreover providing insights into the contribution of each interface residue. This promising pipeline could thus contribute to the design of RNA aptamers interacting with proteins.}, }
@article {pmid39548409, year = {2024}, author = {Ruan, K and Cheng, D and Zhu, X and Sun, S and Bao, F and Zhu, J and Li, F and Shen, M and Ye, Y}, title = {Corneal higher-order aberrations and their relationship with choroid in myopic patients.}, journal = {BMC ophthalmology}, volume = {24}, number = {1}, pages = {500}, pmid = {39548409}, issn = {1471-2415}, support = {81900910//Innovative Research Group Project of the National Natural Science Foundation of China/ ; LQ19H120003//Natural Science Foundation of Zhejiang Province/ ; Y2023809, Y20190638//Basic Scientific Research Project of Wenzhou/ ; }, mesh = {Humans ; Female ; Male ; *Choroid/pathology/diagnostic imaging/blood supply ; Adult ; *Myopia/physiopathology/complications ; *Corneal Wavefront Aberration/physiopathology ; *Tomography, Optical Coherence/methods ; Young Adult ; *Cornea/pathology/diagnostic imaging ; Axial Length, Eye/pathology/diagnostic imaging ; Refraction, Ocular/physiology ; Visual Acuity/physiology ; Corneal Topography ; Middle Aged ; Cross-Sectional Studies ; }, abstract = {BACKGROUND: To investigate corneal higher-order aberrations (HOAs) and choroidal characteristics in myopic individuals and explore the association between HOAs and choroidal parameters.<br><br>METHODS: Myopic participants were categorized into three groups based on axial lengths (ALs). We compared corneal HOAs, including spherical (Z4[0]), comatic (Z3&#x2009;[-&#x2009;1] and Z3[1]), and trefoil (Z3&#x2009;[-&#x2009;3] and Z3[3]) aberrations, as well as choroidal vascularity index (CVI) and choroidal thickness (CT). Linear regression analysis was used to assess the relationships among corneal HOAs, CVI, CT, spherical equivalent, and AL.<br><br>RESULTS: Groups 1, 2, and 3 included 105, 98, and 118 eyes, respectively. Group 3 exhibited lower spherical HOA root mean square and Z4[0] values than group 1(p&#x2009;<&#x2009;0.05). Group 1 showed lower Z3[1] levels than other groups (p&#x2009;<&#x2009;0.001). Groups 1 and 2 had higher mean, central, and I2 vertical CVIs than group 3 (p&#x2009;<&#x2009;0.05). Group 1 had a larger vertical S1 CVI than group 3 (p&#x2009;<&#x2009;0.05). Group 3 had smaller horizontal CVI values in all regions except N2 (p&#x2009;<&#x2009;0.05). Both the mean and CT in all regions decreased as AL increased (p&#x2009;<&#x2009;0.001). The comatic (Z3[1]) and trefoil (Z3[3]) components were predictors of mean horizontal CVI, and the comatic (Z3[1]) component was correlated with both mean vertical and horizontal CT.<br><br>CONCLUSION: Longer AL myopic patients exhibited lower absolute values of spherical aberration and horizontal coma. Alterations in choroid in myopic patients correlated with corneal HOAs. Our results suggest a potential connection between the optical quality and ocular perfusion in myopia.}, }
@article {pmid39548226, year = {2024}, author = {Qin, J and Wang, X and Fan, G and Zhang, W and Wu, X and Wang, B and Liu, Y}, title = {Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {28110}, pmid = {39548226}, issn = {2045-2322}, support = {202103021224405//the Basic Research Project of Shanxi Province/ ; 201903D321049//the Key Research and Development Project Plan of Shanxi Province concerning social advancement/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/cerebrospinal fluid/blood/pathology ; *Diffusion Tensor Imaging/methods ; Middle Aged ; Male ; Female ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid ; Aged ; Adult ; ROC Curve ; Case-Control Studies ; Anisotropy ; Pyramidal Tracts/diagnostic imaging/pathology ; }, abstract = {To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = - 0.813, p < 0.001), Serum-NFL (r = - 0.493, p = 0.001), CSF-pNFH (r = - 0.637, p < 0.001), and Serum-pNFH (r = - 0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = - 0.562, p < 0.001), CSF-pNFH (r = - 0.506, p = 0.001), and Serum-pNFH (r = - 0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.}, }
@article {pmid39547910, year = {2025}, author = {Khamaysa, M and El Mendili, M and Marchand, V and Querin, G and Pradat, PF}, title = {Quantitative spinal cord imaging: Early ALS diagnosis and monitoring of disease progression.}, journal = {Revue neurologique}, volume = {181}, number = {3}, pages = {172-183}, doi = {10.1016/j.neurol.2024.10.005}, pmid = {39547910}, issn = {0035-3787}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/diagnostic imaging/pathology ; Humans ; *Disease Progression ; *Spinal Cord/diagnostic imaging/pathology ; *Early Diagnosis ; Neuroimaging/methods ; Biomarkers/analysis ; Magnetic Resonance Imaging/methods ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. This degeneration leads to muscular weakness, progressively impairing motor functions and ultimately resulting in respiratory failure. The clinical, genetic, and pathological heterogeneity of ALS, combined with the absence of reliable biomarkers, significantly challenge the efficacy of therapeutic trials. Despite these hurdles, neuroimaging, and particularly spinal cord imaging, has emerged as a promising tool. It provides insights into the involvement of both upper and lower motor neurons. Quantitative spinal imaging has the potential to facilitate early diagnosis, enable accurate monitoring of disease progression, and refine the design of clinical trials. In this review, we explore the utility of spinal cord imaging within the broader context of developing spinal imaging biomarkers in ALS. We focus on a both diagnostic and prognostic biomarker in ALS, highlighting its pivotal role in elucidating the disease's underlying pathology. We also discuss the existing limitations and future avenues for research, aiming to bridge the translational gap between academic research and its application in clinical practice and therapeutic trials.}, }
@article {pmid39547816, year = {2024}, author = {Salmerón-Mendoza, AN and Aguilar-Vázquez, CA and Aguilar-Castillo, SJ}, title = {[Electromyography in atypical variants of motor neuron disease: a case series].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {62}, number = {4}, pages = {1-6}, doi = {10.5281/zenodo.11397347}, pmid = {39547816}, issn = {2448-5667}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Electromyography ; Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Adult ; Aged, 80 and over ; Motor Neuron Disease/diagnosis/physiopathology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis.<br><br>CLINICAL CASES: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments.<br><br>CONCLUSIONS: ALS a spectrum of motor neuron disease, a neurodegenerative disease of the CNS, without curative treatment and one with a fatal outcome, the diagnosis of ELA is complex and becomes more complex for atypical phenotypes, as observed in the presented cases EMG is an essential part of the approach and part of the diagnostic criteria.}, }
@article {pmid39546178, year = {2025}, author = {Li, N and Zhang, Z and Shen, L and Song, G and Tian, J and Liu, Q and Ni, J}, title = {Selenium metabolism and selenoproteins function in brain and encephalopathy.}, journal = {Science China. Life sciences}, volume = {68}, number = {3}, pages = {628-656}, pmid = {39546178}, issn = {1869-1889}, mesh = {*Selenoproteins/metabolism ; Humans ; *Selenium/metabolism ; *Brain/metabolism ; Animals ; Brain Diseases/metabolism ; Neurodegenerative Diseases/metabolism ; }, abstract = {Selenium (Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain, how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.}, }
@article {pmid39545975, year = {2024}, author = {Eickhoff, C and Schöne-Seifert, B and Kettemann, D and Bormann, E and Grehl, T and Boentert, M and Koch, JC and Schmitt, C and Schrank, B and Schröter, C and Meyer, T}, title = {[End of life perspectives: a systematic survey of patients with amyotrophic lateral sclerosis].}, journal = {Der Nervenarzt}, volume = {95}, number = {12}, pages = {1131-1138}, pmid = {39545975}, issn = {1433-0407}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; Male ; Female ; Middle Aged ; *Terminal Care/psychology ; Aged ; *Advance Directives/psychology ; Surveys and Questionnaires ; Germany ; Adult ; Aged, 80 and over ; Noninvasive Ventilation ; Palliative Care ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that still has to be primarily treated symptomatically or palliatively. It is therefore all the more important, in addition to initiating treatment, such as percutaneous endoscopic gastrostomy (PEG), noninvasive ventilation therapy (NIVT) and invasive ventilation therapy via tracheotomy (IVT), to discuss the possible termination of these measures early on.<br><br>QUESTION: What is the importance of advance directives for those affected and where are possible deficits in therapy planning for the end of life?<br><br>MATERIAL AND METHOD: Between March 2017 and January 2019 patients with a&#xa0;clinically confirmed diagnosis of ALS at six treatment centers were asked to fill out a&#xa0;questionnaire. A&#xa0;total of 328 people returned the completed forms.<br><br>RESULTS: Of the participants 72% had already made an advance directive (AD), 25% planned to fill one out and only 3% refused to do so. In composing the AD most patients (90%) had support, although 56% lacked medical counselling and only 18% had drawn up the will together with the doctor and relatives, with the majority of the rest also wanting support from a&#xa0;doctor. A&#xa0;total of 37% of all patients wanted a&#xa0;contact person to talk about their illness but only 40% of them had such a&#xa0;contact person. Of the patients 22% stated that they had considered suicide and of these only 55% stated that they had no contact person for the psychological stress caused by the illness but 31% wished to have such a&#xa0;person.<br><br>DISCUSSION AND CONCLUSION: A&#xa0;coordinated care of ALS patients, which also takes the psychosocial aspects into account is urgently needed.}, }
@article {pmid39545606, year = {2024}, author = {A Virata, MC and Catahay, JA and Lippi, G and Henry, BM}, title = {Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {6}, pages = {227-239}, pmid = {39545606}, issn = {1758-2032}, mesh = {Humans ; *Biomarkers/blood ; *Genetic Therapy/methods ; *Neurodegenerative Diseases/diagnosis/drug therapy/genetics ; *Neurofilament Proteins/blood ; }, abstract = {Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.}, }
@article {pmid39545045, year = {2024}, author = {Xu, X and Huang, Y and Zhu, Y and Jin, Q}, title = {Association between dietary patterns and the prognosis of amyotrophic lateral sclerosis in China: a cross-sectional study.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1437521}, pmid = {39545045}, issn = {2296-861X}, abstract = {BACKGROUND: Recently, a growing number of studies have specifically examined the impact of dietary variables on the development and progression of amyotrophic lateral sclerosis (ALS). The purpose of this study was to investigate the correlation between different dietary patterns and Chinese ALS patients' prognosis.<br><br>METHODS: A retrospective study was conducted by recruiting 590 patients with ALS who attended and were regularly followed at hospitals in Nanjing from 2016 to 2023. Nutrient intake was calculated using dietary information collected through the food frequency questionnaire (FFQ), and patients were divided into a control group and special diet groups, including a high-calorie group (HC), a high-protein group (HP), and a ketogenic diet group (KD), based on their specific intake. And used the Kaplan-Meier product limiting distribution to compare the time required to transition between phases of different dietary patterns and to estimate cumulative survival probabilities.<br><br>RESULTS: Patients in the HP had a better nutritional status. And the disease progression rate (&#x394;FS) was significantly associated with dietary patterns, with the KD group having the lowest &#x394;FS. Meanwhile, special diets extended the survival time of stage 4 patients but had no effect on the overall survival of the disease.<br><br>CONCLUSION: A special diet can be one of effective options for patients with advanced ALS. Patients with poor nutritional status may choose the HP diet, whereas those with underlying conditions should consider the ketogenic diet with caution.}, }
@article {pmid39544780, year = {2024}, author = {Silva, JF and de Souza, WM and Mello, JDC and Ceccato, HD and Oliveira, PSP and Ayrizono, MLS and Leal, RF}, title = {Evidence linking gut-brain axis and Crohn's disease, focusing on neurotrophic dysfunctions and radiological imaging analysis - a systematic review.}, journal = {American journal of translational research}, volume = {16}, number = {10}, pages = {6029-6040}, pmid = {39544780}, issn = {1943-8141}, abstract = {OBJECTIVE: To conduct a systematic review (SR) to find evidence for a connection between Crohn's disease (CD) and the gut-brain axis (GBA).<br><br>METHODS: This study conducted a systematic review (SR) employing a search strategy and strict inclusion criteria. It was conducted by searching for studies published between 2017 and 2024 in the following databases: PUBMED, PUBMED PMC, BVS-BIREME, SCOPUS, WEB OF SCIENCE, EMBASE, and COCHRANE.<br><br>RESULTS: Fifty original research articles were included. Among these, 20 studies addressed neuroimaging methods to evaluate CD patients' functional or structural brain changes. Neurodegenerative diseases were the second most addressed topic in the studies, with 18 articles related to different diseases such as Parkinson's disease, Alzheimer's disease, dementia, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Multiple System Atrophy. Eight articles addressed sleep disorders related to CD; two explored Electroencephalography changes; one investigated Brain-Derived Neurotrophic Factor serum levels and one correlated vagotomy with CD.<br><br>CONCLUSION: Interest in the link between CD and GBA is increasing, but studies remain varied and inconclusive, spanning from epidemiology to brain imaging and neglecting to investigate a mechanistic relationship. This SR underscores the need for further research to better understand the potential role of GBA in the prognosis and etiology of CD, highlighting its complexity.}, }
@article {pmid39544700, year = {2024}, author = {Parnianpour, P and Steinbach, R and Buchholz, IJ and Grosskreutz, J and Kalra, S}, title = {T1-weighted MRI texture analysis in amyotrophic lateral sclerosis patients stratified by the D50 progression model.}, journal = {Brain communications}, volume = {6}, number = {6}, pages = {fcae389}, pmid = {39544700}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis, a progressive neurodegenerative disease, presents challenges in predicting individual disease trajectories due to its heterogeneous nature. This study explores the application of texture analysis on T1-weighted MRI in patients with amyotrophic lateral sclerosis, stratified by the D50 disease progression model. The D50 model, which offers a more nuanced representation of disease progression than traditional linear metrics, calculates the sigmoidal curve of functional decline and provides independent quantifications of disease aggressiveness and accumulation. In this research, a representative cohort of 116 patients with amyotrophic lateral sclerosis was studied using the D50 model and texture analysis on MRI images. Texture analysis, a technique used for quantifying voxel intensity patterns in MRI images, was employed to discern alterations in brain tissue associated with amyotrophic lateral sclerosis. This study examined alterations of the texture feature autocorrelation across sub-groups of patients based on disease accumulation, aggressiveness and the first site of onset, as well as in direct regressions with accumulation/aggressiveness. The findings revealed distinct patterns of the texture-derived autocorrelation in grey and white matter, increase in bilateral corticospinal tract, right hippocampus and left temporal pole as well as widespread decrease within motor and extra-motor brain regions, of patients stratified based on their disease accumulation. Autocorrelation alterations in grey and white matter, in clusters within the left cingulate gyrus white matter, brainstem, left cerebellar tonsil grey matter and right inferior fronto-occipital fasciculus, were also negatively associated with disease accumulation in regression analysis. Otherwise, disease aggressiveness correlated with only two small clusters, within the right superior temporal gyrus and right posterior division of the cingulate gyrus white matter. The findings suggest that texture analysis could serve as a potential biomarker for disease stage in amyotrophic lateral sclerosis, with potential for quick assessment based on using T1-weighted images.}, }
@article {pmid39542176, year = {2024}, author = {Tian, Z and Zhang, Q and Wang, L and Li, M and Li, T and Wang, Y and Cao, Z and Jiang, X and Luo, P}, title = {Progress in the mechanisms of pain associated with neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102579}, doi = {10.1016/j.arr.2024.102579}, pmid = {39542176}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Pain/physiopathology/metabolism/etiology ; Animals ; Neuroinflammatory Diseases ; }, abstract = {Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.}, }
@article {pmid39542047, year = {2024}, author = {Ghaderi, S and Fatehi, F and Kalra, S and Okhovat, AA and Nafissi, S and Mohammadi, S and Batouli, SAH}, title = {Metabolite alterations in the left dorsolateral prefrontal cortex and its association with cognitive assessments in amyotrophic lateral sclerosis: A longitudinal magnetic resonance spectroscopy study.}, journal = {Brain research bulletin}, volume = {219}, number = {}, pages = {111125}, doi = {10.1016/j.brainresbull.2024.111125}, pmid = {39542047}, issn = {1873-2747}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnostic imaging ; Male ; Female ; Middle Aged ; *Magnetic Resonance Spectroscopy/methods ; Longitudinal Studies ; Aged ; *Cognition/physiology ; *Dorsolateral Prefrontal Cortex/metabolism ; Choline/metabolism ; Creatine/metabolism ; Neuropsychological Tests ; Adult ; Cognitive Dysfunction/metabolism/diagnostic imaging ; Aspartic Acid/analogs &amp; derivatives/metabolism ; Prefrontal Cortex/metabolism/diagnostic imaging ; }, abstract = {OBJECTIVE: To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments.<br><br>METHODS: Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's).<br><br>RESULTS: Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores.<br><br>CONCLUSIONS: Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.}, }
@article {pmid39541975, year = {2025}, author = {Márquez-Moñino, M&#xc1; and Santiveri, CM and de León, P and Camero, S and Campos-Olivas, R and Jiménez, M&#xc1; and Sáiz, M and González, B and Pérez-Cañadillas, JM}, title = {The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {1}, pages = {39-50.e6}, doi = {10.1016/j.str.2024.10.025}, pmid = {39541975}, issn = {1878-4186}, mesh = {*SARS-CoV-2/drug effects/metabolism ; *Antiviral Agents/pharmacology/chemistry ; Binding Sites ; Humans ; *Riluzole/pharmacology/chemistry/metabolism ; *Protein Binding ; Crystallography, X-Ray ; Coronavirus Nucleocapsid Proteins/chemistry/metabolism ; Phosphoproteins/metabolism/chemistry ; Protein Domains ; COVID-19 Drug Treatment ; Models, Molecular ; }, abstract = {Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.}, }
@article {pmid39541203, year = {2024}, author = {Russo, A and Maiorano, G and Cortese, B and D'Amone, S and Invidia, A and Quattrini, A and Romano, A and Gigli, G and Palamà, IE}, title = {Optimizing TDP-43 silencing with siRNA-loaded polymeric nanovectors in neuronal cells for therapeutic applications: balancing knockdown and function.}, journal = {Nanoscale}, volume = {16}, number = {48}, pages = {22337-22349}, doi = {10.1039/d4nr03159h}, pmid = {39541203}, issn = {2040-3372}, mesh = {*DNA-Binding Proteins/metabolism/genetics/chemistry ; *RNA, Small Interfering/chemistry/metabolism ; Humans ; *Neurons/metabolism/pathology ; Amyotrophic Lateral Sclerosis/therapy/metabolism/pathology/genetics ; Polymers/chemistry ; Nanoparticles/chemistry ; Gene Knockdown Techniques ; Cell Line, Tumor ; Gene Silencing ; }, abstract = {TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA binding protein critical for regulating gene expression, including transcription, splicing, mRNA stability, and protein translation. Aggregation of pathological TDP-43 proteins in the cytoplasm of neurons and glial cells appears to be a common feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as frontotemporal dementia (FTD), contributing to motor neuron degeneration and clinical symptoms. Downregulation of TDP-43 expression to prevent or reduce the formation of pathological aggregates is a potential therapeutic approach for treating TDP-43-related diseases. However, therapeutic strategies to reduce TDP-43 aggregation face significant challenges, as the downregulation of TDP-43 must balance the need to maintain its normal functions, which are essential for RNA metabolism and cellular homeostasis. In this study, we developed novel polymeric nanovectors for the delivery of TDP-43 siRNAs in neuronal cells. These nanovectors were designed to provide adequate TDP-43 silencing to achieve the desired functional reduction of TDP-43 levels, thereby optimizing its impact on cellular functions. Our results demonstrate that the polymeric nanovector formulations effectively reduced TDP-43 mRNA and protein levels to an extent comparable to those observed with traditional lipid-based systems. Concurrently, the polymeric nanovectors exhibited an enhanced capacity to reduce stress granules (SG) formation and facilitate TDP-43-containing SG disassembly, while preserving its essential cellular functions. This study provides the first evidence that polymeric nanovectors may be a valuable tool for developing therapeutic strategies to treat TDP-43 protein diseases, such as ALS and FTD, by directly silencing TDP-43 to reduce its aggregation.}, }
@article {pmid39539269, year = {2024}, author = {Risen, S and Sharma, S and Gilberto, VS and Brindley, S and Aguilar, M and Brown, JM and Chatterjee, A and Moreno, JA and Nagpal, P}, title = {Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs.}, journal = {ACS pharmacology &amp; translational science}, volume = {7}, number = {11}, pages = {3439-3451}, pmid = {39539269}, issn = {2575-9108}, abstract = {Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood-brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (F ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.}, }
@article {pmid39538364, year = {2025}, author = {Terra, R and Éthier, V and Busque, L and Morin-Quintal, A and D'Angelo, G and Hébert, J and Wang, X and Lépine, G and LeBlanc, R and Bergeron, J}, title = {Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {108}, number = {2}, pages = {116-127}, doi = {10.1002/cyto.b.22213}, pmid = {39538364}, issn = {1552-4957}, support = {//BD Biosciences/ ; }, mesh = {Humans ; *Flow Cytometry/methods ; *Immunophenotyping/methods ; *Leukemia, Myeloid, Acute/diagnosis/pathology ; Adult ; Male ; Female ; Middle Aged ; Aged ; Dendritic Cells/pathology ; Adolescent ; Young Adult ; Aged, 80 and over ; Cell Differentiation ; Child ; Mutation/genetics ; }, abstract = {Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.}, }
@article {pmid39538124, year = {2024}, author = {Sun, Y and Hu, S and Lan, Y and Wang, R and Wei, S and Huang, H and Cui, H and Li, X and Huang, Z}, title = {Investigation of resistance mechanisms to flucarbazone-sodium in wild oat (Avena fatua L.) from China.}, journal = {BMC plant biology}, volume = {24}, number = {1}, pages = {1073}, pmid = {39538124}, issn = {1471-2229}, mesh = {*Avena/genetics/drug effects ; China ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant/drug effects ; Plant Weeds/genetics/drug effects ; }, abstract = {BACKGROUND: Wild oat (Avena fatua L.) is a self-pollinating, allohexaploid species in the family Gramineae (grasses), which is a malignant weed that mainly harms crops such as wheat. In recent years, a decline in the control efficiency of flucarbazone-sodium against wild oat has occurred in some regions of China.<br><br>RESULTS: We identified an ALS-resistant A. fatua population (R population). Whole-plant response assays revealed that the R population exhibited a moderate level of resistance (5.9-fold) to flucarbazone-sodium. Pre-treatment with malathion significantly reduced flucarbazone-sodium resistance in the R population. The known mutation sites and ALS gene relative expression that confer resistance to ALS inhibitor herbicides were not found in R population. Following flucarbazone-sodium treatment, the expression of eight genes related to metabolic enzymes was investigated using quantitative real-time PCR (qRT-PCR). CYP92A6 and the Aldo/keto reductase family were highly expressed in the R population after the application of flucarbazone-sodium.<br><br>CONCLUSIONS: The mechanism of flucarbazone-sodium resistance in A. fatua is mediated by NTSR, nor TSR. Two genes, CYP92A6 and the Aldo/keto reductase family, were discovered to be possibly related in the metabolism of NTSR in the A. fatua population, justifying more functional studies. The results will serve as a data resource for further studies on the molecular mechanisms of A. fatua to flucarbazone-sodium.}, }
@article {pmid39537536, year = {2025}, author = {Zou, J and Meng, X and Hong, Z and Rao, Y and Wang, K and Li, J and Yu, H and Wang, C}, title = {Cas9-PE: a robust multiplex gene editing tool for simultaneous precise editing and site-specific random mutation in rice.}, journal = {Trends in biotechnology}, volume = {43}, number = {2}, pages = {433-446}, doi = {10.1016/j.tibtech.2024.10.012}, pmid = {39537536}, issn = {1879-3096}, mesh = {*CRISPR-Associated Protein 9/genetics/metabolism ; *Gene Editing/instrumentation/methods ; *Oryza/genetics ; Mutation ; *Mutagenesis, Site-Directed ; Acetolactate Synthase/genetics ; Herbicide Resistance/genetics ; }, abstract = {In molecular design breeding, the simultaneous introduction of desired functional genes through specific nucleotide modifications and the elimination of genes regulating undesired phenotypic traits or agronomic components require advanced gene editing tools. Due to limited editing efficiency, even with the use of highly precise editing tools, such as prime editing (PE), simultaneous editing of multiple mutation types poses a challenge. Here, we replaced Cas9 nickase (nCas9) with Cas9 to construct a Cas9-mediated PE (Cas9-PE) system in rice. This system not only enables precise editing, but also allows for site-specific random mutation. Moreover, leveraging the precision of Cas9-PE, we established a transgene-free multiplex gene editing system using a co-editing strategy. This strategy involved the Agrobacterium-mediated transient expression of the precise editing rice endogenous acetolactate synthase gene ALS[S627I] to confer herbicide bispyribac-sodium (BS) resistance as a selection marker. This study provides a versatile and efficient multiplex gene editing tool for molecular design breeding.}, }
@article {pmid39536963, year = {2025}, author = {Casiraghi, V and Sorce, MN and Santangelo, S and Invernizzi, S and Bossolasco, P and Lattuada, C and Battaglia, C and Venturin, M and Silani, V and Colombrita, C and Ratti, A}, title = {Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115057}, doi = {10.1016/j.expneurol.2024.115057}, pmid = {39536963}, issn = {1090-2430}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Oxidative Stress/drug effects/physiology ; *Sirolimus/pharmacology ; *TDP-43 Proteinopathies/pathology/metabolism ; DNA-Binding Proteins/metabolism/genetics ; Arsenites/toxicity/pharmacology ; Sodium Compounds/toxicity/pharmacology ; Motor Neurons/drug effects/metabolism/pathology ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined. In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin. Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.}, }
@article {pmid39536438, year = {2024}, author = {Henderson, NL and Ortiz-Olguin, E and Bourne, G and Pywell, C and Rose, JB and Williams, GR and Nipp, RD and Rocque, GB}, title = {Implementation of ePROs Into Multidisciplinary Tumor Board Discussions for Patients With Pancreatic Cancer: The INSPIRE Intervention.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {602-609}, doi = {10.6004/jnccn.2024.7052}, pmid = {39536438}, issn = {1540-1413}, mesh = {Humans ; *Pancreatic Neoplasms/therapy ; Female ; Male ; *Patient Reported Outcome Measures ; Aged ; Middle Aged ; Patient Care Team/standards ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The incorporation of electronic patient-reported outcomes (ePROs), such as the Geriatric Assessment (GA) and treatment preferences, into decision-making for pancreatic cancer has been limited by clinician- and system-level barriers concerning workflow. We hypothesized that ePRO inclusion within multidisciplinary tumor boards (MDTBs) would circumvent barriers and provide a venue for systematic consideration of critical patient-provided information.<br><br>PATIENTS AND METHODS: The INtegrating Systematic PatIent-Reported Evaluations (INSPIRE) intervention consists of (1) patient survey completion, including GA and patient preferences, and (2) screensharing patient ePROs during MDTBs. Proctor et al's implementation outcomes were assessed, with penetration (the proportion of consented patients who were presented at MDTBs) acting as the primary outcome (considered successful at 70%). Secondary outcomes included adoption, feasibility, acceptability, appropriateness, cost, and sustainability, assessed by clinician post-MDTB exit surveys, clinician postintervention surveys, clinician postintervention semistructured interviews, and time-coding analysis of recorded and transcribed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs.<br><br>RESULTS: A total of 50 patients completed surveys and all were presented at MDTBs (penetration=100%). All eligible clinicians (n=9) enrolled patients (adoption=100%) and reported that ePROs were useful in 90% and led to a change in treatment plan in 30% of cases. In postintervention surveys and interviews, clinicians primarily responded positively to feasibility, acceptability, and appropriateness questions. Time-coding analysis found a modest time cost of an additional 51.1 seconds in mean discussion time-per-patient between preintervention (mean [SD], 172.7 [111.4] seconds) and intervention patients (mean [SD], 223.8 [107.1] seconds); 86% of clinicians reported the intervention did not take too much time. All surveyed clinicians reported interest in continuing the intervention and suggested adaptations to further promote sustainability.<br><br>CONCLUSIONS: The integration of ePROs into pancreatic MDTBs was feasible and acceptable, providing a potential approach to increase the utilization of ePROs by clinical teams in their management of patients with pancreatic cancer.}, }
@article {pmid39535960, year = {2024}, author = {Soares, RV and Pedrosa, RBDS and Sandars, J and Cecilio-Fernandes, D}, title = {The importance of combined use of spacing and testing effects for complex skills training: A quasi-experimental study.}, journal = {Medical teacher}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/0142159X.2024.2427735}, pmid = {39535960}, issn = {1466-187X}, abstract = {INTRODUCTION: A major challenge is retention of complex clinical skills. Spacing training and testing have been demonstrated to increase knowledge and skill retention but the combination has not been previously investigated in complex clinical skills. The aim of our study was to compare the effectiveness of combined spacing and testing for Basic Life Support (BLS) and Advance Life Support (ALS) simulation training in one group (intervention group), with combined spacing and testing, and another group (control) that received simulation training in a single-session simulation training without testing.<br><br>METHODS: A quasi-experimental study.<br><br>RESULTS: Thirteen nursing students were in the intervention group and 18 in the control group. After three months, there was no significant reduction in retention of BLS knowledge (p&#x2009;>&#x2009;0.05) or BLS skills (p&#x2009;<&#x2009;0.05) in the intervention group, but there was a significant reduction in both (p&#x2009;<&#x2009;0.05) in the control group. We found no significant reduction in retention of ALS knowledge in the control group (p&#x2009;>&#x2009;0.05), but there was a significant reduction in the intervention group (p&#x2009;<&#x2009;0.05). There was no significant decay of ALS skills in both groups (p&#x2009;<&#x2009;0.05).<br><br>DISCUSSION: This is the first study to demonstrate that combined spacing and testing could be highly effective for complex skills simulation training to increase retention after three months.}, }
@article {pmid39535924, year = {2024}, author = {Hannestad, J and Smith, S and Lam, A and Hurt, J and Harada, N and Kim, R and Das, A and Brunello, J and Whitaker, G and Chalmers, D and Senjoti, F and Lin, W and Coghill, J and Bansal, Y and Sidhu, S and Zann, V and Liu, E}, title = {A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.}, journal = {Clinical and translational science}, volume = {17}, number = {11}, pages = {e70064}, pmid = {39535924}, issn = {1752-8062}, mesh = {Humans ; Male ; *Food-Drug Interactions ; Adult ; Administration, Oral ; *Healthy Volunteers ; Young Adult ; Middle Aged ; Area Under Curve ; Double-Blind Method ; Dose-Response Relationship, Drug ; Methylcellulose/administration &amp; dosage/analogs &amp; derivatives/chemistry ; Spray Drying ; Suspensions ; Cross-Over Studies ; Placebos/administration &amp; dosage ; }, abstract = {TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.}, }
@article {pmid39534418, year = {2024}, author = {Wang, WL and Tam, PKH and Chen, Y}, title = {Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth.}, journal = {World journal of gastroenterology}, volume = {30}, number = {41}, pages = {4490-4495}, pmid = {39534418}, issn = {2219-2840}, mesh = {Humans ; *Carcinoma, Hepatocellular/pathology/metabolism ; *Liver Neoplasms/pathology/metabolism ; *Tumor-Associated Macrophages/metabolism/immunology ; *Cell Proliferation ; *Wnt Signaling Pathway ; *Tumor Microenvironment ; Cell Movement ; Animals ; Disease Progression ; Macrophage Activation ; }, abstract = {In this article, we comment on the article by Huang et al. The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer. Tumor-associated macrophages (TAMs), primarily of the M2 subtype, are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways, including the wingless/integrated (Wnt) pathway. Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization, which in turn can exacerbate hepatocarcinoma cell proliferation and migration. This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer, highlighting the potential therapeutic benefits of inhibiting the Wnt pathway. Lastly, we point out areas in Huang et al's study that require further research, providing guidance and new directions for similar studies.}, }
@article {pmid39525702, year = {2024}, author = {Ravichandran, VV and Coleman, E and Brown, A and Boh, E}, title = {Response to Rodríguez-Cuadrado et al's "Clinical, histopathologic, immunohistochemical, and electron microscopic findings in cutaneous monkeypox: A multicenter retrospective case series in Spain".}, journal = {JAAD case reports}, volume = {53}, number = {}, pages = {149-150}, pmid = {39525702}, issn = {2352-5126}, }
@article {pmid39524179, year = {2024}, author = {Trinh, QD and Mai, HN and Pham, DT}, title = {Application of mesenchymal stem cells for neurodegenerative diseases therapy discovery.}, journal = {Regenerative therapy}, volume = {26}, number = {}, pages = {981-989}, pmid = {39524179}, issn = {2352-3204}, abstract = {Neurodegenerative diseases are central or peripheral nervous system disorders associated with progressive brain cell degeneration. Common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis have been widely studied. However, current therapeutics only reduce the symptoms and do not ameliorate the pathogenesis of these diseases. Recent studies suggested the roles of neuroinflammation, apoptosis, and oxidative stress in neurodegenerative diseases. Mesenchymal stem cells (MSCs) exert anti-apoptotic, anti-inflammatory, and antioxidative effects. Therefore, investigating the effects of MSCs and their applications may lead to the discovery of more effective therapies for neurodegenerative diseases. In this study, we review different approaches used to identify therapies for neurodegenerative diseases using MSCs.}, }
@article {pmid39534515, year = {2024}, author = {Watanabe, S and Sekiguchi, K and Suehiro, H and Yoshikawa, M and Noda, Y and Kamiyama, N and Matsumoto, R}, title = {Decreased diaphragm moving distance measured by ultrasound speckle tracking reflects poor prognosis in amyotrophic lateral sclerosis.}, journal = {Clinical neurophysiology practice}, volume = {9}, number = {}, pages = {252-260}, pmid = {39534515}, issn = {2467-981X}, abstract = {OBJECTIVE: Decreased cephalocaudal diaphragm movement may indicate respiratory dysfunction in amyotrophic lateral sclerosis (ALS). We aimed to evaluate diaphragm function in ALS using ultrasound speckle tracking, an image-analysis technology that follows similar pixel patterns.<br><br>METHODS: We developed an offline application that tracks pixel patterns of recorded ultrasound video images using speckle-tracking methods. Ultrasonography of the diaphragm movement during spontaneous quiet respiration was performed on 19 ALS patients and 21 controls to measure the diaphragm moving distance (DMD) in the cephalocaudal direction during a single respiration. We compared respiratory function measures and analyzed the relationship between the clinical profiles and DMD.<br><br>RESULTS: DMD was significantly lower in ALS patients than in the control group (0.6&#xa0;&#xb1;&#xa0;1.4 mm vs 2.2&#xa0;&#xb1;&#xa0;2.2 mm, p&#xa0;<&#xa0;0.01) and positively correlated with phrenic nerve compound motor action potential amplitude (R&#xa0;=&#xa0;0.63, p&#xa0;=&#xa0;0.01). DMD was negatively correlated with the change in the ALS Functional Rating Scale-Revised scores per month after the exam (R&#xa0;=&#xa0;-0.61, p&#xa0;=&#xa0;0.02), and those with a larger rate of decline had a significantly lower DMD (p&#xa0;=&#xa0;0.03).<br><br>CONCLUSIONS: Diaphragm ultrasound speckle tracking enabled the detection of diaphragm dysfunction in ALS.<br><br>SIGNIFICANCE: Diaphragm ultrasound speckle tracking may be useful for predicting prognosis.}, }
@article {pmid39534483, year = {2024}, author = {Sbarigia, C and Rome, S and Dini, L and Tacconi, S}, title = {New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.}, journal = {Journal of extracellular biology}, volume = {3}, number = {11}, pages = {e70019}, pmid = {39534483}, issn = {2768-2811}, abstract = {Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, and is characterized by muscle weakness, paralysis and ultimately, respiratory failure. The exact causes of ALS are not understood, though it is believed to combine genetic and environmental factors. Until now, it was admitted that motor neurons (MN) in the brain and spinal cord degenerate, leading to muscle weakness and paralysis. However, as ALS symptoms typically begin with muscle weakness or stiffness, a new hypothesis has recently emerged to explain the development of the pathology, that is, the 'dying back hypothesis', suggesting that this degeneration starts at the connections between MN and muscles, resulting in the loss of muscle function. Over time, this damage extends along the length of the MN, ultimately affecting their cell bodies in the spinal cord and brain. While the dying back hypothesis provides a potential framework for understanding the progression of ALS, the exact mechanisms underlying the disease remain complex and not fully understood. In this review, we are positioning the role of extracellular vesicles as new actors in ALS development.}, }
@article {pmid39534022, year = {2024}, author = {Li, Y and Bhinge, A and Inoue, S and Garcia, G}, title = {Editorial: Noncoding RNAs in neurodegenerative disorders: from current insights and future directions to translational modeling and therapeutic approaches.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1497673}, pmid = {39534022}, issn = {1662-4548}, }
@article {pmid39531950, year = {2025}, author = {Kacem, I and Sghaier, I and Ben Rhouma, H and Ratti, A and Ticozzi, N and Silani, V and Gouider-Khouja, N and Gouider, R}, title = {Association of Amyotrophic Lateral Sclerosis and Dopa-responsive dystonia in a Tunisian patient.}, journal = {Parkinsonism &amp; related disorders}, volume = {130}, number = {}, pages = {107171}, doi = {10.1016/j.parkreldis.2024.107171}, pmid = {39531950}, issn = {1873-5126}, mesh = {Adult ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications ; *Dystonic Disorders/genetics/drug therapy ; GTP Cyclohydrolase/genetics ; Tunisia ; }, abstract = {Dopa-responsive dystonia (DRD) is an autosomal dominant disease with parkinsonian and dystonic symptoms caused by GCH1 gene pathogenic variants affecting dopamine synthesis. The present case report is the first to link DRD with childhood-onset with ALS, suggesting that complex inheritance patterns in the North African population may contribute to multiple disorders.}, }
@article {pmid39531940, year = {2024}, author = {Pioro, EP and Brooks, BR and Liu, Y and Zhang, J and Apple, S}, title = {Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial.}, journal = {Journal of the neurological sciences}, volume = {467}, number = {}, pages = {123290}, doi = {10.1016/j.jns.2024.123290}, pmid = {39531940}, issn = {1878-5883}, mesh = {Humans ; *Edaravone/therapeutic use/administration &amp; dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Disease Progression ; Male ; Female ; Middle Aged ; Aged ; Treatment Outcome ; Double-Blind Method ; Free Radical Scavengers/therapeutic use/administration &amp; dosage ; Administration, Intravenous ; }, abstract = {INTRODUCTION: Subjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter "MTPA IV edaravone") in Study MCI186-19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups.<br><br>METHODS: Disease trajectories of MCI186-19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories.<br><br>RESULTS: ALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186-19 double-blind period. Latent classes 2-4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects.<br><br>CONCLUSIONS: This post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.}, }
@article {pmid39529471, year = {2025}, author = {Trojsi, F and Canna, A and Sharbafshaaer, M and di Nardo, F and Canale, F and Passaniti, C and Pirozzi, MA and Silvestro, M and Orologio, I and Russo, A and Cirillo, M and Tessitore, A and Siciliano, M and Esposito, F}, title = {Brain neurovascular coupling in amyotrophic lateral sclerosis: Correlations with disease progression and cognitive impairment.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16540}, pmid = {39529471}, issn = {1468-1331}, support = {NRRP project MNESYS (PE0000006, to NT)//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging ; Male ; Female ; *Disease Progression ; Middle Aged ; *Cognitive Dysfunction/physiopathology/etiology/diagnostic imaging ; Aged ; *Magnetic Resonance Imaging ; *Neurovascular Coupling/physiology ; Adult ; *Brain/physiopathology/diagnostic imaging/blood supply ; Nerve Net/diagnostic imaging/physiopathology ; Default Mode Network/physiopathology/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: 'Neurovascular coupling' (NVC) alterations, assessing the interplay between local cerebral perfusion and neural activity within a given brain region or network, may reflect neurovascular unit impairment in amyotrophic lateral sclerosis (ALS). The aim was to explore NVC as a correlation between the functional connectivity and cerebral blood flow within the large-scale resting-state functional magnetic resonance imaging brain networks in a sample of ALS patients compared to healthy controls (HCs).<br><br>METHODS: Forty-eight ALS patients (30 males; mean age 60.64&#x2009;&#xb1;&#x2009;9.62&#x2009;years) and 32 HC subjects (14 males; mean age 55.06&#x2009;&#xb1;&#x2009;16&#x2009;years) were enrolled and underwent 3&#x2009;T magnetic resonance imaging. ALS patients were screened by clinical and neuropsychological scales and were retrospectively classified as very fast progressors (VFPs), fast progressors and slow progressors (SPs).<br><br>RESULTS: Neurovascular coupling reduction within the default mode network (DMN) (p&#x2009;=&#x2009;0.005) was revealed in ALS patients compared to HCs, observing, for this network, significant NVC differences between VFP and SP groups. Receiver operating characteristic curve analysis showed that impaired NVC in the DMN at baseline best discriminated VFPs and SPs (area under the curve 75%). Significant correlations were found between NVC and the executive (r&#x2009;=&#x2009;0.40, p&#x2009;=&#x2009;0.01), memory (r&#x2009;=&#x2009;0.32, p&#x2009;=&#x2009;0.04), visuospatial ability (r&#x2009;=&#x2009;0.40, p&#x2009;=&#x2009;0.01) and non-ALS-specific (r&#x2009;=&#x2009;0.40, p&#x2009;=&#x2009;0.01) subscores of the Edinburgh Cognitive and Behavioural ALS Screen.<br><br>CONCLUSIONS: The reduction of brain NVC in the DMN may reflect largely distributed abnormalities of the neurovascular unit. NVC alterations in the DMN could play a role in anticipating a faster clinical progression in ALS patients, aiding patient selection and monitoring during clinical trials.}, }
@article {pmid39528814, year = {2024}, author = {Ovchinnikova, LA and Dzhelad, SS and Simaniv, TO and Zakharova, MN and Lomakin, YA and Gabibov, AG and Illarioshkin, SN}, title = {Development of a Panel of Biomarkers for Differential Diagnosis of Multiple Sclerosis.}, journal = {Doklady. Biochemistry and biophysics}, volume = {519}, number = {1}, pages = {593-596}, pmid = {39528814}, issn = {1608-3091}, mesh = {Humans ; *Multiple Sclerosis/diagnosis/metabolism/blood ; *Biomarkers/metabolism ; Diagnosis, Differential ; Female ; Male ; Adult ; Amyotrophic Lateral Sclerosis/diagnosis/metabolism ; Middle Aged ; Neuromyelitis Optica/diagnosis/metabolism ; }, abstract = {Demyelinating diseases are a group of heterogeneous pathologies that affect the nervous system and reduce the quality of life. One of such diseases is multiple sclerosis (MS), an inflammatory autoimmune neurodegenerative disease of the central nervous system (CNS). At the initial stages, MS can mimic some infectious, neoplastic, genetic, metabolic, vascular, and other pathologies. Accurate differential diagnosis of this disease is important to improve the quality of life of patients and reduce possible irreversible damage to the central nervous system. In this work, we confirmed the possibility of using our previously proposed candidate panel of MS biomarkers to distinguish MS from neuromyelitis optica spectrum disorder (NMOSD) and amyotrophic lateral sclerosis (ALS). We have shown that our proposed panel (SPTAN1601-644 + PRX451-494 + PTK6301-344 + LMP1285-330) allows us to distinguish MS from ALS (AUC = 0.796) and NMOSD (AUC = 0.779).}, }
@article {pmid39526716, year = {2024}, author = {Šljivo, A and Jevtić, T and Siručić, I and Terzić-Salihbašić, S and Abdulkhaliq, A and Reiter, L and Salihbašić, F and Bečar-Alijević, A and Alijević, A and Dadić, I and Gavrankapetanović, F}, title = {Out-of-hospital cardiac arrest (OHCA) in Bosnia and Herzegovina in the period 2018-2022: current trends, usage of automated external defibrillators (AED) and bystanders' involvement.}, journal = {Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina}, volume = {21}, number = {2}, pages = {267-273}, doi = {10.17392/1719-21-2}, pmid = {39526716}, issn = {1840-2445}, abstract = {AIM: To investigate out-of-hospital cardiac arrest (OHCA) trend, provided advanced life support (ALS) measures, automated external defibrillator (AEDs) utilization and bystanders' involvement in cardiopulmonary resuscitation (CPR) during OHCA incidents.<br><br>METHODS: This cross-sectional study encompassed data pertaining to all OHCA incidents attended to by the Emergency Medical Service of Canton Sarajevo, Bosnia and Herzegovina, covering the period from January 2018 to December 2022.<br><br>RESULTS: Among a total of 1131 OHCA events, 236 (20.8 %) patients achieved return of spontaneous circulation (ROSC); there were 175 (74.1%) males and 61 (25.9%) females. The OHCA incidence was 54/100,000 inhabitants per year. After a 30-day period post-ROSC, 146 (61.9%) patients fully recovered, while 90 (38.1%) did not survive during this timeframe. Younger age (p<0.05), initial rhythm of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) (p<0.05), and faster emergency medical team (EMT) response time (p<0.05) were significantly associated with obtaining ROSC. Only 38 (3.3%) OHCA events were assisted by bystanders, who were mostly medical professionals, 25 (65.7%), followed by close family members, 13 (34.3%). There was no report of AED usage.<br><br>CONCLUSION: This follow-up study showed less ROSC achievement, similar bystanders' involvement, similar factors associated with achieving ROSC (age, EMT response time), and a decline in OHCA events (especially in year 2021 and 2022) compared to our previous study (2015-2019). There was an extremely low rate of bystander engagement and no AEDs usage. Governments and health organizations must swiftly improve public awareness, promote better practice (basic life support), and actively encourage bystander participation.}, }
@article {pmid39523617, year = {2024}, author = {Iguchi, Y and Katsuno, M}, title = {[Current Status of Drug Development for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1241-1249}, doi = {10.11477/mf.1416202766}, pmid = {39523617}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Drug Development ; Clinical Trials as Topic ; Animals ; Riluzole/therapeutic use ; Neuroprotective Agents/therapeutic use ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease of motor neuron. Although riluzole and edaravone have been approved for the treatment of ALS, it remains a lethal disease that causes rapid motor impairment, and there is an urgent need to develop more effective treatments. Advances in understanding the pathomechanisms of ALS, efficient clinical trial design, and research support programs have led to many clinical trials for ALS both domestically and internationally.}, }
@article {pmid39523616, year = {2024}, author = {Ishiguro, T and Nagata, T and Yokota, T}, title = {[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1233-1239}, doi = {10.11477/mf.1416202765}, pmid = {39523616}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; Mutation ; }, abstract = {Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.}, }
@article {pmid39523615, year = {2024}, author = {Ogino, M}, title = {[Palliative Care for Persons with Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1225-1232}, doi = {10.11477/mf.1416202764}, pmid = {39523615}, issn = {1881-6096}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Analgesics, Opioid/administration &amp; dosage ; Japan ; *Palliative Care ; }, abstract = {Palliative care in Japan is available mainly for patients with cancer, and palliative care specialists do not have sufficient experience with management of palliation in persons with amyotrophic lateral sclerosis (ALS). Treatment of ALS symptoms is an important component of palliative care, and it is important that neurologists and home care physicians familiarize themselves with palliative care for ALS in consultation with palliative care specialists. Notably, the use of opioids at the end of life differs from that of pain relief for cancer. Physicians should be mindful that opioids are not a perfect solution for palliative care of persons with ALS.}, }
@article {pmid39523614, year = {2024}, author = {Yamakawa, I and Urushitani, M}, title = {[Gold Coast Criteria: A New Diagnostic Paradigm in the Era of Disease-Modifying Therapy for Amyotrophic Lateral Sclerosis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1217-1223}, doi = {10.11477/mf.1416202763}, pmid = {39523614}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/drug therapy ; Humans ; }, abstract = {Significant progress has been made in the development of disease-modifying drugs for amyotrophic lateral sclerosis (ALS), with the introduction of tofersen, an antisense oligonucleotide drug for familial ALS, marking a turning point in the treatment. These drugs are most effective when administered early in the disease course, highlighting the need for improved diagnostic sensitivity. The 2020 Gold Coast Diagnostic Criteria allow ALS diagnosis in cases without upper motor neuron symptoms, potentially increasing early detection rates. However, careful differential diagnoses are necessary when applying these criteria to maintain diagnostic specificity. This review outlines the key points to consider when using the Gold Coast Criteria, balancing the need for an early diagnosis with caution to avoid overdiagnosis.}, }
@article {pmid39523613, year = {2024}, author = {Fukutake, T}, title = {[Diagnosis, Notification, and Managements of ALS: A Personal Perspective from 40 years of Experience as a Clinical Neurologist].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {76}, number = {11}, pages = {1205-1216}, doi = {10.11477/mf.1416202762}, pmid = {39523613}, issn = {1881-6096}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Humans ; *Neurologists ; Female ; Middle Aged ; Male ; Aged ; }, abstract = {This narrative summary presents the author's 40-year experience as a clinical neurologist who treated patients with amyotrophic lateral sclerosis (ALS). Five representative cases from the author's first 20 years at Chiba University Hospital and its affiliated hospitals were selected, including a patient of respiratory-onset who was ignorantly extubated by a female relative for patient's distress to the intratracheal tube. Based on the latter 20 years of experience at the author's current hospital, the author first describes a famous patient with ALS who was being treated at this medical center before the author was assigned to this hospital and fought against ALS for 31 years before eventually succumbing to total locked-in syndrome. Thereafter, the author has summarized the ages, sex, phenotypes, comorbidities, responses to the available treatment options, and total number of years that have elapsed for the 24 patients that the author initially examined in the outpatient clinic. In terms of diagnostic delay, the author describes "foot drop" in patients who developed lower limb symptoms, and hoarseness in those who developed bulbar palsy. Furthermore, the author discusses issues regarding family caregiving capacity, patient's and families' understanding of notification, and medical management (i.e., medications, rehabilitation for ADL, nutrition and respiration, complications of frontotemporal dementia, and medical cooperation with other clinics and hospitals).}, }
@article {pmid39522728, year = {2025}, author = {Lauck, KC and Narayanan, D and Tolkachjov, SN}, title = {Regarding response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e59-e60}, doi = {10.1016/j.jaad.2024.10.059}, pmid = {39522728}, issn = {1097-6787}, }
@article {pmid39522725, year = {2025}, author = {Tsai, SY}, title = {Response to Narayanan et al's "Adverse events in cemiplimab therapy for locally advanced or metastatic cSCC: A global propensity-matched retrospective cohort study".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e57}, doi = {10.1016/j.jaad.2024.08.085}, pmid = {39522725}, issn = {1097-6787}, }
@article {pmid39522723, year = {2025}, author = {Nardone, V and Esposito, A and D'Ippolito, E and Argenziano, G and Reginelli, A and Troiani, T}, title = {Response to Sajid et al's "Response to Valerio Nardone et al's 'Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis'".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e55-e56}, doi = {10.1016/j.jaad.2024.10.058}, pmid = {39522723}, issn = {1097-6787}, }
@article {pmid39522697, year = {2024}, author = {Gao, L and Yang, XN and Dong, YX and Han, YJ and Zhang, XY and Zhou, XL and Liu, Y and Liu, F and Fang, JS and Ji, JL and Gao, ZR and Qin, XM}, title = {The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products.}, journal = {Pharmacology &amp; therapeutics}, volume = {264}, number = {}, pages = {108751}, doi = {10.1016/j.pharmthera.2024.108751}, pmid = {39522697}, issn = {1879-016X}, mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.}, }
@article {pmid39522672, year = {2025}, author = {Shapiro, O and Woods, C and Gleixner, AM and Sannino, S and Ngo, M and McDaniels, MD and Wipf, P and Hukriede, NA and Donnelly, CJ and Brodsky, JL}, title = {Assays to measure small molecule Hsp70 agonist activity in vitro and in vivo.}, journal = {Analytical biochemistry}, volume = {697}, number = {}, pages = {115712}, pmid = {39522672}, issn = {1096-0309}, support = {U54 DK137329/DK/NIDDK NIH HHS/United States ; P30 DK079307/DK/NIDDK NIH HHS/United States ; R35 GM131732/GM/NIGMS NIH HHS/United States ; R21 NS133676/NS/NINDS NIH HHS/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 NS105756/NS/NINDS NIH HHS/United States ; }, mesh = {*HSP70 Heat-Shock Proteins/metabolism/agonists ; Animals ; *Zebrafish ; Humans ; Small Molecule Libraries/pharmacology/chemistry ; Optogenetics/methods ; DNA-Binding Proteins/agonists/metabolism ; }, abstract = {Hsp70 prevents protein aggregation and is cytoprotective, but sustained Hsp70 overexpression is problematic. Therefore, we characterized small molecule agonists that augment Hsp70 activity. Because cumbersome assays were required to assay agonists, we developed cell-based and in vivo assays in which disease-associated consequences of Hsp70 activation can be quantified. One assay uses an optogenetic system in which the formation of TDP-43 inclusions can be controlled, and the second assay employs a zebrafish model for acute kidney injury (AKI). These complementary assays will facilitate future work to identify new Hsp70 agonists as well as optimized agonist derivatives.}, }
@article {pmid39521994, year = {2024}, author = {Liang, H and Zhou, X and Zhang, J and Xu, W and Liu, Y and Wang, X and Hu, Y and Xu, R and Li, X}, title = {The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {206}, pmid = {39521994}, issn = {1528-3658}, support = {81960244//National Natural Science Foundation of China/ ; 20212BAB216026//Jiangxi Natural Science Foundation/ ; 202110016//Science and Technology Plan of Jiangxi Provincial Health Commission/ ; 2022B975//Science and Technology Plan of Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Animals ; *Apigenin/pharmacology/therapeutic use ; Mice ; *Signal Transduction/drug effects ; *Mice, Transgenic ; *Disease Models, Animal ; *NF-E2-Related Factor 2/metabolism/genetics ; Oxidative Stress/drug effects ; Aldehyde Dehydrogenase 1 Family/metabolism/genetics ; Humans ; Apoptosis/drug effects ; Retinal Dehydrogenase/metabolism/genetics ; Cell Line ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss leading to muscle weakness and atrophy. Apigenin (APG), known for its antioxidant properties, holds potential as a therapeutic compound in ALS.<br><br>METHODS: We used the Tg(SOD1*G93A)1Gur/J transgenic mouse model of ALS to investigate the therapeutic effects of APG. Key measured included motor function via the ALSTDI score, molecular markers of oxidative stress (OS) and apoptosis in spinal cord tissues. Techniques used included pathological, Western blotting, flow cytometry, and qRT-PCR to assess the effect of ALDH1A2.<br><br>RESULTS: APG treatment attenuated weight loss and improved motor function scores in ALS mice compared to untreated ALS models. Molecular analyses revealed a significant upregulation of ALDH1A2 in APG-treated groups, along with a reduction in markers of OS and apoptosis. In vitro studies in NSC34 cells further confirmed the protective effects of APG against SOD1*G93A mutation-induced cytotoxicity. In addition, suppression of ALDH1A2 by shRNA exacerbated disease markers that were ameliorated by APG treatment.<br><br>CONCLUSIONS: Our results suggest that APG attenuates the progression of ALS pathology by regulating OS and apoptosis through ALDH1A2. These results support further investigation of APG as a potential therapeutic agent for the treatment of ALS.}, }
@article {pmid39521135, year = {2025}, author = {Sajid, SL and Ur Rehman, MA and Sajid, SA and Shahid, N}, title = {Response to Valerio Nardone et al's "Previous radiotherapy increases the efficacy of cemiplimab in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma: A retrospective analysis".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {3}, pages = {e53-e54}, doi = {10.1016/j.jaad.2024.08.084}, pmid = {39521135}, issn = {1097-6787}, }
@article {pmid39520580, year = {2024}, author = {Hyldgaard Andersen, S and Harsløf, S and Tøttrup, A}, title = {Laparoscopic ileopexy for afferent loop syndrome after restorative proctocolectomy-a retrospective case series.}, journal = {International journal of colorectal disease}, volume = {39}, number = {1}, pages = {180}, pmid = {39520580}, issn = {1432-1262}, mesh = {Humans ; *Proctocolectomy, Restorative/adverse effects ; *Laparoscopy/adverse effects ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; *Afferent Loop Syndrome/surgery/etiology ; *Ileum/surgery ; Aged ; Treatment Outcome ; Postoperative Complications/etiology/surgery ; }, abstract = {BACKGROUND: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP).<br><br>METHOD: Ileopexy has been the treatment of choice in patients with ALS for the last 5&#xa0;years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up.<br><br>RESULTS: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5&#xa0;weeks (2-80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1-9) to 2 (0-7) (p&#x2009;=&#x2009;0.02) at the last follow-up.<br><br>CONCLUSIONS: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum.}, }
@article {pmid39520508, year = {2024}, author = {Larose, A and Miller, CCJ and Mórotz, GM}, title = {The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {81}, number = {1}, pages = {447}, pmid = {39520508}, issn = {1420-9071}, mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/enzymology ; Animals ; *Neurons/metabolism/pathology ; Cyclin-Dependent Kinase 5/metabolism/genetics ; Signal Transduction ; Synapses/metabolism/pathology ; Protein-Tyrosine Kinases/metabolism/genetics ; Phosphorylation ; Axonal Transport ; Glycogen Synthase Kinase 3 beta/metabolism ; }, abstract = {The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.}, }
@article {pmid39519213, year = {2024}, author = {Bova, V and Mannino, D and Capra, AP and Lanza, M and Palermo, N and Filippone, A and Esposito, E}, title = {CK and LRRK2 Involvement in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519213}, issn = {1422-0067}, mesh = {Humans ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/genetics ; Animals ; Mutation ; Phosphorylation ; Autophagy/genetics ; }, abstract = {Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer's disease (AD), dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)-all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases.}, }
@article {pmid39519209, year = {2024}, author = {Firdaus, Z and Li, X}, title = {Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues.}, journal = {International journal of molecular sciences}, volume = {25}, number = {21}, pages = {}, pmid = {39519209}, issn = {1422-0067}, support = {DK129241 DK126662/GF/NIH HHS/United States ; }, mesh = {Humans ; *Epigenesis, Genetic ; *DNA Methylation ; Neurodegenerative Diseases/genetics/therapy ; Animals ; Nervous System Diseases/genetics/therapy ; Histones/metabolism/genetics ; Epigenomics/methods ; Histone Code/genetics ; }, abstract = {Neurodegenerative disorders are major health concerns globally, especially in aging societies. The exploration of brain epigenomes, which consist of multiple forms of DNA methylation and covalent histone modifications, offers new and unanticipated perspective into the mechanisms of aging and neurodegenerative diseases. Initially, chromatin defects in the brain were thought to be static abnormalities from early development associated with rare genetic syndromes. However, it is now evident that mutations and the dysregulation of the epigenetic machinery extend across a broader spectrum, encompassing adult-onset neurodegenerative diseases. Hence, it is crucial to develop methodologies that can enhance epigenetic research. Several approaches have been created to investigate alterations in epigenetics on a spectrum of scales-ranging from low to high-with a particular focus on detecting DNA methylation and histone modifications. This article explores the burgeoning realm of neuroepigenetics, emphasizing its role in enhancing our mechanistic comprehension of neurodegenerative disorders and elucidating the predominant techniques employed for detecting modifications in the epigenome. Additionally, we ponder the potential influence of these advancements on shaping future therapeutic approaches.}, }
@article {pmid39518442, year = {2024}, author = {Laucius, O and Drūteika, J and Balnytė, R and Palačionytė, J and Ališauskienė, M and Petrikonis, K and Vaitkus, A}, title = {Phrenic Nerve Sonography Alterations in Patients with ALS: Insight with Clinical and Neurophysiological Findings.}, journal = {Journal of clinical medicine}, volume = {13}, number = {21}, pages = {}, pmid = {39518442}, issn = {2077-0383}, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and although the diagnosis is primarily based on clinical criteria, ENMG, as the "gold standard", does not always show detectable changes. Therefore, our study suggests that alterations in echogenicity and heterogeneity of the phrenic nerve (PN) may serve as potential additional diagnostic tools for ALS. Methods: Our study included 32 patients in the ALS group and 64 individuals in the control group. Each participant underwent an interview and completed questionnaires to collect clinical and demographic data, including age, gender, height, body mass index (BMI), hip and waist circumference, duration of illness, ALS-FRS-R score, comorbidities, and medication use. Ultrasound examinations of the PN were performed by two authors using a high-resolution "Philips EPIQ 7" ultrasound machine equipped with a linear 4-18 MHz transducer. The ALS group participants underwent PN sonography and conduction examinations, arterial blood gas (ABG) analysis, respiratory function tests (RFT), and electroneuromyography (ENMG). Results: The study demonstrated that the phrenic nerve is significantly smaller on both sides in patients with ALS compared to the control group (p < 0.01). Changes in the homogeneity and echogenicity of the PN were also observed on both sides. On the right side, 43.8% of the nerves showed heterogeneity, 40.6% were isoechoic, and 21.9% were hyperechoic. On the left side, 59.4% of the nerves exhibited heterogeneity, 34.4% were isoechoic, and 28.1% were hyperechoic. Moreover, sonography on both sides showed significant correlation with ALS-FRS-R, COMPASS-31, and ENMG results. Conclusions: Our study highlights the importance of phrenic nerve ultrasound as a promising supplementary diagnostic tool for ALS. The significant differences in phrenic nerve size, echogenicity, and homogeneity between patients with ALS and the control group demonstrate that ultrasound imaging can detect morphological changes in the phrenic nerve. Incorporating phrenic nerve ultrasound into routine diagnostic protocols could improve early detection, enhance disease monitoring, and offer a more comprehensive understanding of the neurodegenerative processes in ALS.}, }
@article {pmid39517754, year = {2024}, author = {Ciou, TS and Lin, CH and Wang, CK}, title = {Airborne LiDAR Point Cloud Classification Using Ensemble Learning for DEM Generation.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {21}, pages = {}, pmid = {39517754}, issn = {1424-8220}, abstract = {Airborne laser scanning (ALS) point clouds have emerged as a predominant data source for the generation of digital elevation models (DEM) in recent years. Traditionally, the generation of DEM using ALS point clouds involves the steps of point cloud classification or ground point filtering to extract ground points and labor-intensive post-processing to correct the misclassified ground points. The current deep learning techniques leverage the ability of geometric recognition for ground point classification. However, the deep learning classifiers are generally trained using 3D point clouds with simple geometric terrains, which decrease the performance of model inferencing. In this study, a point-based deep learning model with boosting ensemble learning and a set of geometric features as the model inputs is proposed. With the ensemble learning strategy, this study integrates specialized ground point classifiers designed for different terrains to boost classification robustness and accuracy. In experiments, ALS point clouds containing various terrains were used to evaluate the feasibility of the proposed method. The results demonstrated that the proposed method can improve the point cloud classification and the quality of generated DEMs. The classification accuracy and F1 score are improved from 80.9% to 92.2%, and 82.2% to 94.2%, respectively, by using the proposed methods. In addition, the DEM generation error, in terms of mean squared error (RMSE), is reduced from 0.318-1.362 m to 0.273-1.032 m by using the proposed ensemble learning.}, }
@article {pmid39515011, year = {2024}, author = {Mauri, L and Taccaliti, F and Lingua, E}, title = {Modeling the interaction between wildfires and windthrows: A pilot case study for Italian Alps.}, journal = {Journal of environmental management}, volume = {371}, number = {}, pages = {123150}, doi = {10.1016/j.jenvman.2024.123150}, pmid = {39515011}, issn = {1095-8630}, mesh = {*Wildfires ; Italy ; *Forests ; Pilot Projects ; Models, Theoretical ; Ecosystem ; Wind ; }, abstract = {Wildland fires and windthrows represent relevant disturbances for forest ecosystems worldwide. In this context, especially for Italian catchments, the interaction between windthrows and changes in wildfire behaviour starting from ALS data processing is scarcely investigated. Therefore, this research aims to compute a multi-temporal analysis of the interaction between windthrows and wildfire behaviour in a forested area (Veneto region, northern Italy), recently affected by the renamed Vaia windstorm. The semi-empirical FlamMap model was applied, starting from ALS data processing implemented in R for mapping the spatial distribution of forest attributes and fuels within the catchment. The role of windthrows in altering wildfire behaviour was investigated considering ALS point clouds acquired before and after the occurrence of the storm Vaia. Digital Terrain Models (DTMs), Canopy Height Models (CHMs), topographic data and metrics describing forest structure were extracted from ALS data for both scenarios at 5 m resolution, to compare changes in wildfire behaviour over time. Differences in Rate of Spread (RoS), flame length (FL), midflame windspeed (WS) and arrival time (AT) were assessed, and their correlation with windstorm damages was investigated at the catchment detail. , An increase of RoS, FL, and WS greater than 30 m/min, 3 m and 1.1 m/s were respectively estimated in windthrown areas, as well as a decrease of AT greater than 30 min, attesting the key role of windthrows in altering wildfire behaviour over time. The correlation between windthrows and changes in wildfire attributes was finally modeled by computing regression analysis, with R[2] of 0.86, 0.93, 0.62, and 0.91 resulted for RoS, FL, WS and AT. This research represents a pilot case study for better detecting changes in wildfires behaviour due to windthrows occurrence, therefore proposing and carrying out effective planning and management strategies for disturbed forest stands over time.}, }
@article {pmid39514515, year = {2024}, author = {Ohnari, K and Mafune, K and Adachi, H}, title = {Fasciculation potentials are related to the prognosis of amyotrophic lateral sclerosis.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0313307}, pmid = {39514515}, issn = {1932-6203}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/mortality/diagnosis ; Male ; Female ; Middle Aged ; Prognosis ; *Fasciculation/physiopathology/diagnosis ; *Electromyography ; Aged ; Retrospective Studies ; Disease Progression ; Adult ; Biomarkers/blood ; }, abstract = {Some prognostic biomarkers of amyotrophic lateral sclerosis (ALS) have been described; however, they are inadequate for satisfactorily predicting individual patient outcomes. Fasciculation potentials (FPs) on electromyography (EMG) are useful for the early diagnosis of ALS, and complex FPs are associated with shorter survival in ALS. In this study, we investigated the relationship between the proportion of muscles with FPs, biochemical markers, and the prognosis of ALS. 89 Patients with ALS were retrospectively classified into three groups based on the interval from onset to death or tracheostomy (less than 1 year: fast progression; from 1 year to less than 3 years: average progression; 3 years or more: slow progression). We performed statistical analysis of the electrophysiological findings, including the percentage of examined muscles with FPs, and biochemical markers evaluated on admission. Patients with fast ALS progression had a higher percentage of muscles with FPs (93.1% vs. 37.9%, P<0.001) and lower uric acid (UA) levels (male: 4.19 mg/dl vs 5.55 mg/dl, P<0.001; female: 3.71 mg/dl vs 5.41 mg/dl, P<0.001) than patients with slow progression. Survival curves demonstrated a relationship between these factors and the survival time in patients with ALS. Furthermore, UA levels were correlated with the percentage of muscles with FPs. Our electrophysiological findings suggest that ALS presents with multisystem neurological manifestations, and these manifestations differed among the groups classified by disease progression. The percentage of muscles with FPs on EMG and serum UA levels were especially associated with the prognosis of ALS.}, }
@article {pmid39513379, year = {2025}, author = {Simkins, TJ and Kupfer, S and Malik, FI and Meng, L and Rudnicki, SA and Wei, J and Shefner, JM and Bowser, R}, title = {Plasma neurofilament analysis in VITALITY-ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {103-112}, doi = {10.1080/21678421.2024.2423707}, pmid = {39513379}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/drug therapy ; Middle Aged ; Double-Blind Method ; *Neurofilament Proteins/blood ; Aged ; *Disease Progression ; Biomarkers/blood ; Longitudinal Studies ; Adult ; Intermediate Filaments/metabolism ; }, abstract = {OBJECTIVE: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of tirasemtiv in people with ALS (pALS).<br><br>METHODS: Plasma was collected at baseline and every 8 weeks thereafter. Results were compared between treatment groups and evaluated by clinical characteristics and over time. Pearson's correlation coefficients (r) were calculated to evaluate associations between Nf concentrations and slow vital capacity (SVC), Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score, and pre-study/in-study rates of disease progression (psRDP/isRDP).<br><br>RESULTS: Nf measurements were available from 101 placebo- and 161 tirasemtiv-treated people with ALS (pALS). There were no significant differences in Nf between placebo and tirasemtiv groups at any time point; further analyses grouped all samples. At baseline, Nf concentration did not differ by multiple clinical characteristics. Baseline Nf light chain (NfL) concentration correlated with the psRDP (r&#xa0;=&#xa0;0.50, p&#xa0;<&#xa0;0.001) and isRDP (r&#xa0;=&#xa0;0.53, p&#xa0;<&#xa0;0.0001). Phosphorylated Nf heavy chain (pNfH) demonstrated a similar, but less robust, pattern of results. Baseline Nf concentration correlated with change in SVC and ALSFRS-R score over time. Plasma pNfH concentration continuously decreased over time. There was no meaningful change in plasma NfL concentration over the study period.<br><br>CONCLUSIONS: In this large longitudinal study, baseline NfL concentration correlated with multiple markers of disease progression. The findings suggest Nfs show promise primarily as prognostic markers for pALS, particularly for those with rapid disease progression.}, }
@article {pmid39513316, year = {2024}, author = {Yadav, H and Malviya, R and Kaushik, N and Sridhar, SB}, title = {Therapeutic Potential of Quercetin Analogous: Prospective and Advances.}, journal = {Recent advances in food, nutrition &amp; agriculture}, volume = {}, number = {}, pages = {}, doi = {10.2174/012772574X332803240930065210}, pmid = {39513316}, issn = {2772-5758}, abstract = {The purpose of the article is to investigate the therapeutic potential of quer-cetin and related compounds by elucidating their pharmacological characteristics and molecular mechanisms of action. The potential benefits of quercetin and its analogs for cardiovascular health, disorders of the brain, metabolic disorders, and more are discussed in the discussion part of this page. Concerns about their clinical efficacy due to issues with bioavailability and distribution are also discussed. This region of the paper emphasizes the importance of researchers and clinicians working together to maximize the incorporation of these chemicals into real-world therapeutic approaches. In conclusion, quercetin, along with related substances, shows great potential in a wide range of therapeutic settings. Potentially useful for the management of a wide variety of illnesses, their multiple methods of action include the regulation of pathways for cell signaling and interaction with different enzymes. However, additional clinical tri-als are needed to verify their efficacy and safety.}, }
@article {pmid39512134, year = {2025}, author = {Pattee, GL}, title = {Gastrostomy in Amyotrophic Lateral Sclerosis: Timing Enhances Survival.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {1}, pages = {3-5}, doi = {10.1002/mus.28294}, pmid = {39512134}, issn = {1097-4598}, }
@article {pmid39512085, year = {2024}, author = {White, CG and Hancewicz, TM and Fasasi, A and Wright, J and Lavine, BK}, title = {Alternating and Modified Alternating Least Squares Applied to Raman Spectra of Finished Gasolines.}, journal = {Applied spectroscopy}, volume = {}, number = {}, pages = {37028241292649}, doi = {10.1177/00037028241292649}, pmid = {39512085}, issn = {1943-3530}, abstract = {Extraction of components from individual refinery streams (e.g., reformates and alkylates) in finished gasoline was undertaken using Raman spectroscopy to characterize the chemical content of the finished product. Modified alternating least squares (MALS) was used for separating Raman spectroscopic data sets of the finished product into its pure individual components. The advantages of MALS over alternating least squares (ALS) for multicomponent resolution are highlighted in this study using three Raman spectroscopic data sets which provide a suitable benchmark for comparing the performance of these two methods. MALS is superior to ALS in terms of accuracy and can better resolve components than ALS, and it is also more robust toward collinear data. Finally, components near the noise level usually cannot be extracted by ALS because of instability when inverting the covariance structure which inflates the noise present in the data. However, these same components can be extracted by MALS due to the stabilization of the least squares regression with respect to the matrix inversion using modified techniques from ridge regression.}, }
@article {pmid39511965, year = {2025}, author = {Bhai, S and Levine, T and Moore, D and Bowser, R and Heim, AJ and Walsh, M and Shibani, A and Simmons, Z and Grogan, J and Goyal, NA and Govindarajan, R and Hussain, Y and Papsdorf, T and Schwasinger-Schmidt, T and Olney, N and Goslin, K and Pulley, M and Kasarskis, E and Weiss, M and Katz, SW and Moser, S and Jabari, D and Jawdat, O and Statland, J and Dimachkie, MM and Barohn, R and , }, title = {A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {1}, pages = {63-72}, pmid = {39511965}, issn = {1097-4598}, support = {R01 FD003937/FD/FDA HHS/United States ; R01FD003937//FDA-OPD/ ; //U.S. Food and Drug Administration/ ; }, mesh = {Humans ; *Memantine/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy ; Male ; Female ; Double-Blind Method ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Disease Progression ; Treatment Outcome ; Young Adult ; Excitatory Amino Acid Antagonists/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.<br><br>AIMS: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.<br><br>METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20&#x2009;mg twice daily) or placebo in a 2:1 ratio and completed 36&#x2009;weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.<br><br>RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83&#x2009;years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.<br><br>DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.}, }
@article {pmid39511939, year = {2025}, author = {Eisen, A and Vucic, S and Kiernan, MC}, title = {Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.}, journal = {Muscle &amp; nerve}, volume = {71}, number = {4}, pages = {499-511}, pmid = {39511939}, issn = {1097-4598}, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology/genetics ; Humans ; Animals ; Motor Neurons/pathology ; }, abstract = {Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years have witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. The evolution of an extensive corticomotoneuronal system appears restricted to the human species, with ALS representing a uniquely human disease. While some, very select non-human primates have limited corticomotoneuronal projections, these tend to be absent in all other animals. From a general perspective, the early clinical features of ALS may be considered to reflect failure of the corticomotoneuronal system. The characteristic loss of skilled motor dexterity involving the limbs, and speech impairment through progressive bulbar dysfunction specifically involve those motor units having the strongest corticomotoneuronal projections. A similar explanation likely underlies the unique "split phenotypes" that have now been well characterized in ALS. Large Betz cells and other pyramidal corticomotoneuronal projecting neurons, with their extensive dendritic arborization, are particularly vulnerable to the elements of the ALS exposome such as aging, environmental stress and lifestyle changes. Progressive failure of the proteosome impairs nucleocytoplasmic shuffling and induces toxic but soluble TDP-43 to aggregate in corticomotoneurons. Betz cell failure is further accentuated through dysfunction of its profuse dendritic arborizations. Clarification of system specific genomes and neural networks will likely promote the initiation of precision medicine approaches directed to support the key structure that underlies the neurological manifestations of ALS, the corticomotoneuronal system.}, }
@article {pmid39511821, year = {2025}, author = {Grady, A and Lorch, R and Giles, L and Lamont, H and Anderson, A and Pearson, N and Romiti, M and Lum, M and Stuart, A and Leigh, L and Yoong, SL}, title = {The impact of early childhood education and care-based interventions on child physical activity, anthropometrics, fundamental movement skills, cognitive functioning, and social-emotional wellbeing: A systematic review and meta-analysis.}, journal = {Obesity reviews : an official journal of the International Association for the Study of Obesity}, volume = {26}, number = {2}, pages = {e13852}, pmid = {39511821}, issn = {1467-789X}, support = {APP1170042//National Health and Medical Research Council/ ; Heart Foundation Postdoctoral Fellowship 102518//National Heart Foundation of Australia/ ; Heart Foundation Future Leader Fellowship 106654//National Heart Foundation of Australia/ ; }, mesh = {Humans ; *Cognition ; Child, Preschool ; *Exercise/psychology ; Child ; Infant ; Motor Skills/physiology ; Pediatric Obesity/psychology/prevention &amp; control ; Anthropometry ; Early Intervention, Educational ; }, abstract = {This review assessed the effectiveness of ECEC-based interventions to improve child physical activity, and intervention impact on child weight-based anthropometrics, fundamental movement skills (FMS), cognitive functioning, and social-emotional wellbeing. Adverse effects and costs were assessed. Finch et al's 2014 systematic review was updated. Electronic databases were searched 10 September 2014 to 27 October 2022. Included studies were randomized controlled trials of ECEC interventions targeting physical activity among children aged 0-6 years. The methodological quality of studies was assessed using Cochrane's Risk of Bias tool v2. Standardized mean differences (SMD) were calculated for each outcome with meta-analysis undertaken; otherwise, findings were described narratively. Fifty-three studies were included. ECEC-based interventions were found to significantly improve child physical activity (SMD 0.193, 95% confidence interval [CI] 0.09 to 0.3; p < 0.001) and FMS (SMD 0.544, 95% CI 0.1 to 0.98; p = 0.015), compared to control. Small positive, but non-significant, effects were found for weight-based anthropometrics, cognitive functioning, and social-emotional wellbeing. Few studies reported adverse effects (n = 10), and no studies reported formal economic analyses. While ECEC-based interventions can significantly improve child physical activity and FMS, further evidence of their impact on cognitive functioning, social-emotional wellbeing, and the cost-effectiveness of such interventions is required to inform policy and practice.}, }
@article {pmid39511709, year = {2024}, author = {Fontaine, M and Horowitz, K and Anoja, N and Genge, A and Salmon, K}, title = {How the prospect of a clinical trial impacts decision-making for predictive genetic testing in ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/21678421.2024.2423718}, pmid = {39511709}, issn = {2167-9223}, abstract = {Objective: Genetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing. Methods: This study used both quantitative and qualitative data analyses. Data were collected through an online questionnaire, followed by semi-structured interviews conducted with twelve (n = 12) individuals at-risk for either SOD1- or C9orf72-ALS who had predictive testing prior to study participation. Interview data were analyzed using reflexive thematic analysis. Results: Three overarching themes were conceptualized from the data: i) the psychosocial impact of fALS; ii) perspectives of at-risk individuals on research involvement; and iii) predictive genetic counseling and testing considerations. These results contribute perspectives of the lived experience to inform predictive genetic counseling and testing practices for individuals at-risk for fALS. Conclusion: Individuals at-risk for fALS view potential participation in a presymptomatic clinical trial as an actionable measure that may increase their desire for predictive genetic testing. Genetic counseling was identified as a critical component of the predictive testing process given the life-changing implications associated with a positive result. Increased access to predictive genetic counseling, and in a timely manner, is a significant need in the ALS population given potential access to gene-specific therapies in the presymptomatic stage.}, }
@article {pmid39511225, year = {2024}, author = {Silvestri, B and Mochi, M and Mawrie, D and de Turris, V and Colantoni, A and Borhy, B and Medici, M and Anderson, EN and Garone, MG and Zammerilla, CP and Simula, M and Ballarino, M and Pandey, UB and Rosa, A}, title = {HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9618}, pmid = {39511225}, issn = {2041-1723}, support = {CN00000041//Ministero dell&apos;Istruzione, dell&apos;Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; 2022BYB33L//Ministero dell&apos;Istruzione, dell&apos;Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; CN00000041//Ministero dell&apos;Istruzione, dell&apos;Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; RP123188EC9F2349//Sapienza Universit&#xe0; di Roma (Sapienza University of Rome)/ ; RM12117A5DE7A45B//Sapienza Universit&#xe0; di Roma (Sapienza University of Rome)/ ; LT0024/2022-L//Human Frontier Science Program (HFSP)/ ; }, mesh = {Humans ; *Neuromuscular Junction/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Apoptosis/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *RNA-Binding Protein FUS/metabolism/genetics ; *Disease Models, Animal ; *ELAV-Like Protein 4/metabolism/genetics ; Mutation ; Oxidative Stress ; Drosophila Proteins/metabolism/genetics ; Drosophila melanogaster/genetics ; Female ; Male ; Drosophila ; }, abstract = {Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the "dying-back" hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUS[P525L] mutation, while its knockdown rescues the FUS[P525L] phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.}, }
@article {pmid39510899, year = {2024}, author = {Kaul, M and Mukherjee, D and Weiner, HL and Cox, LM}, title = {Gut microbiota immune cross-talk in amyotrophic lateral sclerosis.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00469}, pmid = {39510899}, issn = {1878-7479}, support = {P51 OD011133/OD/NIH HHS/United States ; R01 NS115951/NS/NINDS NIH HHS/United States ; R21 NS126866/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/immunology/microbiology ; *Gastrointestinal Microbiome/immunology/physiology ; Humans ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.}, }
@article {pmid39510439, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {BRD7 regulates cellular senescence and apoptosis in ALS by modulating p21 expression and p53 mitochondrial translocation respectively.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {51-62}, doi = {10.1016/j.neuroscience.2024.11.004}, pmid = {39510439}, issn = {1873-7544}, mesh = {*Cellular Senescence/physiology ; *Apoptosis/physiology ; *Tumor Suppressor Protein p53/metabolism/genetics ; Humans ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Mitochondria/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Motor Neurons/metabolism/pathology ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Male ; Female ; Middle Aged ; Aged ; Bromodomain Containing Proteins ; }, abstract = {Cellular senescence is involved in the progression of neurodegenerative diseases. Motor neurons exhibit senescence-like alterations in ALS. BRD7, identified as a regulatory factor associated with cellular senescence, its function in ALS remains unclear. This study aims to investigate the potential role and mechanisms of BRD7 in ALS. We analyzed RNA levels using qRT-PCR, protein levels through immunofluorescence and western blot, and apoptosis via TUNEL staining. Cell transfection was conducted for in vitro experiments. The level of β-galactosidase was measured by β-galactosidase activity detection kit. ALS motor neurons exhibited senescence-like alterations, characterized by increased activity of p53, p21, and β-galactosidase, as well as reduced lamin B1 staining. Additionally, the expression of BRD7 was upregulated and induced cellular senescence and apoptosis. Downregulation of BRD7 alleviates the cellular senescence by inhibiting p21 rather than p53. Knockdown of BRD7 inhibited p53 mitochondrial translocation, leading to reduced apoptosis. Our results suggest that BRD7 plays an important role in the survival of ALS motor neurons. BRD7 knockdown can reduce cellular senescence and apoptosis by inhibiting p21 and p53 mitochondrial translocation.}, }
@article {pmid39509425, year = {2024}, author = {Deng, YC and Liu, JW and Ting, HC and Kuo, TC and Chiang, CH and Lin, EY and Harn, HJ and Lin, SZ and Chang, CY and Chiou, TW}, title = {n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0311573}, pmid = {39509425}, issn = {1932-6203}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; Humans ; *Motor Neurons/drug effects/metabolism/pathology ; *Calcium/metabolism ; *Homeostasis/drug effects ; *Superoxide Dismutase-1/genetics/metabolism ; *Phthalic Anhydrides/pharmacology ; Cell Differentiation/drug effects ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.}, }
@article {pmid39508675, year = {2024}, author = {}, title = {DSP-01 conversion from PLS to ALS: a Dutch cohort study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {262-279}, doi = {10.1080/21678421.2024.2403307}, pmid = {39508675}, issn = {2167-9223}, }
@article {pmid39508663, year = {2024}, author = {}, title = {Platform Communications: Abstract Book 35th International Symposium on ALS/MND (Complete printable file).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {sup1}, pages = {1-92}, doi = {10.1080/21678421.2024.2403293}, pmid = {39508663}, issn = {2167-9223}, }
@article {pmid39508354, year = {2025}, author = {Bhatele, P and Pai, AR}, title = {Wine Glass Sign in Bulbar Onset Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {3}, pages = {558-560}, doi = {10.1002/ana.27131}, pmid = {39508354}, issn = {1531-8249}, }
@article {pmid39506867, year = {2024}, author = {Ishihara, T and Koyama, A and Atsuta, N and Tada, M and Toyoda, S and Kashiwagi, K and Hirokawa, S and Hatano, Y and Yokoseki, A and Nakamura, R and Tohnai, G and Izumi, Y and Kaji, R and Morita, M and Tamura, A and Kano, O and Aoki, M and Kuwabara, S and Kakita, A and Sobue, G and Onodera, O}, title = {SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {263}, pmid = {39506867}, issn = {1755-8794}, support = {17K09750//Scientific Research from the Japan Society for the Promotion of Science/ ; 21K07272//Scientific Research from the Japan Society for the Promotion of Science/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 17ek0109284h0001//Japan Agency for Medical Research and Development/ ; 26117006//Scientific Research on Innovative Areas from MEXT/ ; JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; }, mesh = {Humans ; *Survival of Motor Neuron 2 Protein/genetics ; Male ; Japan/epidemiology ; Middle Aged ; Female ; Prognosis ; *Motor Neuron Disease/genetics ; *Gene Dosage ; Incidence ; Amyotrophic Lateral Sclerosis/genetics ; Aged ; Adult ; Case-Control Studies ; DNA Copy Number Variations ; }, abstract = {BACKGROUND: The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND.<br><br>METHODS: We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction.<br><br>RESULTS: The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR)&#x2009;=&#x2009;1.37, 95% confidence interval (CI)&#x2009;=&#x2009;1.04-1.82, p&#x2009;<&#x2009;0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p&#x2009;<&#x2009;0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio&#x2009;=&#x2009;0.84, 95% CI&#x2009;=&#x2009;0.72-0.98, p&#x2009;<&#x2009;0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR&#x2009;=&#x2009;2.73, 95% CI&#x2009;=&#x2009;1.06-6.98, p&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.}, }
@article {pmid39506789, year = {2024}, author = {Niccolai, E and Di Gloria, L and Trolese, MC and Fabbrizio, P and Baldi, S and Nannini, G and Margotta, C and Nastasi, C and Ramazzotti, M and Bartolucci, G and Bendotti, C and Nardo, G and Amedei, A}, title = {Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1[G93A] mice.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {174}, pmid = {39506789}, issn = {2051-5960}, support = {SG-2019-12371083//Italian Ministry of Health/ ; PE0000006//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Animals ; *Gastrointestinal Microbiome/physiology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/microbiology/pathology ; Mice ; *Mice, Transgenic ; *Lipid Metabolism/genetics ; Inflammation/metabolism/pathology ; Mice, Inbred C57BL ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1[G93A] mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.}, }
@article {pmid39508106, year = {2024}, author = {Gao, XF and Chen, AQ and Tang, HY and Kong, XQ and Zhang, H and Wang, ZM and Lu, W and Wang, LG and Wang, F and Zhou, WY and Gu, Y and Zuo, GF and Ge, Z and Zhang, JJ and Chen, SL}, title = {m[6]A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {44}, number = {12}, pages = {2543-2559}, pmid = {39508106}, issn = {1524-4636}, mesh = {Animals ; *Neointima ; *Muscle, Smooth, Vascular/metabolism/pathology ; *Hyperplasia ; *Phenotype ; *STAT3 Transcription Factor/metabolism/genetics ; *Myocytes, Smooth Muscle/metabolism/pathology ; *Signal Transduction ; *Disease Models, Animal ; *Proto-Oncogene Mas ; Male ; *Profilins/metabolism/genetics ; *Mice, Knockout ; *Adenosine/metabolism/analogs &amp; derivatives ; Humans ; Mice ; Mice, Inbred C57BL ; Rats ; Cells, Cultured ; Rats, Sprague-Dawley ; Phosphorylation ; Coronary Restenosis/metabolism/pathology/genetics/etiology ; Carotid Stenosis/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {BACKGROUND: In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia.<br><br>METHODS: Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia.<br><br>RESULTS: Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1[SMC-IKO] (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1[SMC-IKO] mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N[6]-methyladenosine methyltransferase) and YTHDF3 (YTH N6-methyladenosine RNA binding protein F3; N[6]-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N[6]-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src (SRC proto-oncogene, nonreceptor tyrosine kinase), promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), a typical transcription factor known to induce VSMC phenotype switching.<br><br>CONCLUSIONS: This study unveils the significance of PFN1 N[6]-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.}, }
@article {pmid39505881, year = {2024}, author = {Li, J and Jaiswal, MK and Chien, JF and Kozlenkov, A and Jung, J and Zhou, P and Gardashli, M and Pregent, LJ and Engelberg-Cook, E and Dickson, DW and Belzil, VV and Mukamel, EA and Dracheva, S}, title = {Author Correction: Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9588}, doi = {10.1038/s41467-024-53972-1}, pmid = {39505881}, issn = {2041-1723}, }
@article {pmid39505319, year = {2024}, author = {Lee, J and Kim, A and Choi, SJ and Cho, E and Seo, J and Oh, SI and Jung, J and Kim, JS and Sung, JJ and Abrahams, S and Hong, YH}, title = {Erratum: Development and Validation of the Korean Version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-K).}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {6}, pages = {637}, doi = {10.3988/jcn.2022.0403e}, pmid = {39505319}, issn = {1738-6586}, abstract = {This corrects the article on p. 454 in vol. 19, PMID: 37488957.}, }
@article {pmid39505137, year = {2024}, author = {Abbasi, H and Jourabchi-Ghadim, N and Asgarzade, A and Mirshekari, M and Ebrahimi-Mameghani, M}, title = {Unveiling the veil of adipokines: A meta-analysis and systematic review in amyotrophic lateral sclerosis.}, journal = {Neuroscience}, volume = {563}, number = {}, pages = {1-9}, doi = {10.1016/j.neuroscience.2024.11.003}, pmid = {39505137}, issn = {1873-7544}, mesh = {*Amyotrophic Lateral Sclerosis/blood/metabolism ; Humans ; *Adipokines/blood ; Ghrelin/blood ; Leptin/blood ; Adiponectin/blood ; Disease Progression ; }, abstract = {BACKGROUND: Adipokines are proposed to be associated with ALS progression through assorted pathways. Therefore, The present meta-analysis explored the link between various adipokines and ALS progression.<br><br>METHOD: International database like PubMed, Scopus, and Web of Science databases were searched to achieve eligible papers published before December 2023. The following PICO structure was utilized: Population (patients with ALS); Intervention (serum concentrations of ghrelin, leptin, and adiponectin), Comparison (with or without controls), and Outcome (ALS progression). the risk of bias of selected papers was assessed through the Newcastle-Ottawa Scale (NOS) tool.<br><br>RESULTS: 11 out of 240 papers were selected for this study which were published between 2010 and 2024. Lower serum leptin concentrations were detected in the ALS compared to control groups (WMD: -0.91, 95% CI:-1.77, -0.05). Serum concentrations of adiponectin were higher in ALS compared to control groups (WMD: 0.41, 95% CI:-0.7, 0.89). Ultimately, The serum concentrations of ghrelin in the ALS groups were lower than control groups (WMD: -1.21, 95% CI: -2.95, 0.53).<br><br>CONCLUSION: Our findings revealed that serum concentrations of ghrelin and leptin were higher in ALS patients compared to control, unlike adiponectin.}, }
@article {pmid39503426, year = {2025}, author = {Shimizu, M and Okuno, T}, title = {Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2589-2590}, pmid = {39503426}, issn = {1673-5374}, }
@article {pmid39503423, year = {2025}, author = {Alfahel, L and Rajkovic, A and Israelson, A}, title = {Translational challenges in amyotrophic lateral sclerosis therapy with macrophage migration inhibitory factor.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2583-2584}, pmid = {39503423}, issn = {1673-5374}, }
@article {pmid39503319, year = {2024}, author = {Bedlack, R and Li, X and Evangelista, BA and Panzetta, ME and Kwan, J and Gittings, LM and Sattler, R}, title = {The Scientific and Therapeutic Rationale for Off-Label Treatments in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {97}, number = {1}, pages = {15-27}, pmid = {39503319}, issn = {1531-8249}, support = {//ALS Association/ ; }, abstract = {There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off-label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024.}, }
@article {pmid39503018, year = {2024}, author = {Rennie, O and Sharma, M and Helwa, N}, title = {Hepatobiliary anastomotic leakage: a narrative review of definitions, grading systems, and consequences of leaks.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {70}, pmid = {39503018}, issn = {2415-1289}, abstract = {BACKGROUND AND OBJECTIVE: Hepatobiliary diseases are a longstanding and significant medical challenge which, despite advances in surgical techniques, still carry risks for postoperative complications such as anastomotic leaks (ALs), which can include both postoperative pancreatic fistula (POPF) and bile leaks (BL). These complications incur significant human and economic costs on all those involved, including the patient, healthcare providers, and hospital systems. The aim of this study was to construct a narrative review of literature surrounding definitions and grading systems for ALs in the context of hepato-pancreato-biliary (HPB) procedures, and consequences of POPF and BL.<br><br>METHODS: A literature review was conducted by examining databases including PubMed, Web of Science, OVID Embase, Google Scholar, and Cochrane library databases. Searches were performed with the following search criteria: (((((((anastomosis) OR (anastomotic leak*)) OR (postoperative pancreatic fistula)) OR (bile leak*)) OR (pancreaticoduodenectomy)) OR (whipple)) AND ((hepatobiliary) OR (hepato-pancreato-biliary)) AND ((definition) OR (grading system*) OR (consequences) OR (outcomes) OR (risk factor*) OR (morbidity) OR (mortality))). Publications that were retrieved underwent further assessment to ensure other relevant publications were identified and included.<br><br>KEY CONTENT AND FINDINGS: A universally accepted definition and grading system for POPF and BL continues to be lacking, leading to variability in reported incidence in the literature. Various groups have worked to publish guidelines for defining and grading POPF and BL, with the International Study Group in Pancreatic Surgery (ISGPS) and International Study Group for Liver Surgery (ISGLS) definitions the current most recommended definitions for POPF and BL, respectively. The burden of AL on patients, healthcare providers, and hospitals is well documented in evidence from leak consequences, such as increased morbidity and mortality, higher reoperation rates, and increased readmission rates, among others.<br><br>CONCLUSIONS: AL remains a significant challenge in HPB surgery, despite medical advancements. Understanding the progress made in defining and grading leaks, as well as the range of negative outcomes that arise from AL, is crucial in improving patient care, reduce surgical mortality, and drive further advancements in earlier detection and treatment of AL.}, }
@article {pmid39502740, year = {2024}, author = {Nishiyama, A and Niihori, T and Suzuki, N and Izumi, R and Akiyama, T and Kato, M and Funayama, R and Nakayama, K and Warita, H and Aoki, Y and Aoki, M}, title = {Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants.}, journal = {Neurology. Genetics}, volume = {10}, number = {6}, pages = {e200196}, pmid = {39502740}, issn = {2376-7839}, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated.<br><br>METHODS: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes.<br><br>RESULTS: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 &#xb1; 12.2 (mean &#xb1; SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 &#xb1; 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression.<br><br>DISCUSSION: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.}, }
@article {pmid39501538, year = {2024}, author = {Bampton, A and McHutchison, C and Talbot, K and Benatar, M and Thompson, AG and Turner, MR}, title = {The Basis of Cognitive and Behavioral Dysfunction in Amyotrophic Lateral Sclerosis.}, journal = {Brain and behavior}, volume = {14}, number = {11}, pages = {e70115}, pmid = {39501538}, issn = {2162-3279}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Jan20/952-795//Motor Neurone Disease Association Lady Edith Wolfson Clinician Scientist Fellowship/ ; //Foulkes Foundation/ ; //National Institutes of Health (NIH)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cognitive Dysfunction/etiology/physiopathology ; }, abstract = {OBJECTIVE: To summarize and evaluate evidence pertaining to the clinical, genetic, histopathological, and neuroimaging correlates of cognitive and behavioral dysfunction in amyotrophic lateral sclerosis (ALS).<br><br>METHODOLOGY: We comprehensively reviewed the literature on cognitive and behavioral manifestations of ALS, narrating findings from both cross-sectional and longitudinal studies. We discussed knowledge gaps in the evidence base and key limitations affecting studies to date, before formulating a framework for future research paradigms aimed at investigating clinicopathological correlates of neuropsychological dysfunction in ALS.<br><br>RESULTS: Studies have demonstrated clinical associations with cognitive dysfunction in ALS e.g., bulbar-onset of symptoms, pathological associations (extramotor TDP-43 deposition), and imaging associations (frontotemporal involvement). The most common behavioral deficit, apathy, is highly associated with verbal fluency, but longitudinal studies assessing behavioral dysfunction in ALS are comparatively lacking.<br><br>CONCLUSION: Longitudinal studies have been helpful in identifying several potential correlates of cognitive and behavioral dysfunction but have frequently been confounded by selection bias and inappropriate testing platforms. This review provides a framework for more robust assessment of clinicopathological associations of neuropsychological abnormalities in ALS in the future, advocating for greater utilization of pre-symptomatic C9orf72 repeat expansion-carrying cohorts.}, }
@article {pmid39501102, year = {2025}, author = {Howard, J and Chaouch, A and Douglas, AGL and MacLeod, R and Roggenbuck, J and McNeill, A}, title = {Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members.}, journal = {European journal of human genetics : EJHG}, volume = {33}, number = {1}, pages = {7-13}, pmid = {39501102}, issn = {1476-5438}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Family ; Genetic Counseling ; *Genetic Testing/methods/standards ; *Motor Neuron Disease/genetics/diagnosis ; }, abstract = {Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. Increasing numbers of people with MND are requesting genetic testing, and indeed receiving a genetic diagnosis. Consequently, requests for genetic counselling and predictive testing (i.e. of unaffected family members) are similarly expected to rise, alongside pre-symptomatic clinical trials. Despite this, there is no evidence-based guideline for predictive genetic testing in MND. This paper provides an overview of the genomic basis of MND, focusing specifically on the most common monogenic causes of MND. It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. Additionally, there is limited research on the psychosocial impact of predictive genetic testing for MND, with studies suggesting potential difficulty in adjusting to the news, in part due to a lack of support and follow-up. This underscores a case for evidence-based, disease-specific guidance for predictive testing in MND.}, }
@article {pmid39500920, year = {2024}, author = {Yu, M and Xu, J and Dutta, R and Trapp, B and Pieper, AA and Cheng, F}, title = {Network medicine informed multiomics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis.}, journal = {NPJ systems biology and applications}, volume = {10}, number = {1}, pages = {128}, pmid = {39500920}, issn = {2056-7189}, support = {R21 AG083003/AG/NIA NIH HHS/United States ; R01 AG082118/AG/NIA NIH HHS/United States ; R56 AG074001/AG/NIA NIH HHS/United States ; RF1 AG082211/AG/NIA NIH HHS/United States ; R01 AG084250/AG/NIA NIH HHS/United States ; RF1 NS133812/NS/NINDS NIH HHS/United States ; RF1NS133812//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; U01 AG073323/AG/NIA NIH HHS/United States ; U01AG073323//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG082118//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG066707//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG066707/AG/NIA NIH HHS/United States ; R01AG076448//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21AG083003//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG076448/AG/NIA NIH HHS/United States ; RF1AG082211//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG084250//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; Humans ; *Quantitative Trait Loci/genetics ; Genome-Wide Association Study/methods ; Drug Repositioning/methods ; Genomics/methods ; Protein Interaction Maps/genetics/drug effects ; Multiomics ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.}, }
@article {pmid39500483, year = {2024}, author = {Piotrkiewicz, M}, title = {Possible changes in motor neuron discharge characteristics in presymptomatic amyotrophic lateral sclerosis.}, journal = {The Journal of physiology}, volume = {602}, number = {24}, pages = {6631-6635}, doi = {10.1113/JP287788}, pmid = {39500483}, issn = {1469-7793}, }
@article {pmid39496878, year = {2025}, author = {Yang, T and Wei, Q and Pang, D and Cheng, Y and Huang, J and Lin, J and Xiao, Y and Jiang, Q and Wang, S and Li, C and Shang, H}, title = {Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis.}, journal = {Molecular neurobiology}, volume = {62}, number = {4}, pages = {4854-4865}, pmid = {39496878}, issn = {1559-1182}, support = {82371430//National Natural Science Foundation of China/ ; 2022ZDZX0023//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Ataxin-3/genetics ; Female ; *Ataxin-2/genetics ; Male ; *Ataxin-1/genetics ; Middle Aged ; *Genetic Predisposition to Disease ; Mutation/genetics ; Aged ; DNA Mutational Analysis ; Cohort Studies ; Repressor Proteins ; }, abstract = {Emerging evidence suggests potential disease modifying roles of ATXN1, ATXN2, and ATXN3 in amyotrophic lateral sclerosis (ALS). We aimed to provide a comprehensive variants profile of the ATXN1, ATXN2, and ATXN3 genes and examine the association of these variants with the risk and clinical characteristics of ALS. We screened and analyzed the rare variants in a cohort of 2220 ALS patients from Southwest China, using controls from the Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP). The over-representation of rare variants and their association with disease risk in ALS patients were assessed using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis was employed to explore the relationship between the distribution of variants and survival. A total of 62 eligible rare missense variants were identified, comprising 32 from ATXN1, 21 from ATXN2, and 9 from ATXN3. Allelic association testing revealed a significant enrichment of the ATXN1 (c.2122C > G, p.Leu708Val) variant and the ATXN2 (c.3778C > G, p.Pro1260Ala) variant in ALS. Gene burden analysis indicated that variants in the ATXN1 and ATXN3 genes had a higher burden in ALS. Substantial heterogeneity in survival time was observed among patients carrying different variants within the same gene. However, there were no significant differences in survival between ALS patients grouped by N-terminal or C-terminal distribution. Our results provided a genetic variation profile of ATXN1, ATXN2, and ATXN3 in ALS patients, along with the clinical characteristics of individuals carrying these variations. This information might offer valuable insights for the ongoing ALS disease-modifying treatments.}, }
@article {pmid39496465, year = {2024}, author = {Baker, MR and Maitland, S}, title = {Response to: 'Cortical Inexcitability in ALS: Correlating a Clinical Phenotype'.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-334587}, pmid = {39496465}, issn = {1468-330X}, }
@article {pmid39496035, year = {2024}, author = {Xu, W and Zhao, X and Wang, J and Guo, Y and Ren, Z and Cai, L and Wu, S and Zhou, M}, title = {Different intensities of physical activity for amyotrophic lateral sclerosis and Parkinson disease: A Mendelian randomization study and meta-analysis.}, journal = {Medicine}, volume = {103}, number = {44}, pages = {e40141}, pmid = {39496035}, issn = {1536-5964}, support = {ZYYLJRC201911//the Anhui Province Traditional Chinese Medicine Leading Talents Construction Project/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Amyotrophic Lateral Sclerosis/genetics ; *Parkinson Disease/genetics/epidemiology ; *Exercise ; Genome-Wide Association Study ; }, abstract = {BACKGROUND: The causal relationships between amyotrophic lateral sclerosis (ALS), Parkinson disease and different intensities of physical activity (PA) are still inconclusive. To evaluate the causal impact of PA on ALS and Parkinson disease (PD), this study integrates evidence from Mendelian randomization (MR) using a meta-analysis approach.<br><br>METHODS: MR analyses on genetically predicted levels of PA (compose of self-reported moderate-to-vigorous physical activity [MVPA], self-reported vigorous physical activity [VPA], and strenuous sports or other exercises [SSOE]) regarding ALS and PD published up to July 27, 2024, were obtained from PubMed, Scopus, Web of Science, and Embase. De novo MR studies were analyzed utilizing publicly accessible datasets from genome-wide association studies and then meta-analyses were performed to pool the results.<br><br>RESULTS: Meta-analyses of results of 12 de novo MR studies analyses and 2 published MR studies indicated that genetic predicted levels of MVPA (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.08-1.38), VPA (OR: 1.32, 95% CI: 1.08-1.60), and SSOE (OR: 1.35, 95% CI: 1.07-1.70) were related to a raised risk of ALS, but not causally with PD.<br><br>CONCLUSION: Our findings showed no causal relationships between MVPA, VPA, SSOE, and PD, while MVPA, VPA, and SSOE were associated with increased ALS risk, highlighting the need for targeted PA recommendations for disease management.}, }
@article {pmid39495912, year = {2024}, author = {Wheeler, HB and Madrigal, AA and Chaim, IA}, title = {Mapping the future of oxidative RNA damage in neurodegeneration: Rethinking the status quo with new tools.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {46}, pages = {e2317860121}, pmid = {39495912}, issn = {1091-6490}, support = {R00 NS121511/NS/NINDS NIH HHS/United States ; 4R00NS121511-03//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *RNA/metabolism/genetics ; *Oxidation-Reduction ; Oxidative Stress ; RNA-Binding Proteins/metabolism/genetics ; Proteomics/methods ; Animals ; }, abstract = {Over two decades ago, increased levels of RNA oxidation were reported in postmortem patients with ALS, Alzheimer's, Parkinson's, and other neurodegenerative diseases. Interestingly, not all cell types and transcripts were equally oxidized. Furthermore, it was shown that RNA oxidation is an early phenomenon, altogether indicating that oxidative RNA damage could be a driver, and not a consequence, of disease. Despite all these exciting observations, the field appears to have stagnated since then. We argue that this is a consequence of the shortcomings of technologies to model these diseases, limiting our understanding of which transcripts are being oxidized, which RNA-binding proteins are interacting with these RNAs, what their implications are in RNA processing, and as a result, what their potential role is in disease onset and progression. Here, we discuss the limits of previous technologies and propose ways by which advancements in iPSC-derived disease modeling, proteomics, and sequencing technologies can be combined and leveraged to answer new and decades-old questions.}, }
@article {pmid39494889, year = {2024}, author = {Ito, SI and Tanaka, Y}, title = {Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/67385}, pmid = {39494889}, issn = {1940-087X}, mesh = {*Extracellular Vesicles/metabolism ; Humans ; *Microtubule-Associated Proteins/metabolism/genetics ; Autophagy/physiology ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {(Macro)autophagy represents a fundamental cellular degradation pathway. In this process, double-membraned vesicles known as autophagosomes engulf cytoplasmic contents, subsequently fusing with lysosomes for degradation. Beyond the canonical role, autophagy-related genes also modulate a secretory pathway involving the release of inflammatory molecules, tissue repair factors, and extracellular vesicles (EVs). Notably, the process of disseminating pathological proteins between cells, particularly in neurodegenerative diseases affecting the brain and spinal cord, underscores the significance of understanding this phenomenon. Recent research suggests that the transactive response DNA-binding protein 43 kDa (TDP-43), a key player in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, is released in an autophagy-dependent manner via EVs enriched with the autophagosome marker microtubule-associated proteins 1A/1B light chain 3B-II (LC3-II), especially when autophagosome-lysosome fusion is inhibited. To elucidate the mechanism underlying the formation and release of LC3-II-positive EVs, it is imperative to establish an accessible and reproducible method for evaluating both intracellular and extracellular LC3-II-positive vesicles. This study presents a detailed protocol for assessing LC3-II levels via immunoblotting in cellular and EV fractions obtained through differential centrifugation. Bafilomycin A1 (Baf), an inhibitor of autophagosome-lysosome fusion, serves as a positive control to enhance the levels of intracellular and extracellular LC3-II-positive vesicles. Tumor susceptibility gene 101 (TSG101) is used as a marker for multivesicular bodies. Applying this protocol, it is demonstrated that siRNA-mediated knockdown of syntaxin-6 (STX6), a genetic risk factor for sporadic Creutzfeldt-Jakob disease, augments LC3-II levels in the EV fraction of cells treated with Baf while showing no significant effect on TSG101 levels. These findings suggest that STX6 may negatively regulate the extracellular release of LC3-II via EVs, particularly under conditions where autophagosome-lysosome fusion is impaired. Combined with established methods for evaluating autophagy, this protocol provides valuable insights into the role of specific molecules in the formation and release of LC3-II-positive EVs.}, }
@article {pmid39494653, year = {2025}, author = {Springer, SA}, title = {Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.}, journal = {Addiction (Abingdon, England)}, volume = {120}, number = {1}, pages = {21-22}, pmid = {39494653}, issn = {1360-0443}, support = {DP1 DA056106/DA/NIDA NIH HHS/United States ; NIDA DP1DA056106/DA/NIDA NIH HHS/United States ; }, abstract = {Provision of buprenorphine treatment for opioid use disorder is often stymied by clinicians’ concerns for precipitated opioid withdrawal. Gregory et al’s systematic review identified a low level of precipitated withdrawal with buprenorphine induction even among persons who reported fentanyl use. Evidence, not fear should guide treatment.}, }
@article {pmid39494632, year = {2025}, author = {Uzunçakmak-Uyanık, H and Tan, E and Temuçin, &#xc7;M and Yıldız, FG}, title = {Lack of habituation in somatosensory cortex but not in visual cortex of ALS patients.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {93-102}, doi = {10.1080/21678421.2024.2421747}, pmid = {39494632}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Visual Cortex/physiopathology ; Aged ; *Habituation, Psychophysiologic/physiology ; *Somatosensory Cortex/physiopathology ; *Evoked Potentials, Somatosensory/physiology ; *Evoked Potentials, Visual/physiology ; Adult ; Electroencephalography/methods ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease with extra-motor components. In ALS, there is also hyperexcitability of extra-motor areas. Habituation is defined as ''a response decrement" caused by repeated stimulations. Studies on evoked potential habituation can be conducted to detect cortical excitability. This study aimed to explore lack of habituation in non-motor cortical structures in ALS.<br><br>METHODS: Twenty-one ALS patients and 14 controls were enrolled. Recordings were obtained in 3 and 10 consecutive blocks (each containing 100 responses) during right median somatosensory evoked potential (SEP) and bilateral visual evoked potential (VEP), respectively. "Habituation" and "lack of habituation" were defined as the amount of increase or decrease in the average N20 or N75-P100 amplitude of the last blocks compared to the first blocks, respectively. Comparative analyses were performed between patient and control groups, as well as the first and last block within groups.<br><br>RESULTS: Paired sample t-test showed that in control group N20 peak amplitude of last blocks were significantly lower than first block values (p&#x2009;=&#x2009;0.025) that indicate the physiological habituation as expected. On the other hand, there was not such a difference in ALS group (p&#x2009;=&#x2009;0.239) which indicated lack of habituation.<br><br>CONCLUSIONS: Our study results suggest somatosensory hyperexcitability in line with cortical reorganization in ALS patients.}, }
@article {pmid39494512, year = {2024}, author = {Donohoe, MN and Upadhyay, A and Pratt, DA}, title = {Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants.}, journal = {Journal of the American Chemical Society}, volume = {146}, number = {45}, pages = {31307-31320}, doi = {10.1021/jacs.4c12713}, pmid = {39494512}, issn = {1520-5126}, mesh = {*Thiosemicarbazones/chemistry/pharmacology ; Ligands ; *Platinum/chemistry/pharmacology ; *Coordination Complexes/chemistry/pharmacology/chemical synthesis ; Humans ; Antioxidants/chemistry/pharmacology ; Lipid Peroxidation/drug effects ; Molecular Structure ; Copper/chemistry ; Neuroprotective Agents/chemistry/pharmacology/chemical synthesis ; }, abstract = {CuATSM, a copper(II) complex of a bis(thiosemicarbazone) of diacetyl, prevents oxidative cell death and acts as a neuroprotectant in vivo, prompting its evaluation to treat amyotrophic lateral sclerosis and other neurodegenerative conditions in the clinic. We recently demonstrated that CuATSM functions as a potent radical-trapping antioxidant (RTA), inhibiting lipid peroxidation and associated ferroptotic cell death by a noncanonical mechanism based on radical addition to the ligand backbone. Herein we report our investigations of the generality of this reactivity, which include studies of corresponding complexes of various other metals, including Co, Ru, Ni, Pd, Pt, and Au. Inhibited autoxidations of styrene and dioxane reveal that most of these complexes exhibit RTA activity, consistent with ligand-based reactivity, but the identity of the metal atom nevertheless plays a role. In particular, analyses of the electronic structures of the complexes of metals within the same group (i.e., the group 10 metals Ni, Pd and Pt) highlight how the metal atom can modulate the ligand-based reactivity by enabling spin delocalization to the other thiosemicarbazone moiety. The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu.}, }
@article {pmid39494508, year = {2024}, author = {Mariani, D and Setti, A and Castagnetti, F and Vitiello, E and Stufera Mecarelli, L and Di Timoteo, G and Giuliani, A and D'Angelo, A and Santini, T and Perego, E and Zappone, S and Liessi, N and Armirotti, A and Vicidomini, G and Bozzoni, I}, title = {ALS-associated FUS mutation reshapes the RNA and protein composition of stress granules.}, journal = {Nucleic acids research}, volume = {52}, number = {21}, pages = {13269-13289}, pmid = {39494508}, issn = {1362-4962}, support = {ERC-2019-SyG 855923-ASTRA//ERC/ ; IG 2019 Id. 23053//Associazione Italiana per la Ricerca sul Cancro/ ; CN00000041//NextGenerationEU/ ; //Istituto Italiano di Tecnologia/ ; }, mesh = {*RNA-Binding Protein FUS/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Mutation ; *Stress Granules/metabolism/genetics ; Cell Line, Tumor ; Transcriptome ; RNA/metabolism/genetics ; RNA, Messenger/metabolism/genetics ; RNA-Binding Proteins/metabolism/genetics ; Cytoplasmic Granules/metabolism/genetics ; }, abstract = {Stress granules (SG) are part of a cellular protection mechanism where untranslated messenger RNAs and RNA-binding proteins are stored upon conditions of cellular stress. Compositional variations due to qualitative or quantitative protein changes can disrupt their functionality and alter their structure. This is the case of different forms of amyotrophic lateral sclerosis (ALS) where a causative link has been proposed between the cytoplasmic de-localization of mutant proteins, such as FUS (Fused in Sarcoma), and the formation of cytotoxic inclusions. Here, we describe the SG transcriptome in neuroblastoma cells and define several features for RNA recruitment in these condensates. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of mutant FUS, switching to a more unstructured, AU-rich SG transcriptome. Moreover, we show that mutant FUS, together with its protein interactors and their target RNAs, are responsible for the reshaping of the mutant SG transcriptome with alterations that can be linked to neurodegeneration. Our data describe the molecular differences between physiological and pathological SG in ALS-FUS conditions, showing how FUS mutations impact the RNA and protein composition of these condensates.}, }
@article {pmid39494098, year = {2024}, author = {Xu, AX and Zhao, ZF and Zhu, L and Zhang, YH and Li, Y and Wei, YF and Zhang, BY and Jiang, B and Gao, TZ and Li, MS and Liu, JY}, title = {Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment.}, journal = {World journal of gastroenterology}, volume = {30}, number = {40}, pages = {4380-4385}, pmid = {39494098}, issn = {2219-2840}, mesh = {Humans ; Drugs, Chinese Herbal/therapeutic use ; *Liver Neoplasms/therapy/pathology/mortality ; *Medicine, Chinese Traditional/methods ; Neoplasm Staging ; Quality of Life ; Treatment Outcome ; }, abstract = {Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.}, }
@article {pmid39493687, year = {2024}, author = {Kato, N and Hashida, G and Kobayashi, M and Sahara, W}, title = {Characteristics and factors associated with independence in the activities of daily living of patients with amyotrophic lateral sclerosis at diagnosis.}, journal = {Journal of physical therapy science}, volume = {36}, number = {11}, pages = {692-698}, pmid = {39493687}, issn = {0915-5287}, abstract = {[Purpose] To investigate the characteristics and factors associated with independence in the activities of daily living in patients with amyotrophic lateral sclerosis at diagnosis based on clinical phenotypes. [Participants and Methods] Fifty-seven participants diagnosed with amyotrophic lateral sclerosis were assessed using the Barthel Index. Participants were classified into three clinical phenotypes (bulbar-onset, upper limb-onset, and lower limb-onset), and the total and subitem scores were compared. To statistically examine factors associated with independence in the activities of daily living, the participants were divided into two groups: Barthel Index of 100 and ≤95. [Results] The total, bulbar-onset, upper limb-onset, and lower limb-onset Barthel Index scores were 87.9 ± 17.7, 96.7 ± 5.9, 92.5 ± 11.9, and 70.0 ± 22.2, respectively. The Total Barthel Index and lower limb-related activities of daily living scores were significantly lower in the lower limb-onset group, and knee extension muscle strength was identified as a factor associated with independence, with a cutoff value of 32.0%. [Conclusion] Patients with lower limb onset had more impairments in lower limb-related activities of daily living than those with other clinical phenotypes. To maintain independence in patients with amyotrophic lateral sclerosis at diagnosis, it is necessary to improve knee extension muscle strength through exercise and perform environment adjustments using the cutoff values as indicators.}, }
@article {pmid39492846, year = {2024}, author = {Matera, AG and Steiner, RE and Mills, CA and McMichael, BD and Herring, LE and Garcia, EL}, title = {Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.}, journal = {Frontiers in RNA research}, volume = {2}, number = {}, pages = {}, pmid = {39492846}, issn = {2813-7116}, support = {P30 CA016086/CA/NCI NIH HHS/United States ; R35 GM136435/GM/NIGMS NIH HHS/United States ; }, abstract = {INTRODUCTION: Molecular chaperones and co-chaperones are highly conserved cellular components that perform a variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an assembly chaperone and serves as a paradigm for studying how specific RNAs are identified and paired with their client substrate proteins to form RNPs. SMN is the eponymous component of a large complex, required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs), that localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN protein forms the oligomeric core of this complex, and missense mutations in the human SMN1 gene are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known. However, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood.<br><br>METHODS: Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. We carried out affinity purification mass spectrometry (AP-MS) of Drosophila SMN complexes using fly lines exclusively expressing either wildtype or SMA-causing missense alleles.<br><br>RESULTS: Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially associated with SMA-causing alleles of SMN.<br><br>DISCUSSION: Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.}, }
@article {pmid39492487, year = {2023}, author = {Xu, L and Ma, Y and Ji, Y and Ma, Y and Wang, Y and Zhao, X and Ge, S}, title = {Obesity exacerbates postoperative cognitive dysfunction by activating the PARP1/NAD[+]/SIRT1 axis through oxidative stress.}, journal = {Experimental gerontology}, volume = {}, number = {}, pages = {112320}, doi = {10.1016/j.exger.2023.112320}, pmid = {39492487}, issn = {1873-6815}, abstract = {The purposes of this study were to explore the impact of obesity on postoperative cognitive dysfunction (POCD) and to investigate the underlying mechanism by which obesity exacerbates POCD. In this study, fifteen-month-old male C57BL/6 J mice were fed a High-fat diet for three months to establish obesity models. Internal fixation of tibial fractures under isoflurane inhalation was performed to construct a POCD animal model. Three days after surgery, mice were subjected to the Morris water maze (MWM) experiment to evaluate their learning and memory abilities. The findings from the MWM experiment revealed that in comparison to the Ad Libitum Surgical group (ALS), mice in the High-fat Surgical group (HFS) exhibited prolonged escape latencies and reduced platform crossings. These outcomes suggest the potential exacerbating role of obesity in cognitive impairment within the POCD mouse models. Immunofluorescence (IF) findings demonstrate that obesity intensifies anesthesia and surgery-induced oxidative stress levels within the hippocampus. Compared to the Ad Libitum Control group (ALC), an elevation in PARP1 expression and a reduction in the NAD[+]/NADH ratio and SIRT1 expression were observed in the hippocampus of mice from the ALS. Moreover, when contrasting the HFS group with the ALS group, increased PARP1 expression along with decreased NAD[+]/NADH ratio and SIRT1 expression were evident. In vitro studies found that compared with the Control group (CON), oil red staining and BODIPY probe staining showed significant lipid droplet aggregation in the palmitic acid (PA) group. IF results demonstrated that HT22 cells in the PA group experienced oxidative stress and activation of the PARP1/NAD[+]/SIRT1 axis in contrast to the CON group. Moreover, manipulation of PARP1 expression in HT22 cells through PARP1 lentivirus-based silencing or overexpression revealed a converse relationship between PARP1 expression levels and the NAD[+]/NADH ratio as well as SIRT1 expression levels. This study concludes that obesity may exacerbate POCD by triggering activation of the oxidative stress-induced PARP1/NAD[+]/SIRT1 axis.}, }
@article {pmid39492438, year = {2023}, author = {Hamzeh, O and Rabiei, F and Shakeri, M and Parsian, H and Saadat, P and Rostami-Mansoor, S}, title = {Mitochondrial dysfunction and inflammasome activation in neurodegenerative diseases: Mechanisms and therapeutic implications.}, journal = {Mitochondrion}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mito.2023.10.003}, pmid = {39492438}, issn = {1872-8278}, abstract = {Impaired mitochondrial function is crucial to the pathogenesis of several neurodegenerative diseases. It causes the release of mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (mtROS), ATP, and cardiolipin, which activate the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. NLRP3 inflammasome is an important innate immune system element contributing to neuroinflammation and neurodegeneration. Therefore, targeting the NLRP3 inflammasome has become an interesting therapeutic approach for treating neurodegenerative diseases. This review describes the role of mitochondrial abnormalities and over-activated inflammasomes in the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA). We also discuss the therapeutic strategies focusing on signaling pathways associated with inflammasome activation, which potentially alleviate neurodegenerative symptoms and impede disease progression.}, }
@article {pmid39492095, year = {2023}, author = {Mohammadi, S and Mohammadi, M and Ghaderi, S}, title = {Sleep-related regions in neurodegenerative diseases by central nervous system localization using magnetic resonance imaging.}, journal = {Psychiatry research. Neuroimaging}, volume = {336}, number = {}, pages = {111727}, doi = {10.1016/j.pscychresns.2023.111727}, pmid = {39492095}, issn = {1872-7506}, abstract = {Sleep disruptions associated with neurodegenerative diseases (NDDs) damage the brain's sleep-regulating regions. Advanced magnetic resonance imaging (MRI) techniques can characterize the signature of each neurodegenerative pathology. We performed an evaluation of sleep-related regions in NDDs using MRI to localize the central nervous system (CNS). In the initial search, 61 related papers were discovered using predetermined inclusion and exclusion criteria. Finally, 30 articles were included in this study. The study included patients with Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), rapid eye movement (REM) sleep behavior disorder (RBD), idiopathic RBD (iRBD), amyotrophic lateral sclerosis (ALS), and mild cognitive impairment (MCI). Sleep-related regions recognized by CNS localization in NDDs can be linked to important regions. MRI also revealed cortical thinning, GM atrophy, WM, and tract loss, changes in diffusion tensor imaging (DTI) biomarkers (fractional anisotropy (FA), axial diffusivity (Da), and radial diffusivity (Dr)), a decrease in DMN connectivity, a reduction in functional connectivity (FC), and amplitude of low-frequency fluctuation (ALFF) alterations. Sleep plays an important role in predicting future risks for the development of NDDs. Other neuroimaging, cognitive-behavioral, and clinical research can use the information found in this research about the brain regions, MRI biomarker changes, and their relationships.}, }
@article {pmid39491718, year = {2024}, author = {Sharma, R and Khan, Z and Mehan, S and Das Gupta, G and Narula, AS}, title = {Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons.}, journal = {Mutation research. Reviews in mutation research}, volume = {794}, number = {}, pages = {108518}, doi = {10.1016/j.mrrev.2024.108518}, pmid = {39491718}, issn = {1388-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Mutation/genetics ; RNA-Binding Protein FUS/genetics ; C9orf72 Protein/genetics ; Animals ; Superoxide Dismutase-1/genetics ; DNA-Binding Proteins/genetics ; Genetic Predisposition to Disease ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, primarily impairs upper and lower motor neurons, leading to debilitating motor dysfunction and eventually respiratory failure, widely known as Lou Gehrig's disease. ALS presents with diverse symptomatology, including dysarthria, dysphagia, muscle atrophy, and hyperreflexia. The prevalence of ALS varies globally, with incidence rates ranging from 1.5 to 3.8 per 100,000 individuals, significantly affecting populations aged 45-80. A complex interplay of genetic and environmental factors underpins ALS pathogenesis. Key genetic contributors include mutations in chromosome 9 open reading frame 72 (C9ORF72), superoxide dismutase type 1 (SOD1), Fusedin sarcoma (FUS), and TAR DNA-binding protein (TARDBP) genes, accounting for a considerable fraction of both familial (fALS) and sporadic (sALS) cases. The disease mechanism encompasses aberrant protein folding, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation, contributing to neuronal death. This review consolidates current insights into ALS's multifaceted etiology, highlighting the roles of environmental exposures (e.g., toxins, heavy metals) and their interaction with genetic predispositions. We emphasize the polygenic nature of ALS, where multiple genetic variations cumulatively influence disease susceptibility and progression. This aspect underscores the challenges in ALS diagnosis, which currently lacks specific biomarkers and relies on symptomatology and familial history. Therapeutic strategies for ALS, still in nascent stages, involve symptomatic management and experimental approaches targeting molecular pathways implicated in ALS pathology. Gene therapy, focusing on specific ALS mutations, and stem cell therapy emerge as promising avenues. However, effective treatments remain elusive, necessitating a deeper understanding of ALS's genetic architecture and the development of targeted therapies based on personalized medicine principles. This review aims to provide a comprehensive understanding of ALS, encouraging further research into its complex genetic underpinnings and the development of innovative, effective treatment modalities.}, }
@article {pmid39491634, year = {2024}, author = {Tedeschi, V and Nele, V and Valsecchi, V and Anzilotti, S and Vinciguerra, A and Zucaro, L and Sisalli, MJ and Cassiano, C and De Iesu, N and Pignataro, G and Canzoniero, LMT and Pannaccione, A and De Rosa, G and Secondo, A}, title = {Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel.}, journal = {Pharmacological research}, volume = {210}, number = {}, pages = {107491}, doi = {10.1016/j.phrs.2024.107491}, pmid = {39491634}, issn = {1096-1186}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/physiopathology ; Animals ; *Transient Receptor Potential Channels/metabolism ; *Lysosomes/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; *Disease Models, Animal ; Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Humans ; Mice ; Phosphatidylinositols/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Male ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca[2+] dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models. Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1[G93A] ALS mice, thereby establishing its therapeutic profile. F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca[2+]]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1[G93A] mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level. Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.}, }
@article {pmid39491419, year = {2023}, author = {Talebi, M and Sadoughi, MM and Ayatollahi, SA and Ainy, E and Kiani, R and Zali, A and Miri, M}, title = {Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {168}, number = {}, pages = {115805}, doi = {10.1016/j.biopha.2023.115805}, pmid = {39491419}, issn = {1950-6007}, abstract = {Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits. This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington's disease, Alzheimer's disease, Parkinson's disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.}, }
@article {pmid39491120, year = {2023}, author = {Stachel, SJ and Wang, D and Ginnetti, AT and Niroomand, S and Ma, L and Hu, Y and Fay, JF and Lemaire, W and Krosky, DJ and Ramirez, AD and Zariwala, HA and Coleman, PJ}, title = {Virtual screening for early identification of potent and selective histone deacetylase 6 inhibitor series.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {}, number = {}, pages = {129537}, doi = {10.1016/j.bmcl.2023.129537}, pmid = {39491120}, issn = {1464-3405}, abstract = {Virtual screening was leveraged to identify novel series of histone deacetylase 6 (HDAC6) inhibitors prior to conducting a high-throughput screen. The virtual screen was designed to augment and expand on chemical matter that would otherwise be unavailable for high-throughput screening. Through this effort we succeeded in identifying four novel, potent and highly selective HDAC6 inhibitor series. These series displayed favorable ligand binding efficiencies and good potential for further optimization. The virtual design specifications and results are discussed herein.}, }
@article {pmid39490684, year = {2024}, author = {Liu, YJ and Lee, CW and Liao, YC and Huang, JJ and Kuo, HC and Jih, KY and Lee, YC and Chern, Y}, title = {The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106715}, doi = {10.1016/j.nbd.2024.106715}, pmid = {39490684}, issn = {1095-953X}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; *Adiponectin/metabolism ; *DNA-Binding Proteins/metabolism ; Male ; Female ; Middle Aged ; *AMP-Activated Protein Kinases/metabolism ; Aged ; Motor Neurons/metabolism ; Severity of Illness Index ; }, abstract = {Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.}, }
@article {pmid39490682, year = {2024}, author = {Leykam, L and Forsberg, KME and Nordström, U and Hjertkvist, K and Öberg, A and Jonsson, E and Andersen, PM and Marklund, SL and Zetterström, P}, title = {Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106718}, doi = {10.1016/j.nbd.2024.106718}, pmid = {39490682}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/cerebrospinal fluid ; *Superoxide Dismutase-1/genetics ; Male ; *Mutation ; Female ; Middle Aged ; Superoxide Dismutase/genetics/cerebrospinal fluid ; Adult ; Aged ; }, abstract = {Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.}, }
@article {pmid39490400, year = {2024}, author = {Zhang, Y and Zou, M and Wu, H and Zhu, J and Jin, T}, title = {The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {202}, number = {}, pages = {106710}, doi = {10.1016/j.nbd.2024.106710}, pmid = {39490400}, issn = {1095-953X}, mesh = {Humans ; *Nucleotidyltransferases/metabolism ; *Membrane Proteins/metabolism ; *Neurodegenerative Diseases/metabolism ; *Signal Transduction/physiology ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.}, }
@article {pmid39489870, year = {2024}, author = {Van Weehaeghe, D and Devrome, M and de Vocht, J and Masrori, P and Schramm, G and Deckers, W and Baete, K and De Weerdt, C and Van Damme, P and Koole, M and Van Laere, K}, title = {Combined brain and spinal FDG PET in the differentiation between ALS and ALS mimics - correction and additional validation study.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {52}, number = {1}, pages = {109-112}, pmid = {39489870}, issn = {1619-7089}, }
@article {pmid39489397, year = {2024}, author = {Desouky, MA and Michel, HE and Elsherbiny, DA and George, MY}, title = {Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation.}, journal = {Life sciences}, volume = {359}, number = {}, pages = {123206}, doi = {10.1016/j.lfs.2024.123206}, pmid = {39489397}, issn = {1879-0631}, mesh = {*Proteasome Endopeptidase Complex/metabolism ; Humans ; Animals ; Neurodegenerative Diseases/metabolism/drug therapy ; Nervous System Diseases/drug therapy/metabolism ; Proteolysis/drug effects ; Signal Transduction/drug effects ; Proteostasis/drug effects ; Ubiquitin/metabolism ; }, abstract = {Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators.}, }
@article {pmid39487163, year = {2024}, author = {Cai, S and Venugopalan, S and Seaver, K and Xiao, X and Tomanek, K and Jalasutram, S and Morris, MR and Kane, S and Narayanan, A and MacDonald, RL and Kornman, E and Vance, D and Casey, B and Gleason, SM and Nelson, PQ and Brenner, MP}, title = {Using large language models to accelerate communication for eye gaze typing users with ALS.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9449}, pmid = {39487163}, issn = {2041-1723}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Communication Devices for People with Disabilities ; Female ; Male ; Pilot Projects ; *Fixation, Ocular/physiology ; Language ; Adult ; User-Computer Interface ; Middle Aged ; Communication ; }, abstract = {Accelerating text input in augmentative and alternative communication (AAC) is a long-standing area of research with bearings on the quality of life in individuals with profound motor impairments. Recent advances in large language models (LLMs) pose opportunities for re-thinking strategies for enhanced text entry in AAC. In this paper, we present SpeakFaster, consisting of an LLM-powered user interface for text entry in a highly-abbreviated form, saving 57% more motor actions than traditional predictive keyboards in offline simulation. A pilot study on a mobile device with 19 non-AAC participants demonstrated motor savings in line with simulation and relatively small changes in typing speed. Lab and field testing on two eye-gaze AAC users with amyotrophic lateral sclerosis demonstrated text-entry rates 29-60% above baselines, due to significant saving of expensive keystrokes based on LLM predictions. These findings form a foundation for further exploration of LLM-assisted text entry in AAC and other user interfaces.}, }
@article {pmid39486809, year = {2024}, author = {Van Loon, FT and Seitidis, G and Mavridis, D and van Unnik, JWJ and Weemering, DN and van den Berg, LH and Bethani, I and Nikolakopoulos, S and van Eijk, RPA}, title = {Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e087970}, pmid = {39486809}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Clinical Trials as Topic ; Disease Progression ; Network Meta-Analysis ; Research Design ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials.<br><br>METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape.<br><br>ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.}, }
@article {pmid39484239, year = {2024}, author = {Leinders, S and Aarnoutse, EJ and Branco, MP and Freudenburg, ZV and Geukes, SH and Schippers, A and Verberne, MSW and van den Boom, M and van der Vijgh, B and Crone, NE and Denison, T and Ramsey, NF and Vansteensel, MJ}, title = {DO NOT LOSE SLEEP OVER IT: IMPLANTED BRAIN-COMPUTER INTERFACE FUNCTIONALITY DURING NIGHTTIME IN LATE-STAGE AMYOTROPHIC LATERAL SCLEROSIS.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484239}, support = {U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Brain-computer interfaces (BCIs) hold promise as augmentative and alternative communication technology for people with severe motor and speech impairment (locked-in syndrome) due to neural disease or injury. Although such BCIs should be available 24/7, to enable communication at all times, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an individual with amyotrophic lateral sclerosis (ALS) who was implanted with an electrocorticography-based BCI that enabled the generation of click-commands for spelling words and call-caregiver signals.<br><br>METHODS: We investigated nocturnal dynamics of neural signal features used for BCI control, namely low (LFB: 10-30Hz) and high frequency band power (HFB: 65-95Hz). Additionally, we assessed the nocturnal performance of a BCI decoder that was trained on daytime data by quantifying the number of unintentional BCI activations at night. Finally, we developed and implemented a nightmode decoder that allowed the participant to call a caregiver at night, and assessed its performance.<br><br>RESULTS: Power and variance in HFB and LFB were significantly higher at night than during the day in the majority of the nights, with HFB variance being higher in 88% of nights. Daytime decoders caused 245 unintended selection-clicks and 13 unintended caregiver-calls per hour when applied to night data. The developed nightmode decoder functioned error-free in 79% of nights over a period of &#xb1;1.5 years, allowing the user to reliably call the caregiver, with unintended activations occurring only once every 12 nights.<br><br>DISCUSSION: Reliable nighttime use of a BCI requires decoders that are adjusted to sleep-related signal changes. This demonstration of a reliable BCI nightmode and its long-term use by an individual with advanced ALS underscores the importance of 24/7 BCI reliability.<br><br>TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov under number NCT02224469 (https://clinicaltrials.gov/study/NCT02224469?term=NCT02224469&amp;rank=1). Date of submission to registry: August 21, 2014. Enrollment of first participant: September 7, 2015.}, }
@article {pmid39483635, year = {2024}, author = {Murakami, Y and Ando, M and Imamura, A and Oketani, R and Leproux, P and Honjoh, S and Kano, H}, title = {Molecular Fingerprinting of Mouse Brain Using Ultrabroadband Coherent Anti-Stokes Raman Scattering (CARS) Microspectroscopy Empowered by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS).}, journal = {Chemical &amp; biomedical imaging}, volume = {2}, number = {10}, pages = {689-697}, pmid = {39483635}, issn = {2832-3637}, abstract = {The Raman fingerprint spectral region provides abundant structural information on molecules. However, analyzing vibrational images within this region using coherent Raman imaging remains challenging due to the small Raman cross section and congested spectral features. In this study, we combined ultrabroadband coherent anti-Stokes Raman scattering (CARS) microspectroscopy across the spectral range of 500-4000 cm[-1] with multivariate curve resolution-alternating least-squares (MCR-ALS) to reveal hidden Raman bands in the fingerprint region. Applying this method to mouse brain tissue, we extracted information on cholesterol and collagen, leveraging their distinctive molecular signatures, as well as on key molecules such as lipids, proteins, water, and nucleic acids. Moreover, the simultaneous detection of second harmonic generation facilitated label-free visualization of organelles, including arachnoid membrane and Rootletin filaments.}, }
@article {pmid39483234, year = {2024}, author = {Fujimoto, A and Kinjo, M and Kitamura, A}, title = {Short Repeat Ribonucleic Acid Reduces Cytotoxicity by Preventing the Aggregation of TDP-43 and Its 25 KDa Carboxy-Terminal Fragment.}, journal = {JACS Au}, volume = {4}, number = {10}, pages = {3896-3909}, pmid = {39483234}, issn = {2691-3704}, abstract = {TAR DNA/RNA-binding protein 43 kDa (TDP-43) proteinopathy is a hallmark of neurodegenerative disorders, such as amyotrophic lateral sclerosis, in which cytoplasmic aggregates containing TDP-43 and its C-terminal fragments, such as TDP-25, are observed in degenerative neuronal cells. However, few reports have focused on small molecules that can reduce their aggregation and cytotoxicity. Here, we show that short RNA repeats of GGGGCC and AAAAUU are aggregation suppressors of TDP-43 and TDP-25. TDP-25 interacts with these RNAs, as well as TDP-43, despite the lack of major RNA-recognition motifs using fluorescence cross-correlation spectroscopy. Expression of these RNAs significantly decreases the number of cells harboring cytoplasmic aggregates of TDP-43 and TDP-25 and ameliorates cell death by TDP-25 and mislocalized TDP-43 without altering the cellular transcriptome of molecular chaperones. Consequently, short RNA repeats of GGGGCC and AAAAUU can maintain proteostasis by preventing the aggregation of TDP-43 and TDP-25.}, }
@article {pmid39488863, year = {2024}, author = {Lopes, M and Swash, M and de Carvalho, M}, title = {F-waves responses derived from low-intensity electrical stimulation: A method to explore split-hand pathogenesis.}, journal = {Neurophysiologie clinique = Clinical neurophysiology}, volume = {54}, number = {6}, pages = {103018}, doi = {10.1016/j.neucli.2024.103018}, pmid = {39488863}, issn = {1769-7131}, mesh = {Humans ; Male ; Female ; *Hand/physiopathology ; Adult ; *Muscle, Skeletal/physiopathology/physiology ; *Electric Stimulation/methods ; Middle Aged ; Motor Neurons/physiology ; Electromyography ; Amyotrophic Lateral Sclerosis/physiopathology/therapy ; Young Adult ; Evoked Potentials, Motor/physiology ; Aged ; }, abstract = {OBJECTIVES: The "split-hand syndrome" is a common clinical sign in amyotrophic lateral sclerosis (ALS), being characterized by more severe atrophy of the hand muscles on the radial side of the hand compared to the ulnar side. We aimed to investigate possible physiological differences between relevant hand muscles using low-intensity F-wave stimulation to assess spinal motoneuron excitability.<br><br>METHODS: We recruited 36 healthy volunteers. F-waves were recorded from the abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM), using 20 supramaximal stimuli followed by 20 stimuli at a low-intensity required to obtain M-waves with 10 % amplitude of maximal CMAP. We evaluated the following F-wave parameters: F-M latency, chronodispersion, persistence, amplitude, F/CMAP amplitude ratio and number of F-wave repeaters (with low-intensity). In 10 subjects, low-intensity stimulation F-waves were compared after 20 and 50 stimuli in each muscle.<br><br>RESULTS: Low-intensity stimulation resulted in lower F-wave amplitude and persistence and higher F/CMAP amplitude ratios. There were no significant differences in F-wave latencies and chronodispersion. When comparing the three muscles, we found higher F-wave persistence and F/CMAP amplitude ratios when recording over the ADM and APB compared to the FDI. We also found a higher number of F-wave repeaters in the ADM with low-intensity stimulation. Results from 20 to 50 low-intensity stimuli were similar.<br><br>DISCUSSION: A small number of low-intensity stimuli is appropriate to study F-wave latencies and chronodispersion. We found differences in some physiological properties of the ADM spinal motoneuron pool compared to other hand muscles.}, }
@article {pmid39480764, year = {2024}, author = {Perrin, S and Ladha, S and Maragakis, N and Rivner, MH and Katz, J and Genge, A and Olney, N and Lange, D and Heitzman, D and Bodkin, C and Jawdat, O and Goyal, NA and Bornstein, JD and Mak, C and Appel, SH and Paganoni, S}, title = {Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.}, journal = {PLoS medicine}, volume = {21}, number = {10}, pages = {e1004469}, pmid = {39480764}, issn = {1549-1676}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; Adult ; CD40 Ligand/blood ; Biomarkers/blood ; Antibodies, Monoclonal, Humanized/adverse effects/administration &amp; dosage/therapeutic use/pharmacokinetics ; Antibodies, Monoclonal/adverse effects/administration &amp; dosage/therapeutic use ; Neurofilament Proteins/blood ; Dose-Response Relationship, Drug ; Treatment Outcome ; Disease Progression ; Imidazoles ; Pyrazines ; }, abstract = {BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).<br><br>METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.<br><br>CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.<br><br>TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.}, }
@article {pmid39480562, year = {2025}, author = {Cao, G and Wang, S and Yu, J and Wang, X and Shi, X and Yang, L and Zhang, X and Tong, P and Tan, H}, title = {Outcomes of combined single-bundle anterior cruciate ligament reconstruction and anterolateral structure reconstruction through a modified single femoral tunnel.}, journal = {International orthopaedics}, volume = {49}, number = {1}, pages = {83-91}, pmid = {39480562}, issn = {1432-5195}, support = {82104896//National Natural Science Foundation of China/ ; 242102310025//Henan Provincial Science and Technology Research Project/ ; 2024HLTJ17//Heluo Youth Talent Support Program/ ; }, mesh = {Humans ; Male ; Female ; *Anterior Cruciate Ligament Reconstruction/methods ; Adult ; Middle Aged ; Young Adult ; Adolescent ; *Femur/surgery ; *Anterior Cruciate Ligament Injuries/surgery ; Treatment Outcome ; Arthroscopy/methods ; Hamstring Tendons/transplantation ; Transplantation, Autologous/methods ; }, abstract = {PURPOSE: To explore the clinical outcomes of combining anterior cruciate ligament (ACL) reconstruction and anterolateral structure (ALS) reconstruction through a modified single femoral tunnel in patients with high risk of clinical failure.<br><br>METHODS: From December 2018 to August 2022, a total of 62 patients with ACL injury in our institution were enrolled in this study. All patients were associated with high risk of clinical failure, meeting the indications of ALS reconstruction. All patients accepted arthroscopic single-bundle ACL reconstruction and ALS reconstruction using hamstring autograft through a modified single femoral tunnel. Perioperative clinical outcome measurements consisted of functions, stability and safety evaluation at different time points (preoperative, postoperative three&#xa0;month, six&#xa0;month, one&#xa0;year, two&#xa0;year, three&#xa0;year and more). Functional evaluation included Lysholm score, Tegner activity scale, subjective and objective International Knee Documentation Committee (IKDC) score.<br><br>RESULTS: All patients, including 47 males and 15 females, aged 16-52&#xa0;years with an average age of 29.3&#x2009;&#xb1;&#x2009;9.2&#xa0;years, were followed up for 12-58&#xa0;months. At the last follow-up, the Lysholm, subjective IKDC and Tegner activity scale (93.8&#x2009;&#xb1;&#x2009;7.0, 88.8&#x2009;&#xb1;&#x2009;10.7 and 5.8&#x2009;&#xb1;&#x2009;1.4 respectively) were significantly higher than those before surgery (65.0&#x2009;&#xb1;&#x2009;20.8, 51.2&#x2009;&#xb1;&#x2009;21.1 and 2.3&#x2009;&#xb1;&#x2009;1.3 respectively)(P&#x2009;<&#x2009;0.05). Postoperative pivot shift and Lachman test were markedly improved (P&#x2009;<&#x2009;0.05). One patient still had grade II pivot shift, defined as clinical failure. During follow-up, no graft&#xa0;rupture&#xa0;occurred according to magnetic resonance imaging and physical examination, no lateral compartment osteoarthritis were found in all patients.<br><br>CONCLUSIONS: Combined single bundle ACL reconstruction and ALS reconstruction through a modified single femoral tunnel could significantly improve knee function and stability with low related risk in patients with high risk of failure in ACL injury.}, }
@article {pmid39487710, year = {2025}, author = {van Veenhuijzen, K and Tan, HHG and Nitert, AD and van Es, MA and Veldink, JH and van den Berg, LH and Westeneng, HJ}, title = {Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.}, journal = {Annals of neurology}, volume = {97}, number = {2}, pages = {281-295}, pmid = {39487710}, issn = {1531-8249}, support = {//Stichting ALS Nederland/ ; 772376-EScORIAL//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging/pathology ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Female ; Male ; Middle Aged ; *Magnetic Resonance Imaging/methods ; Aged ; Longitudinal Studies ; *Mutation ; Adult ; Atrophy/pathology ; Heterozygote ; Prospective Studies ; Brain/diagnostic imaging/pathology ; }, abstract = {OBJECTIVE: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).<br><br>METHODS: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3&#x2009;T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n&#x2009;=&#x2009;107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n&#x2009;=&#x2009;10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.<br><br>RESULTS: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6&#x2009;years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.<br><br>INTERPRETATION: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2025;97:281-295.}, }
@article {pmid39487328, year = {2024}, author = {Paganoni, S and Harkey, B and Giacomelli, E and Cudkowicz, M and , }, title = {Lessons from the HEALEY adaptive platform trial in amyotrophic lateral sclerosis.}, journal = {Nature aging}, volume = {4}, number = {11}, pages = {1512-1515}, pmid = {39487328}, issn = {2662-8465}, }
@article {pmid39486621, year = {2024}, author = {Stephani, C and Krämer, H and Chakalov, I and Bähr, M and Paulus, W and Antal, A and Koch, JC}, title = {Static transcranial magnetic stimulation does not alter cortical excitability in patients with amyotrophic lateral sclerosis on riluzole.}, journal = {Brain stimulation}, volume = {17}, number = {6}, pages = {1244-1246}, doi = {10.1016/j.brs.2024.10.013}, pmid = {39486621}, issn = {1876-4754}, }
@article {pmid39486473, year = {2024}, author = {Wang, HE and Daya, MR and Schmicker, R and Nassal, M and Okubo, M and Aramendi, E and Alonso, E and Idris, A and Panchal, AR and Jaureguibeitia, X and Aufderheide, T and Carlson, J and Nichol, G}, title = {Vasopressor or advanced airway first in cardiac arrest?.}, journal = {Resuscitation}, volume = {205}, number = {}, pages = {110422}, doi = {10.1016/j.resuscitation.2024.110422}, pmid = {39486473}, issn = {1873-1570}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Airway Management/methods ; *Cardiopulmonary Resuscitation/methods ; Epinephrine/administration &amp; dosage ; Intubation, Intratracheal/methods ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Return of Spontaneous Circulation ; *Vasoconstrictor Agents/therapeutic use/administration &amp; dosage ; Vasopressins/therapeutic use/administration &amp; dosage ; }, abstract = {BACKGROUND: While resuscitation guidelines emphasize early vasopressor administration and advanced airway management, their optimal sequence remains unclear. We sought to determine the associations between vasopressor-airway resuscitation sequence and out-of-hospital cardiac arrest (OHCA) outcomes in the Pragmatic Airway Resuscitation Trial (PART).<br><br>METHODS: We analyzed data from the PART trial. For each patient we determined times of first vasopressor administration (epinephrine or vasopressin), and successful advanced airway insertion (laryngeal tube or endotracheal tube). We classified each case as vasopressor-first or advanced airway-first. We used Generalized Estimating Equations to determine associations between vasopressor-airway sequence and outcomes (72-hour survival, return of spontaneous circulation (ROSC) on emergency department arrival, survival to hospital discharge, hospital survival with favorable neurologic status) and CPR outside of recommended parameters (chest compression fraction&#xa0;<0.8, chest compression rate&#xa0;<100 or&#xa0;>120 per min, or ventilation rate&#xa0;<8 or&#xa0;>12 breaths/min), adjusting for confounders.<br><br>RESULTS: Of 3,004 patients in the parent trial, we analyzed 2,404, including 1,821 vasopressor-first and 583 advanced airway-first. Median intervention times: ALS arrival-to-vasopressor 8&#xa0;min (IQR 6-11) and ALS arrival-to-airway 11&#xa0;min (8-15). Compared with airway-first, vasopressor-first sequence was not associated with 72-hour survival (adjusted OR 0.96; 95% CI: 0.71-1.31), ROSC (0.83; 0.66-1.06), hospital survival (1.09; 0.68-1.73), or hospital survival with favorable neurologic status (0.97; 0.53-1.78). Vasopressor-first sequence was not associated with non-compliance with recommended CPR performance parameters.<br><br>CONCLUSIONS: Vasopressor-airway resuscitation sequence was not associated with OHCA outcomes or CPR quality.}, }
@article {pmid39486415, year = {2024}, author = {Al-Azzam, N and To, JH and Gautam, V and Street, LA and Nguyen, CB and Naritomi, JT and Lam, DC and Madrigal, AA and Lee, B and Jin, W and Avina, A and Mizrahi, O and Mueller, JR and Ford, W and Schiavon, CR and Rebollo, E and Vu, AQ and Blue, SM and Madakamutil, YL and Manor, U and Rothstein, JD and Coyne, AN and Jovanovic, M and Yeo, GW}, title = {Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes.}, journal = {Neuron}, volume = {112}, number = {24}, pages = {4033-4047.e8}, doi = {10.1016/j.neuron.2024.10.007}, pmid = {39486415}, issn = {1097-4199}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; *RNA Splicing ; *Motor Neurons/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Cell Nucleus/metabolism ; Phenotype ; Active Transport, Cell Nucleus ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.}, }
@article {pmid39478664, year = {2024}, author = {Ropert, B and Bannwarth, S and Genin, EC and Vaillant-Beuchot, L and Lacas-Gervais, S and Hounoum, BM and Bernardin, A and Dinh, N and Mauri-Crouzet, A and D'Elia, MA and Augé, G and Lespinasse, F and Di Giorgio, A and Meira, W and Bonnefoy, N and Monassier, L and Schiff, M and Sago, L and Kilinc, D and Brau, F and Redeker, V and Bohl, D and Tribouillard-Tanvier, D and Procaccio, V and Azoulay, S and Ricci, JE and Delahodde, A and Paquis-Flucklinger, V}, title = {Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awae348}, pmid = {39478664}, issn = {1460-2156}, abstract = {The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.}, }
@article {pmid39478194, year = {2024}, author = {Yang, M and You, D and Liu, G and Lu, Y and Yang, G and O'Brien, T and Henshall, DC and Hardiman, O and Cai, L and Liu, M and Shen, S}, title = {Polyethyleneimine facilitates the growth and electrophysiological characterization of iPSC-derived motor neurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {26106}, pmid = {39478194}, issn = {2045-2322}, support = {16/RC/3948/SFI_/Science Foundation Ireland/Ireland ; C2024205026//Natural Science Foundation of Hebei Province/ ; L2024B36//Doctoral Research Initiation Fund Project of Hebei Normal University/ ; GJHZ20200731095005016//International Scientific and Technological Cooperation Foundation of Shenzhen/ ; 00000326//Medical-Engineering Interdisciplinary Research Foundation of ShenZhen University/ ; }, mesh = {*Polyethyleneimine/pharmacology ; *Electrophysiology ; *Induced Pluripotent Stem Cells/drug effects ; *Cell Proliferation/drug effects ; Motor Neurons/drug effects ; Amyotrophic Lateral Sclerosis/physiopathology ; Humans ; Cells, Cultured ; Cell Differentiation ; }, abstract = {Induced pluripotent stem cell (iPSC) technology, in combination with electrophysiological characterization via multielectrode array (MEA), has facilitated the utilization of iPSC-derived motor neurons (iPSC-MNs) as highly valuable models for underpinning pathogenic mechanisms and developing novel therapeutic interventions for motor neuron diseases (MNDs). However, the challenge of MN adherence to the MEA plate and the heterogeneity presented in iPSC-derived cultures raise concerns about the reproducibility of the findings obtained from these cellular models. We discovered that one novel factor modulating the electrophysiological activity of iPSC-MNs is the extracellular matrix (ECM) used in the coating to support in vitro growth, differentiation and maturation of iPSC-MNs. The current study showed that two coating conditions, namely, Poly-L-ornithine/Matrigel (POM) and Polyethyleneimine (PEI) strongly promoted attachment of iPSC-MNs on MEA culture dishes compared to three other coating conditions, and both facilitated the maturation of iPSC-MNs as characterized by the detection of extensive electrophysiological activities from the MEA plates. POM coating accelerated the maturation of the iPSC-MNs for up to 5 weeks, which suits modeling of neurodevelopmental disorders. However, the application of PEI resulted in more even distribution of the MNs on the culture dish and reduced variability of electrophysiological signals from the iPSC-MNs in 7-week cultures, which permitted the detection of enhanced excitability in iPSC-MNs from patients with amyotrophic lateral sclerosis (ALS). This study provides a comprehensive comparison of five coating conditions and offers POM and PEI as favorable coatings for in vitro modeling of neurodevelopmental and neurodegenerative disorders, respectively.}, }
@article {pmid39475611, year = {2024}, author = {Wang, LQ and Ma, Y and Zhang, MY and Yuan, HY and Li, XN and Xia, W and Zhao, K and Huang, X and Chen, J and Li, D and Zou, L and Wang, Z and Le, W and Liu, C and Liang, Y}, title = {Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations.}, journal = {Science advances}, volume = {10}, number = {44}, pages = {eado8499}, pmid = {39475611}, issn = {2375-2548}, mesh = {*Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Amyloid/metabolism ; *Mutation ; *Ferroptosis/genetics ; Cryoelectron Microscopy ; Models, Molecular ; Mitochondria/metabolism ; }, abstract = {Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.}, }
@article {pmid39475283, year = {2025}, author = {Ziser, L and van Eijk, RPA and Kiernan, MC and McRae, A and Henderson, RD and Schultz, D and Needham, M and Mathers, S and McCombe, P and Talman, P and Vucic, S}, title = {Amyotrophic lateral sclerosis established as a multistep process across phenotypes.}, journal = {European journal of neurology}, volume = {32}, number = {1}, pages = {e16532}, pmid = {39475283}, issn = {1468-1331}, support = {//National Health and Medical Research Council/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Middle Aged ; *Phenotype ; Male ; Female ; Aged ; *Registries ; *Age of Onset ; Australia/epidemiology ; Disease Progression ; Incidence ; Adult ; }, abstract = {BACKGROUND AND PURPOSE: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.<br><br>METHODS: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R[2] used to assess the goodness of fit of the model.<br><br>RESULTS: In total, 2647 ALS patients were included, with mean disease-onset age being 62.2&#x2009;&#xb1;&#x2009;12.1&#x2009;years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6-5.6); cervical 2.7 (95% CI 2.3-3.0); lumbar 3.5 (95% CI 3.2-3.9); flail arm 4.7 (95% CI 3.9-5.5); flail leg 3.6 (95% CI 2.6-4.5); primary lateral sclerosis 2.7 (95% CI 1.8-3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R[2] values were >0.4 for all phenotypes indicating excellent model fit.<br><br>DISCUSSION: A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance.}, }
@article {pmid39475135, year = {2024}, author = {Jackowski, T and Horodnicka-Józwa, A and Berus, E and Walczak, M and Petriczko, E}, title = {An analysis of acid-labile subunit (ALS) levels in children with short stature born with normal weight.}, journal = {Endokrynologia Polska}, volume = {75}, number = {5}, pages = {548-557}, doi = {10.5603/ep.100285}, pmid = {39475135}, issn = {2299-8306}, mesh = {Humans ; Child ; Female ; Male ; *Glycoproteins ; Growth Disorders/diagnosis ; Carrier Proteins ; Child, Preschool ; Insulin-Like Growth Factor I/metabolism/analysis ; Insulin-Like Growth Factor Binding Protein 3/blood ; Body Height ; }, abstract = {INTRODUCTION: The acid-labile subunit (ALS) is a protein best known for its function in stabilising the insulin like growth factor-1/2-insulin-like growth factor-1 binding protein 3/5 (IGF-1/2-IGFBP3/5) binary complex by creating the ternary complex and in consequence regulating the biological activity of IGF-1. The aim of the study was to assess ALS concentrations in a chosen population of children with short stature taking into account their clinical diagnosis.<br><br>MATERIAL AND METHODS: A total of 109 prepubertal children were involved in the study - 85 children in the study group and 24 in controls. In all the children IGF-1, IGFBP3, and ALS were measured. The study group was divided according to diagnosis into groups: growth hormone deficiency (GHD), constitutional delay of growth and puberty (CDGP), idiopathic short stature (ISS), and familial short stature (FSS).<br><br>RESULTS: In the control group the ALS concentration ranged from 4.81 to 13.66 &#x3bc;g/mL. In the whole study group the ALS concentration ranged from 2.73 to 15.81 &#x3bc;g/mL. The difference between both groups was statistically significant (p < 0.0001, R = 0.39). A strong, statistically significant correlation between ALS levels and age was observed, but only in the study group (p < 0.0001, r = 0.59). The ALS standard deviation score (SDS) was not significantly different between the control and CDGP children (p = 0.0644). The ALS concentration was significantly lower in children with short stature. There was, however, no difference between the subgroups of the study group.<br><br>CONCLUSION: There was no significant difference in ALS SDS between the control group and children with constitutional delay of growth and development. The usefulness of ALS in routine short stature diagnostics is uncertain, but it might play a role in the diagnosis of children with ISS and CDGP in the future.}, }
@article {pmid39474398, year = {2024}, author = {Goyal, O and Goyal, MK}, title = {Critical analysis of the effects of proton pump inhibitors on inflammatory bowel disease: An updated review.}, journal = {World journal of gastroenterology}, volume = {30}, number = {37}, pages = {4160-4162}, pmid = {39474398}, issn = {2219-2840}, mesh = {Humans ; *Colitis, Ulcerative/drug therapy/immunology/diagnosis ; *Crohn Disease/diagnosis/drug therapy/immunology ; *Proton Pump Inhibitors/therapeutic use/adverse effects ; Treatment Outcome ; Review Literature as Topic ; }, abstract = {This letter critically evaluates the effects of proton pump inhibitors (PPIs) on inflammatory bowel disease, particularly focusing on Crohn's disease (CD) and ulcerative colitis (UC), as discussed in Liang et al's recent review. While the review provides significant insights, it relies heavily on cross-sectional and observational studies, which limits the ability to draw causal inferences. The heterogeneous study populations and inconsistent definitions of long-term PPI use further complicate the findings. This letter also highlights the need for rigorous control of confounding factors and considers the potential publication bias in the existing literature. The implications of these issues are discussed in the context of both CD and UC, and future research directions are proposed to address these shortcomings.}, }
@article {pmid39474168, year = {2024}, author = {Sandler, AB and Wells, ME and Tran, C and Arakawa, R and Klahs, KJ and Scanaliato, JP and Green, CK and Hettrich, CM and Dunn, JC and Adler, A and Parnes, N}, title = {High rates of return to sport after suprascapular nerve decompression: an updated systematic review.}, journal = {JSES reviews, reports, and techniques}, volume = {4}, number = {4}, pages = {654-661}, pmid = {39474168}, issn = {2666-6391}, abstract = {BACKGROUND: Suprascapular nerve decompression (SSND) remains a controversial procedure. In 2018, Momaya et al published the first systematic review of SSND noting satisfactory outcomes with low rates of complications; however, numerous studies published since have noted no benefit in routinely adding SSND to other arthroscopic surgeries, contributing to existing contention regarding the procedure. The purpose of this study is to provide an updated assessment of outcomes after SSND.<br><br>METHODS: To conduct this updated systematic review, a search of PubMed (MEDLINE) for relevant studies published prior to January 21, 2023 was conducted. Outcomes including patient-reported clinical outcomes, return to sport, preoperative and postoperative electrodiagnostic testing, and adverse events were collected and pooled for assessment. Studies were eligible for inclusion if they met Momaya et&#xa0;al's inclusion criteria and/or reported outcomes following SSND at either the suprascapular notch or spinoglenoid notch.<br><br>RESULTS: In total, 730 patients from 33 studies were eligible for inclusion. All patient-reported outcome measure scores including American Shoulder Elbow Surgeon Standardized Shoulder Assessment; Constant-Murley score; Disabilities of the Arm, Shoulder, and Hand; Subjective Shoulder Value; University of California-Los Angeles shoulder; and visual analog scale pain scores improved significantly postoperatively, with improvements ranging from 53.5% to 102.6% of preoperative values. Ultimately, 98% (n&#xa0;= 90/92) of patients returned to sport or military duty and 96% of these patients returned at their previous level of activity (n&#xa0;= 48/50) without heterogeneity among rates between studies (P&#xa0;= .176, P&#xa0;= .238, respectively). Preoperative electrodiagnostic testing was conducted in 93% of patients, and 90% had associated abnormal findings. Continued symptoms were noted among 12% of patients (n&#xa0;= 39/322) with significantly different rates observed between studies. Complications from operative management not limited to SSND occurred in 11% of patients (n&#xa0;= 64/576) and reoperations occurred in 3.3% of patients (n&#xa0;= 15/455).<br><br>CONCLUSION: Suprascapular neuropathy treated with SSND significantly improves patient-reported outcomes and is noninferior to similar procedures without SSND. Appropriate clinical diagnosis of suprascapular neuropathy is required as opposed to a routine adjunct procedure with other arthroscopic shoulder surgery. Ultimately, SSND is associated with high rates of return to sport and relatively low rates of adverse events; however, the risk of continued symptoms and electrodiagnostic test-related complications is an important point on preoperative counseling.}, }
@article {pmid39473991, year = {2024}, author = {Hobro, AJ and Sakaguchi, T and Akira, S and Smith, NI}, title = {Correlative Quantitative Raman Chemical Imaging and MCR-ALS in Mouse NASH Model Reveals Direct Relationships between Diet and Resultant Liver Pathology.}, journal = {Chemical &amp; biomedical imaging}, volume = {2}, number = {8}, pages = {577-583}, pmid = {39473991}, issn = {2832-3637}, abstract = {Raman imaging has the capability to provide unlabeled, spatially aware analysis of chemical components, with no a priori assumptions. Several lifestyle diseases such as nonalcoholic steatohepatitis (NASH) can appear in the liver as changes in the nature, abundance, and distribution of lipids, proteins, and other biomolecules and are detectable by Raman imaging. In order to identify which of these liver-associated changes occur as a direct result of the diet and which are secondary effects, we developed correlative imaging and analysis of diet and liver samples. Oleic acid was found to be a direct contributor to NASH liver composition, whereas protein and collagen distributions were found to be affected in a manner consistent with early fibrotic transformation, as a secondary consequence of the high-fat diet.}, }
@article {pmid39473807, year = {2024}, author = {Oliveira, GC and Ngo, QC and Passos, LA and Oliveira, LS and Stylianou, S and Papa, JP and Kumar, D}, title = {Video Assessment to Detect Amyotrophic Lateral Sclerosis.}, journal = {Digital biomarkers}, volume = {8}, number = {1}, pages = {171-180}, pmid = {39473807}, issn = {2504-110X}, abstract = {INTRODUCTION: Weakened facial movements are early-stage symptoms of amyotrophic lateral sclerosis (ALS). ALS is generally detected based on changes in facial expressions, but large differences between individuals can lead to subjectivity in the diagnosis. We have proposed a computerized analysis of facial expression videos to detect ALS.<br><br>METHODS: This study investigated the action units obtained from facial expression videos to differentiate between ALS patients and healthy individuals, identifying the specific action units and facial expressions that give the best results. We utilized the Toronto NeuroFace Dataset, which includes nine facial expression tasks for healthy individuals and ALS patients.<br><br>RESULTS: The best classification accuracy was 0.91 obtained for the pretending to smile with tight lips expression.<br><br>CONCLUSION: This pilot study shows the potential of using computerized facial expression analysis based on action units to identify facial weakness symptoms in ALS.}, }
@article {pmid39473490, year = {2024}, author = {Fei, Y and Ding, Y}, title = {The role of ferroptosis in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1475934}, pmid = {39473490}, issn = {1662-5102}, abstract = {Ferroptosis represents an iron[-] and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.}, }
@article {pmid39473462, year = {2024}, author = {Zhang, Y and Xu, N and Yan, C and Zhou, X and Qiao, Q and Miao, L and Xu, Z}, title = {Live-Cell Imaging to Resolve Salt-Induced Liquid-Liquid Phase Separation of FUS Protein by Dye Self-Labeling.}, journal = {Chemical &amp; biomedical imaging}, volume = {2}, number = {1}, pages = {70-80}, pmid = {39473462}, issn = {2832-3637}, abstract = {The aggregation of fusion in sarcoma (FUS) in the cytoplasm and nucleus is a pathological feature of Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD). Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. Salt ions are essential to many physiological processes in the body, and the imbalance of them is an important environmental stress factor in cells. However, their effect on liquid-liquid phase separation (LLPS) of FUS proteins in living cells is not well understood. Here, we map the various salt-induced LLPS of FUS in living cells by genetically coding and self-labeling FUS with organic dyes. The brightness and photostability of the dyes enable long-term imaging to track the mechanism of the assembly and disappearance of FUS phase separation. The FUS protein showed a better phase separation tendency under 0.3 M salt stimulation, and there was a large amount of FUS shuttling from the nucleus to the cytoplasm. At this concentration, various salt solutions displayed different effects on the phase separation of FUS protein, following the Hofmeister effects. We further observed that the assembly of FUS droplets underwent a process of rapid formation of small droplets, plateaus, and mutual fusion. Strikingly, The CsCl-stimulated FUS droplets were not completely reversible after washing, and some solid-like granules remained in the nucleus. Taken together, these results help broaden our understanding of the LLPS of FUS proteins in cellular stress responses.}, }
@article {pmid39473221, year = {2024}, author = {Ito, D and Okada, K}, title = {Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.}, journal = {Annals of clinical and translational neurology}, volume = {11}, number = {12}, pages = {3054-3063}, pmid = {39473221}, issn = {2328-9503}, support = {21H02812//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/genetics/therapy ; *Oligonucleotides, Antisense/administration &amp; dosage/genetics ; Superoxide Dismutase-1/genetics ; }, abstract = {Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.}, }
@article {pmid39472924, year = {2024}, author = {Stikvoort García, DJL and Sleutjes, BTHM and Mugge, W and Plouvier, JJ and Goedee, HS and Schouten, AC and van der Helm, FCT and van den Berg, LH}, title = {Instrumented assessment of lower and upper motor neuron signs in amyotrophic lateral sclerosis using robotic manipulation: an explorative study.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {21}, number = {1}, pages = {193}, pmid = {39472924}, issn = {1743-0003}, support = {AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; AV20180012//Stichting ALS Nederland/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Robotics/instrumentation/methods ; *Electromyography/methods/instrumentation ; Aged ; *Motor Neurons/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Torque ; Wrist Joint/physiopathology ; Adult ; Muscle Strength/physiology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a lethal progressive neurodegenerative disease characterized by upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Their varying degree of involvement results in a clinical heterogenous picture, making clinical assessments of UMN signs in patients with ALS often challenging. We therefore explored whether instrumented assessment using robotic manipulation could potentially be a valuable tool to study signs of UMN involvement.<br><br>METHODS: We examined the dynamics of the wrist joint of 15 patients with ALS and 15 healthy controls using a Wristalyzer single-axis robotic manipulator and electromyography (EMG) recordings in the flexor and extensor muscles in the forearm. Multi-sinusoidal torque perturbations were applied, during which participants were asked to either relax, comply or resist. A neuromuscular model was used to study muscle viscoelasticity, e.g. stiffness (k) and viscosity (b), and reflexive properties, such as velocity, position and force feedback gains (kv, kp and kf, respectively) that dominated the responses. We further obtained clinical signs of LMN (muscle strength) and UMN (e.g. reflexes, spasticity) dysfunction, and evaluated their relation with the estimated neuromuscular model parameters.<br><br>RESULTS: Only force feedback gains (kf) were elevated in patients (p&#x2009;=&#x2009;0.033) compared to controls. Higher kf, as well as the resulting reflexive torque (Tref), were both associated with more severe UMN dysfunction in the examined arm (p&#x2009;=&#x2009;0.040 and p&#x2009;<&#x2009;0.001). Patients with UMN symptoms in the examined arm had increased kf and Tref compared to controls (both p&#x2009;=&#x2009;0.037). Neither of these measures was related to muscle strength, but muscle stiffness (k) was lower in weaker patients (p&#x2009;=&#x2009;0.012). All these findings were obtained from the relaxed test. No differences were observed during the instructions comply and resist.<br><br>CONCLUSIONS: This findings are proof-of-concept that instrumented assessment using robotic manipulation is a feasible technique in ALS, which may provide quantitative, operator-independent measures relating to UMN symptoms. Elevated force feedback gains, driving larger reflexive muscle torques, appear to be particularly indicative of clinically established levels of UMN dysfunction in the examined arm.}, }
@article {pmid39472842, year = {2024}, author = {Guazzo, A and Atzeni, M and Idi, E and Trescato, I and Tavazzi, E and Longato, E and Manera, U and Chió, A and Gromicho, M and Alves, I and de Carvalho, M and Vettoretti, M and Di Camillo, B}, title = {Predicting clinical events characterizing the progression of amyotrophic lateral sclerosis via machine learning approaches using routine visits data: a feasibility study.}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {Suppl 4}, pages = {318}, pmid = {39472842}, issn = {1472-6947}, support = {GA01017598//HORIZON EUROPE Health/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; *Feasibility Studies ; *Disease Progression ; *Machine Learning ; Male ; Middle Aged ; Female ; Aged ; Prognosis ; Noninvasive Ventilation ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death within a short time span (3-5 years). One of the major challenges in treating ALS is its highly heterogeneous disease progression and the lack of effective prognostic tools to forecast it. The main aim of this study was, then, to test the feasibility of predicting relevant clinical outcomes that characterize the progression of ALS with a two-year prediction horizon via artificial intelligence techniques using routine visits data.<br><br>METHODS: Three classification problems were considered: predicting death (binary problem), predicting death or percutaneous endoscopic gastrostomy (PEG) (multiclass problem), and predicting death or non-invasive ventilation (NIV) (multiclass problem). Two supervised learning models, a logistic regression (LR) and a deep learning multilayer perceptron (MLP), were trained ensuring technical robustness and reproducibility. Moreover, to provide insights into model explainability and result interpretability, model coefficients for LR and Shapley values for both LR and MLP were considered to characterize the relationship between each variable and the outcome.<br><br>RESULTS: On the one hand, predicting death was successful as both models yielded F1 scores and accuracy well above 0.7. The model explainability analysis performed for this outcome allowed for the understanding of how different methodological approaches consider the input variables when performing the prediction. On the other hand, predicting death alongside PEG or NIV proved to be much more challenging (F1 scores and accuracy in the 0.4-0.6 interval).<br><br>CONCLUSIONS: In conclusion, predicting death due to ALS proved to be feasible. However, predicting PEG or NIV in a multiclass fashion proved to be unfeasible with these data, regardless of the complexity of the methodological approach. The observed results suggest a potential ceiling on the amount of information extractable from the database, e.g., due to the intrinsic difficulty of the prediction tasks at hand, or to the absence of crucial predictors that are, however, not currently collected during routine practice.}, }
@article {pmid39472796, year = {2024}, author = {Zheng, K and Chen, M and Xu, X and Li, P and Yin, C and Wang, J and Liu, B}, title = {Chemokine CXCL13-CXCR5 signaling in neuroinflammation and pathogenesis of chronic pain and neurological diseases.}, journal = {Cellular &amp; molecular biology letters}, volume = {29}, number = {1}, pages = {134}, pmid = {39472796}, issn = {1689-1392}, support = {82474625//National Natural Science Foundation of China/ ; 82305368//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Chemokine CXCL13/metabolism/genetics ; *Chronic Pain/metabolism/immunology ; *Receptors, CXCR5/metabolism ; *Signal Transduction ; *Nervous System Diseases/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism ; }, abstract = {Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C-X-C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13-CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13-CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13-CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13-CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases.}, }
@article {pmid39471924, year = {2024}, author = {Xu, Y and Xu, T and Huang, C and Liu, L and Kwame, AW and Zhu, Y and Ren, J}, title = {Preventive intervention with Agaricus blazei murill polysaccharide exerts anti-tumor immune effect on intraperitoneal metastasis colorectal cancer.}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 3}, pages = {136810}, doi = {10.1016/j.ijbiomac.2024.136810}, pmid = {39471924}, issn = {1879-0003}, mesh = {Animals ; *Agaricus/chemistry ; *Colorectal Neoplasms/pathology/immunology/prevention &amp; control/drug therapy ; Mice ; Cell Line, Tumor ; Tumor Microenvironment/drug effects ; Peritoneal Neoplasms/secondary/drug therapy/prevention &amp; control/immunology ; Fungal Polysaccharides/pharmacology/chemistry ; CD8-Positive T-Lymphocytes/drug effects/immunology ; Polysaccharides/pharmacology/chemistry ; Antineoplastic Agents/pharmacology ; }, abstract = {Agaricus blazei murill (ABM) mainly exerts its antitumor effect via modulation of the immune system. However, the immunomodulatory role of the ABM polysaccharide (ABMP) in mice with subcutaneously and intraperitoneally implanted MC38 tumor remains to be explored. This study aimed to define the progression effect of inhibiting tumor of ABMP in subcutaneous and intraperitoneal models and its effect on tumor microenvironment (TME) metabolism. In vitro experiments showed that ABMP could significantly promote the activity of CD8+ T immune cells in the co-culture system and promoted their colorectal cancer killing function (p < 0.05). In vivo animal exploration further showed that ABMP could inhibit the growth of intraperitoneal but not subcutaneous tumors. MCR-ALS analysis revealed a significant reduction in the signal of lipid-related spectral components in the TME of peritoneal tumors after ABMP intervention. In addition, preventive intervention with ABMP increased ω-3 polyunsaturated fatty acids content in intraperitoneal TME, revealing that ABMP shifted the metabolic landscape of the TME to promote T cell function and achieved immune regulation. These results suggest that the inhibitory effect of ABMP on colon cancer may be tumor stage-dependent, and that remodeling of fatty acid composition may be an important determinant of its action at any given stage.}, }
@article {pmid39471842, year = {2024}, author = {Ferro, F and Wolf, CR and Henstridge, C and Inesta-Vaquera, F}, title = {Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240073}, pmid = {39471842}, issn = {2046-2441}, support = {//MND Scotland/ ; //ARUK/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/genetics/pathology ; Animals ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Disease Models, Animal ; Humans ; *Mice, Transgenic ; *Genes, Reporter ; Oxidative Stress/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Drug Development ; DNA Damage ; Biomarkers ; }, abstract = {The development of therapies to combat neurodegenerative diseases is widely recognized as a research priority. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS, before moderate clinical signs are observed. Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters' expression. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.}, }
@article {pmid39471269, year = {2024}, author = {Stenson, K and Chew, S and Dong, S and Heithoff, K and Wang, MJ and Rosenfeld, J}, title = {Health care resource utilization and costs across stages of amyotrophic lateral sclerosis in the United States.}, journal = {Journal of managed care &amp; specialty pharmacy}, volume = {30}, number = {11}, pages = {1239-1247}, pmid = {39471269}, issn = {2376-1032}, mesh = {*Amyotrophic Lateral Sclerosis/economics/therapy ; Humans ; United States ; Male ; Female ; Middle Aged ; Aged ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; *Health Care Costs/statistics &amp; numerical data ; Adult ; Health Resources/economics/statistics &amp; numerical data ; Severity of Illness Index ; Retrospective Studies ; Disease Progression ; Cost of Illness ; Databases, Factual ; }, abstract = {BACKGROUND: People living with ALS (plwALS) experience motor control loss, speech/swallowing difficulties, respiratory insufficiency, and early death. Advancing disease stage is typically associated with a greater burden on the health care system, and delays in diagnosis can result in substantial health care resource utilization (HCRU).<br><br>OBJECTIVE: To estimate HCRU and cost burden of plwALS across disease stages from a US payer perspective we assessed HCRU and costs in early-, mid-, and late-stage ALS.<br><br>METHODS: Using insurance claims data from the IBM MarketScan Databases between January 2013 and December 2019, we identified plwALS as having at least 2 claims at least 27 days apart with an ALS International Classification of Diseases, Ninth or Tenth Revision diagnosis code (335.20/G12.21) or at least 1 ALS diagnosis code and prescription filled for riluzole/edaravone. Eligible plwALS were aged at least 18 years and had at least 12 months of enrollment data before and at least 6 months after the index date (date diagnosis criteria met). plwALS were grouped into disease stages using an ALS severity-based staging algorithm developed using ALS symptom and staging survey data from 142 neurologists reporting on 880 plwALS. The starting date of each severity stage was defined as the first date of an ALS symptom within the early-, mid-, and late-stage categories, respectively. The ending date for a severity stage was defined as the day before the first date of an ALS symptom from a more severe category. plwALS could transition to more severe stages, with reverse transition of severity excluded. Mixed regression modeling was used to assess differences in HCRU and costs per person-year between severity stages, adjusted for age and sex.<br><br>RESULTS: 2,273 plwALS were included in the total ALS study sample, with 1,215 early-stage, 1,511 midstage, and 1,186 late-stage plwALS. 90% of early-stage plwALS had ALS symptoms before diagnosis, and 27% of late-stage plwALS had a late-stage symptom before diagnosis. In the evaluation period, later-stage ALS groups had more overall hospital admissions (early = 0.15, middle = 0.23, and late = 0.74; P < 0.01), outpatient visits/service (early = 26.81, middle = 32.78, and late = 48.54; P < 0.01), emergency department visits (early = 0.46, middle = 0.69, and late = 1.03; P < 0.01), and total prescription count (early = 9.23, middle = 11.37, and late = 12.72; P < 0.01) over 12 months. Annualized costs increased as ALS progressed (early = $31,411, middle = $51,481, and late = $121,903; P < 0.01), which was primarily driven by higher frequency of and cost per hospital admission.<br><br>CONCLUSIONS: HCRU and costs increased with ALS progression, with diagnosis frequently occurring even after experiencing late-stage symptoms. These findings highlight the potential value of delaying progression into a more resource-intensive stage by diagnosing and adequately treating plwALS earlier in the disease course.}, }
@article {pmid39470866, year = {2024}, author = {Liu, Y and Fu, R and Jia, H and Yang, K and Ren, F and Zhou, MS}, title = {GHRH and its analogues in central nervous system diseases.}, journal = {Reviews in endocrine &amp; metabolic disorders}, volume = {}, number = {}, pages = {}, pmid = {39470866}, issn = {1573-2606}, support = {82270434//National Natural Science Foundation of China/ ; }, abstract = {Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases.}, }
@article {pmid39470847, year = {2025}, author = {Jellinger, KA}, title = {Mild cognitive impairment in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {3}, pages = {357-368}, pmid = {39470847}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {Humans ; *Cognitive Dysfunction/etiology/physiopathology/metabolism/diagnostic imaging ; *Amyotrophic Lateral Sclerosis/complications/metabolism/physiopathology ; Brain/diagnostic imaging/pathology/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.}, }
@article {pmid39470585, year = {2024}, author = {Lin, W and Wu, X and Ou, G}, title = {Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {20}, pages = {e70176}, pmid = {39470585}, issn = {1582-4934}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/blood ; *Genome-Wide Association Study ; *Cytokines/blood/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Alzheimer Disease/genetics/blood ; Amyotrophic Lateral Sclerosis/genetics/blood ; Inflammation/genetics/blood ; Multiple Sclerosis/genetics/blood ; Parkinson Disease/genetics/blood ; }, abstract = {Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.}, }
@article {pmid39470153, year = {2024}, author = {Xu, R}, title = {Overview of nomenclature and diagnosis of amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2422572}, pmid = {39470153}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/classification/physiopathology ; Humans ; *Terminology as Topic ; Electromyography/methods ; Motor Neurons/pathology ; }, abstract = {The nomenclature of amyotrophic lateral sclerosis (ALS) currently is blurred, indistinct and no accurate and haven't been properly updated since the first description, which is far from being suitable for the current implementation of clinical practise and scientific research of ALS, and urgently need an solution. Furthermore, the current diagnostic criteria need also further been improved, because the current clinical diagnosis of ALS majorly depends on the clinical manifestations yet. Up to now, no any objective clinical auxiliary examination can be helpful to diagnose ALS besides the electromyogram identifying the lower motor neuron damage, which isn't conducive to early diagnosis and prolongs the time of ALS confirmed diagnosis. In this mini review, we discussed the current doubt about the nomenclature and diagnostic criteria of ALS, and prospected in order to further improve and normalize the nomenclature and diagnosis of ALS.}, }
@article {pmid39468607, year = {2024}, author = {Liu, C and Wu, Y and Wang, F and Sun, S and Wei, J and Tao, L}, title = {Cost-utility analysis for sublingual versus intravenous edaravone in the treatment of amyotrophic lateral sclerosis.}, journal = {Orphanet journal of rare diseases}, volume = {19}, number = {1}, pages = {400}, pmid = {39468607}, issn = {1750-1172}, mesh = {*Edaravone/therapeutic use/economics/administration &amp; dosage ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/economics ; *Cost-Benefit Analysis ; Administration, Sublingual ; Antipyrine/analogs &amp; derivatives/therapeutic use/economics/administration &amp; dosage ; Free Radical Scavengers/therapeutic use/economics/administration &amp; dosage ; Administration, Intravenous ; Male ; }, abstract = {BACKGROUND: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context.<br><br>METHODS: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed.<br><br>RESULTS: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of &#xa5;12,670.04 and an additional 0.034 QALYs over 20&#xa0;years (life time) of modeling analysis, and the ICER was &#xa5;372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection.<br><br>CONCLUSIONS: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis.}, }
@article {pmid39467933, year = {2025}, author = {Kang, M and Kim, BJ and Nguyen, B and Park, JS}, title = {Computed tomography-based radiological gynecomastia in SBMA as an independent differential diagnostic biomarker: a retrospective study.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {783-789}, doi = {10.1007/s10072-024-07820-1}, pmid = {39467933}, issn = {1590-3478}, mesh = {Humans ; *Gynecomastia/diagnostic imaging ; Retrospective Studies ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; Diagnosis, Differential ; *Tomography, X-Ray Computed/methods ; Aged ; Adult ; }, abstract = {BACKGROUND: Spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are motor neuron disorders that demonstrate overlapping clinical features, especially in the early stage. Therefore, the aim of this study was to investigate the utility of chest tomography (CT) imaging in distinguishing between SBMA and ALS.<br><br>METHODS: This was a retrospective study reviewing CT images from patients with SBMA and sporadic ALS and those in the control group. The CT images were assessed to measure the diameter and morphology of glandular tissue associated with gynecomastia. We compared CT-measured gynecomastia between the SBMA, ALS, and control groups. Additionally, correlation analyses were performed between the quantitative measurements of gynecomastia obtained from CT scans and various clinical/laboratory parameter in the SBMA group.<br><br>RESULTS: 15 chest CT images were collected from SBMA, 41 from ALS, and 29 from control group. No statistical differences were observed in BMI, functional scales, or age at the time of CT scans between the SBMA and ALS groups. Despite similar functional scales and age in both groups, the mean glandular tissue diameter of breast tissue observed in chest CT imaging differed significantly between SBMA, ALS, and controls: 32.22&#x2009;&#xb1;&#x2009;12.57&#xa0;mm, 15.91&#x2009;&#xb1;&#x2009;4.81&#xa0;mm, and 15.76&#x2009;&#xb1;&#x2009;7.26&#xa0;mm, respectively. This disparity allowed for the differentiation of SBMA from ALS and controls with statistical significance. Clinical gynecomastia was 80%, while radiological gynecomastia was 93.3% in SBMA. A significantly higher prevalence of diffuse glandular morphology pattern in SBMA (50%) was observed, contrasting with the predominance of nodular morphology in ALS and controls (9.1% and 20%). Correlative analysis between glandular tissue diameter and other clinical/laboratory parameters within the SBMA group showed no specific finding.<br><br>CONCLUSION: CT-based radiological gynecomastia effectively differentiated SBMA from ALS. These findings support the usefulness of radiological gynecomastia as a potential differential diagnostic marker for SBMA, especially in the early stages.}, }
@article {pmid39466798, year = {2025}, author = {Correa, T and Owen, SR}, title = {Invited Commentary on: Santamaría-Gadea et al's "Non-Surgical Rhinoplasty After Rhinoplasty: A Systematic Review of the Technique, Results, and Complications".}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {27}, number = {1}, pages = {75-76}, doi = {10.1089/fpsam.2024.0267}, pmid = {39466798}, issn = {2689-3622}, }
@article {pmid39465944, year = {2024}, author = {Chen, C and Rafael, KA and Cho, G and Lim, Y}, title = {Split-Luciferase Reassembly Assay to Measure Endoplasmic Reticulum-Mitochondria Contacts in Live Cells.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {212}, pages = {}, doi = {10.3791/66862}, pmid = {39465944}, issn = {1940-087X}, mesh = {*Endoplasmic Reticulum/metabolism ; *Mitochondria/metabolism ; Humans ; Luciferases/metabolism/genetics ; Animals ; Mitochondria Associated Membranes ; }, abstract = {Endoplasmic reticulum (ER)-mitochondria contact sites play a critical role in cell health and homeostasis, such as the regulation of Ca[2+] and lipid homeostasis, mitochondrial dynamics, autophagosome and mitophagosome biogenesis, and apoptosis. Failure to maintain normal ER-mitochondrial coupling is implicated in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegia. It is of considerable significance to explore how the dysregulation of ER-mitochondrial contacts could lead to cell death and whether repairing these contacts to the normal level could ameliorate neurodegenerative conditions. Thus, improved assays that measure the level of these contacts could help to illuminate the pathogenic mechanisms of these diseases. Ultimately, establishing simple and reliable assays will facilitate the development of new therapeutic strategies. Here we describe a split-luciferase assay to quantitatively measure the level of ER-mitochondria contacts in live cells. This assay can be used to study the pathophysiological role of these contacts as well as to identify their modulators in high-throughput screening.}, }
@article {pmid39465642, year = {2024}, author = {Erdaş, &#xc7;B and Sümer, E}, title = {CNN-Based Neurodegenerative Disease Classification Using QR-Represented Gait Data.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70100}, pmid = {39465642}, issn = {2162-3279}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/classification/diagnosis/physiopathology ; *Huntington Disease/diagnosis/physiopathology/classification ; *Parkinson Disease/classification/diagnosis/physiopathology ; *Neurodegenerative Diseases/classification/diagnosis/physiopathology ; Male ; Middle Aged ; Female ; Neural Networks, Computer ; Gait/physiology ; Aged ; Deep Learning ; Gait Analysis/methods ; Adult ; }, abstract = {PURPOSE: The primary aim of this study is to develop an effective and reliable diagnostic system for neurodegenerative diseases by utilizing gait data transformed into QR codes and classified using convolutional neural networks (CNNs). The objective of this method is to enhance the precision of diagnosing neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD), through the introduction of a novel approach to analyze gait patterns.<br><br>METHODS: The research evaluates the CNN-based classification approach using QR-represented gait data to address the diagnostic challenges associated with neurodegenerative diseases. The gait data of subjects were converted into QR codes, which were then classified using a CNN deep learning model. The dataset includes recordings from patients with Parkinson's disease (n = 15), Huntington's disease (n = 20), and amyotrophic lateral sclerosis (n = 13), and from 16 healthy controls.<br><br>RESULTS: The accuracy rates obtained through 10-fold cross-validation were as follows: 94.86% for NDD versus control, 95.81% for PD versus control, 93.56% for HD versus control, 97.65% for ALS versus control, and 84.65% for PD versus HD versus ALS versus control. These results demonstrate the potential of the proposed system in distinguishing between different neurodegenerative diseases and control groups.<br><br>CONCLUSION: The results indicate that the designed system may serve as a complementary tool for the diagnosis of neurodegenerative diseases, particularly in individuals who already present with varying degrees of motor impairment. Further validation and research are needed to establish its wider applicability.}, }
@article {pmid39464638, year = {2024}, author = {Altuwaijri, F and Alrabiah, A and Alqarni, A and Habash, AK and Alghofili, M and Alotaibi, O and Altuwaijri, M}, title = {Comparison Between the Advanced Cardiac Life Support and Adult Advanced Life Support Protocols: A Simulation-Based Pilot Study.}, journal = {Emergency medicine international}, volume = {2024}, number = {}, pages = {6696879}, pmid = {39464638}, issn = {2090-2840}, abstract = {Introduction: Cardiac arrest is a public health concern associated with unfavorable disease outcomes. Cardiopulmonary resuscitation (CPR) of optimal quality is widely acknowledged as an indispensable technique in restoring spontaneous circulation. In order to perform advanced cardiac life support (ACLS), chest compression must be paused twice: once to assess the rhythm and again to administer the shock. Australian advanced life support (ALS) recommends that the defibrillator needs to be precharged in order to administer the shock during a solitary interval in chest compressions. While performing chest compressions, precharging defibrillators can decrease hands-off time without posing a risk of injury. Aim: To compare chest compression fraction (CCF)-which is the cumulative time spent providing chest compressions divided by the total time taken for the entire resuscitation-by calculating the hands-off time duration in cardiac arrest between the Australian Resuscitation Council (ARC) and American Heart Association (AHA) protocols for CPR. Methods: A simulation-based pilot study was designed using a Laerdal Resusci Anne mannequin and a LIFEPACK 20 defibrillator. The study included six participants recruited from King Khalid University Hospital in Riyadh, Saudi Arabia, where three participants were certified ACLS providers and there were certified ALS providers. Participants were divided into two groups, ALS and ACLS, each following one protocol. For each scenario, a random job was assigned to each participant, regardless of their role as assistant, team leader, or performer of CPR. Each case's shockable and nonshockable rhythms were hidden from the team leader and the chest compressor. Ten trials of CPR were performed, each for four cycles with a total time of 8 min. The simulation was video recorded for hands-off time counting. Comparison between CCF (seconds) per cycle between the two protocols was performed using an independent sample t-test. A p value of 0.05 was used to measure statistical significance. Results: Comparing CCF in shockable rhythms between ARC and AHA protocols, it was observed that the CCF of ALS-ARC was significantly higher than ACLS-AHA in all cycles; the first cycle: t = 3.782, p=0.004; the second cycle: t = 3.380, p=0.007; the third cycle: t = 3.803, p=0.003; and the fourth cycle: t = 4.341, p=0.001. Conclusion: Precharging a defibrillator before a rhythm check during chest compression, in anticipation of a potentially shockable rhythm, reduces the time required for defibrillation and limits interruptions in chest compression during CPR. This practice effectively enhances the CCF. Enhancing the continuity of chest compressions can potentially improve survival rates in ARC.}, }
@article {pmid39464461, year = {2024}, author = {Karunakaran, V and Dadgar, S and Paidi, SK and Mordi, AF and Lowe, WA and Mim, UM and Ivers, JD and Rodriguez Troncoso, JI and McPeake, JA and Fernandes, A and Tripathi, SD and Barman, I and Rajaram, N}, title = {Investigating In Vivo Tumor Biomolecular Changes Following Radiation Therapy Using Raman Spectroscopy.}, journal = {ACS omega}, volume = {9}, number = {42}, pages = {43025-43033}, pmid = {39464461}, issn = {2470-1343}, support = {P20 GM139768/GM/NIGMS NIH HHS/United States ; P41 EB015871/EB/NIBIB NIH HHS/United States ; R01 CA238025/CA/NCI NIH HHS/United States ; R15 CA238861/CA/NCI NIH HHS/United States ; }, abstract = {Treatment resistance is a major bottleneck in the success of cancer therapy. Early identification of the treatment response or lack thereof in patients can enable an earlier switch to alternative treatment strategies that can enhance response rates. Here, Raman spectroscopy was applied to monitor early tumor biomolecular changes in sensitive (UM-SCC-22B) and resistant (UM-SCC-47) head and neck tumor xenografts for the first time in in vivo murine tumor models in response to radiation therapy. We used a validated multivariate curve resolution-alternating least-squares (MCR-ALS) model to resolve complex multicomponent Raman spectra into individual pure spectra and their respective contributions. We observed a significant radiation-induced increase in the contributions of lipid-like species (p = 0.0291) in the radiation-sensitive UM-SCC-22B tumors at 48 h following radiation compared to the nonradiated baseline (prior to commencing treatment). We also observed an increase in the contribution of collagen-like species in the radiation-resistant UM-SCC-47 tumors at 24 h following radiation compared to the nonradiated baseline (p = 0.0125). In addition to the in vivo analysis, we performed ex vivo confocal Raman microscopic imaging of frozen sections derived from the same tumors. A comparison of all control and treated tumors revealed similar trends in the contributions of lipid-like and collagen-like species in both in vivo and ex vivo measurements; however, when evaluated as a function of time, longitudinal trends in the scores of collagen-like and lipid-like components were not consistent between the two data sets, likely due to sample numbers and differences in sampling depth at which information is obtained. Nevertheless, this study demonstrates the potential of fiber-based Raman spectroscopy for identifying early tumor microenvironmental changes in response to clinical doses of radiation therapy.}, }
@article {pmid39464100, year = {2024}, author = {Du, M and Akerman, SC and Fare, CM and Ruan, L and Vidensky, S and Mamedova, L and Lee, J and Rothstein, JD}, title = {Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464100}, issn = {2692-8205}, support = {P50 AG005146/AG/NIA NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.}, }
@article {pmid39463426, year = {2025}, author = {Yang, SF and Patel, PN}, title = {Invited Commentary on: Youssefi et al's 3D Smartphone Photography During Rhinoplasty Surgery.}, journal = {Facial plastic surgery &amp; aesthetic medicine}, volume = {27}, number = {2}, pages = {199-200}, doi = {10.1089/fpsam.2024.0265}, pmid = {39463426}, issn = {2689-3622}, }
@article {pmid39462586, year = {2024}, author = {Kurita, H and Hirasawa, N and Yabe, S and Okuda, A and Murakami, T and Ohuchi, K and Ogata, A and Yoshioka, H and Kakita, A and Hozumi, I and Inden, M}, title = {MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {47}, number = {10}, pages = {1717-1725}, doi = {10.1248/bpb.b24-00418}, pmid = {39462586}, issn = {1347-5215}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Endoplasmic Reticulum Stress/drug effects/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; *Zinc/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; HEK293 Cells ; Transfection ; Tunicamycin/toxicity ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS. Previously, we first reported miR-5572 as a microRNA (miRNA) among those identified in the spinal cords of patients with sporadic ALS. However, since its function in ALS remained unknown, this study further examined the role of miR-5572 in low-zinc status and ALS model cells which transfected with causative gene, Cu/Zn superoxide dismutase 1 (SOD1) G85R mutant vector. The miR-5572 level was increased by low-zinc condition accompanied by increase of endoplasmic reticulum (ER) stress. In addition, increase of miR-5572 enhanced the cellular toxicity induced by low-zinc treatment. The expression of miR-5572 was also increased, which was accompanied by an increase of ER stress markers associated with SOD1 aggregation formation. Cell death and ER stress makers levels induced by tunicamycin treatment were further increased in miR-5572 mimic-transfected cells. This study showed that miR-5572 exacerbated ER stress toxicity associated with low-zinc status and mutant SOD1 aggregates in ALS.}, }
@article {pmid39462509, year = {2024}, author = {Dauer, LT and Mumma, MT and Lima, JC and Cohen, SS and Andresen, D and Bahadori, AA and Bellamy, M and Bierman, DA and Blattnig, S and French, B and Giunta, E and Held, K and Hertel, N and Keohane, L and Leggett, R and Lipworth, L and Miller, KB and Norman, RB and Samuels, C and Thomas, KS and Tolmachev, SY and Walsh, L and Boice, JD}, title = {A Million Person Study Innovation: Evaluating Cognitive Impairment and other Morbidity Outcomes from Chronic Radiation Exposure Through Linkages with the Centers for Medicaid and Medicare Services Assessment and Claims Data.}, journal = {Radiation research}, volume = {202}, number = {6}, pages = {847-861}, doi = {10.1667/RADE-23-00186.1}, pmid = {39462509}, issn = {1938-5404}, mesh = {Humans ; United States/epidemiology ; *Radiation Exposure/adverse effects ; Centers for Medicare and Medicaid Services, U.S. ; Male ; Medicare ; Female ; Cognition Disorders/epidemiology/etiology ; }, abstract = {The study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.}, }
@article {pmid39461864, year = {2024}, author = {Imamura, K and Izumi, Y and Egawa, N and Ayaki, T and Nagai, M and Nishiyama, K and Watanabe, Y and Murakami, T and Hanajima, R and Kataoka, H and Kiriyama, T and Nanaura, H and Sugie, K and Hirayama, T and Kano, O and Nakamori, M and Maruyama, H and Haji, S and Fujita, K and Atsuta, N and Tatebe, H and Tokuda, T and Takahashi, N and Morinaga, A and Tabuchi, R and Oe, M and Kobayashi, M and Lobello, K and Morita, S and Sobue, G and Takahashi, R and Inoue, H}, title = {Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study.}, journal = {BMJ open}, volume = {14}, number = {10}, pages = {e082142}, pmid = {39461864}, issn = {2044-6055}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Aniline Compounds/therapeutic use ; Clinical Trials, Phase II as Topic ; *Drug Repositioning ; Induced Pluripotent Stem Cells ; Japan ; Multicenter Studies as Topic ; *Nitriles/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; *Quinolines/therapeutic use ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.<br><br>METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200&#x2009;mg quaque die (QD) group and 13 patients in the 300&#x2009;mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.<br><br>ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.<br><br>TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.}, }
@article {pmid39461630, year = {2024}, author = {Kouhi, ZH and Seyedalipour, B and Hosseinkhani, S and Chaichi, MJ}, title = {Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).}, journal = {International journal of biological macromolecules}, volume = {282}, number = {Pt 2}, pages = {136701}, doi = {10.1016/j.ijbiomac.2024.136701}, pmid = {39461630}, issn = {1879-0003}, mesh = {*Diarylheptanoids/chemistry/pharmacology ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/metabolism ; *Protein Aggregates/drug effects ; *Amyloid/metabolism/chemistry ; *Superoxide Dismutase-1/genetics/metabolism/chemistry ; *Mutation ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; Curcumin/pharmacology/analogs &amp; derivatives/chemistry ; Polyphenols/pharmacology/chemistry ; Protein Aggregation, Pathological/genetics/drug therapy ; Hemolysis/drug effects ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Protein misfolding is a biological process that leads to protein aggregation. Anomalous misfolding and aggregation of human superoxide dismutase (hSOD1) into amyloid aggregates is a characteristic feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness. Thus, focusing on the L38R mutant may be a wise decision to comprehend the SOD1 disease process in ALS. We suggest that Bisdemethoxycurcumin (BDMC) may be a strong anti-amyloidogenic polyphenol against L38R mutant aggregation. Protein stability, hydrophobicity, and flexibility were altered when BDMC was bound to the L38R mutant, as shown by molecular dynamic (MD) simulations and molecular docking. FTIR data shows α-Helix dominance in BDMC-containing samples, with reduced β-sheet and disordered peaks, indicating the decrease of aggregate species. ThT aggregation kinetics curves show BDMC reduces L38R mutant aggregation dose-dependently, with higher BDMC concentrations yielding greater reductions. TEM images showed various quantities of amorphous aggregates, but notably, 60 μM BDMC markedly reduced aggregate density, underscoring BDMC's inhibitory effect. Hemolysis tests revealed aggregate species in BDMC-treated samples were less toxic than in L38R mutant samples alone at the same concentrations and exposure times. Overall, BDMC has substantial potential to develop highly effective inhibitors that mitigate the risk of fatal ALS.}, }
@article {pmid39461320, year = {2024}, author = {Didcote, L and Vitoratou, S and Al-Chalabi, A and Goldstein, LH}, title = {The reliability and validity of in-person and remote behavioural screening tools for people with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123282}, doi = {10.1016/j.jns.2024.123282}, pmid = {39461320}, issn = {1878-5883}, support = {GOLDSTEIN/OCT17/892-792/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/psychology ; Male ; Female ; Middle Aged ; Reproducibility of Results ; Aged ; *Psychometrics/methods/standards ; Surveys and Questionnaires/standards ; Neuropsychological Tests/standards ; Adult ; }, abstract = {OBJECTIVE: This study aimed to assess the psychometric properties of and relationships between total scores on different screening tools assessing behavioural change for people with amyotrophic lateral sclerosis (ALS), and whether administering the screens as online questionnaires (rather than on paper, in-person) influences total scores.<br><br>METHODS: The behavioural component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASb); the behavioural component of the ALS Cognitive Behavioural Screen (ALS-CBSb), the ALS-Frontotemporal Dementia Questionnaire (ALS-FTD-Q), the Beaumont Behavioural Inventory (BBI), and the Motor Neuron Disease Behavioural Instrument (MiND-B) were administered to 35 informants on paper. Online questionnaire versions of the behavioural screens were administered to 49 informants. Forward stepwise linear regressions were conducted to assess whether scores on behavioural screens were predicted by scores on the other behavioural screens and to assess whether total scores were predicted by the mode of administration (paper or online) of the screens.<br><br>RESULTS: Behavioural screening tools, except the ECASb, had good internal consistency but mixed item-total correlations. All regression models assessing whether behavioural screen scores predict other behavioural screen scores were significant. The BBI performed best and the ECASb performed worst in terms of their predictive relationships with other screening tools. The administration mode of the questionnaires did not significantly affect total scores.<br><br>CONCLUSIONS: The psychometric properties of the scales varied. The scales predicted each other's scores, supporting convergent validity. Online and paper versions performed similarly, and demographics did not predict scores.}, }
@article {pmid39460670, year = {2025}, author = {Gondim, FAA and Fernandes, JMA}, title = {ALS due to c.1189 + 1G &gt; T (splice donor) TBK1 mutation.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {180}, doi = {10.1080/21678421.2024.2421754}, pmid = {39460670}, issn = {2167-9223}, }
@article {pmid39459584, year = {2024}, author = {Silva, F and Silva, J and Salgueira, S and Mendes, A and Matos, E and Conde, B}, title = {Sleep Disturbances in Amyotrophic Lateral Sclerosis and Prognostic Impact-A Retrospective Study.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459584}, issn = {2075-1729}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with sleep disturbance, namely insomnia and sleep-disordered breathing. This study aims to evaluate the overall sleep characteristics of ALS patients, their association with lung function tests, and possible predictive survival factors. We conducted a retrospective observation study among ALS patients monitored during a pulmonology consultation. Type one polysomnography (PSG) and lung function tests were performed once the patients presented with sleep-related symptoms, and the relationship between their parameters was assessed, as well as a survival analysis. We included 35 patients, with an overall diminished sleep efficiency, a partially conserved forced vital capacity (FVC), and low maximal inspiratory pressure (MIP). A positive correlation between FVC and REM sleep percentage was observed. A survival analysis showed that a normal rapid eye movement (REM) sleep percentage and respiratory disturbance index (RDI) ≥ 15/h were independent predictors of survival. We observed a trend for higher sleep quality in patients with conserved lung function. A better sleep quality was associated with a higher survival. Obstructive events (reduced or absence of airflow associated with continued or increased inspiratory effort) did not seem to impact survival.}, }
@article {pmid39459534, year = {2024}, author = {Nakhal, MM and Yassin, LK and Alyaqoubi, R and Saeed, S and Alderei, A and Alhammadi, A and Alshehhi, M and Almehairbi, A and Al Houqani, S and BaniYas, S and Qanadilo, H and Ali, BR and Shehab, S and Statsenko, Y and Meribout, S and Sadek, B and Akour, A and Hamad, MIK}, title = {The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {39459534}, issn = {2075-1729}, support = {12M159//UAEU/ ; G00004325//UAEU/ ; 12M142//UAEU/ ; }, abstract = {Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.}, }
@article {pmid39459490, year = {2024}, author = {Banciu, C and Chiriac, S and Pojoga, C and Marian, L and Fabian, A and Gogulescu, A and Simu, M and Parvanescu, R and Mioc, A and Racoviceanu, R and Munteanu, A}, title = {An Uncommon Overlap Syndrome Between Ankylosing Spondylitis and Amyotrophic Lateral Sclerosis-Case Report.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {10}, pages = {}, pmid = {39459490}, issn = {1648-9144}, support = {//"Victor Babes" University of Medicine and Pharmacy Timisoara/ ; }, mesh = {Humans ; *Spondylitis, Ankylosing/complications/drug therapy ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Male ; Middle Aged ; Etanercept/therapeutic use ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; Syndrome ; }, abstract = {This case report describes an uncommon overlap syndrome between ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS). Initially, the patient was diagnosed with AS, for which he received various specific treatments, including TNF-α inhibitors. After five years of treatment with TNF-α inhibitor etanercept, the patient was referred for a full neurological assessment after he reported balance disturbances, postural instability, muscle weakness, and other neurological symptoms that indicated the presence of a neurological disorder. After a thorough investigation, the patient was diagnosed with ALS. This case report aims to contribute to the limited literature by providing a detailed case study regarding the crosstalk between AS and ALS while also exploring the potential underlying mechanisms and the possible link between TNF-α inhibitors therapy and ALS.}, }
@article {pmid39459030, year = {2024}, author = {Al-Khayri, JM and Ravindran, M and Banadka, A and Vandana, CD and Priya, K and Nagella, P and Kukkemane, K}, title = {Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39459030}, issn = {1424-8247}, support = {GRANT0000//Deanship of Scientific Research, King Faisal University/ ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.}, }
@article {pmid39458929, year = {2024}, author = {Giannakou, M and Akrani, I and Tsoka, A and Myrianthopoulos, V and Mikros, E and Vorgias, C and Hatzinikolaou, DG}, title = {Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {10}, pages = {}, pmid = {39458929}, issn = {1424-8247}, support = {MIS-5000432//state scholarship foundation (GR)/ ; }, abstract = {BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.<br><br>METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC[&#xae;]) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.<br><br>RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 &#xb0;C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 &#xb0;C, suggesting possible interactions or non-specific binding.}, }
@article {pmid39458862, year = {2024}, author = {Palacıoğlu, G}, title = {Chitosan, Methyl Jasmonate, and Silicon Induce Resistance to Angular Leaf Spot in Common Bean, Caused by Pseudocercospora griseola, with Expression of Defense-Related Genes and Enzyme Activities.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {20}, pages = {}, pmid = {39458862}, issn = {2223-7747}, abstract = {This study assessed the efficacy of chitosan, methyl jasmonate, and silicon in the reduction of disease severity and the induction of defense responses in common bean plants against angular leaf spot caused by Pseudocercospora griseola. The expression level of several pathogenesis-related (PR) proteins, PR1, PR2 (β-1,3-glucanase), and PR3 (chitinase), and defense-related enzymes, phenylalanine ammonia-lyase, peroxidase, and lipoxygenase, was analyzed at different time points in common bean plants after different treatments. Elicitor treatments significantly reduced disease severity 21 days after inoculation, with silicon at a 2 mM concentration proving most effective with 38.93% disease control, followed by 1 mM MeJA and 2% chitosan, respectively. Treatments with chitosan, methyl jasmonate, and silicon, regardless of pathogen infection, significantly elevated PR1, PR2, and PR3 gene expressions at 48 h after inoculation (hpi). PAL and POD activities were similarly increased following elicitor treatments and pathogen infection, especially at 48 hpi. Chemical elicitors applied post-inoculation induced PR proteins, PAL, and POD enzyme activities at 48 hpi, while LOX activity exhibited a variable fluctuation with treatments. These findings suggested that chemical elicitors, especially silicon, were effective in reducing ALS disease severity in common beans, with improved resistance associated with the expression of pathogen-responsive genes. This study is the first to analyze the expression profiles of defense-related genes in common beans treated with chemical elicitors prior to P. griseola infection.}, }
@article {pmid39457680, year = {2024}, author = {McGrath, MS and Zhang, R and Bracci, PM and Azhir, A and Forrest, BD}, title = {Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457680}, issn = {2227-9059}, support = {Neuvivo-NP001//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.<br><br>METHODS: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.<br><br>CONCLUSIONS: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.}, }
@article {pmid39457678, year = {2024}, author = {Forrest, BD and Goyal, NA and Fleming, TR and Bracci, PM and Brett, NR and Khan, Z and Robinson, M and Azhir, A and McGrath, M}, title = {The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457678}, issn = {2227-9059}, support = {01//Neuvivo, Inc./ ; }, abstract = {BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months' treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis.<br><br>METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities.<br><br>RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged &#x2264; 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years.<br><br>CONCLUSIONS: The findings from this study suggest that a 6 months' treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.}, }
@article {pmid39457513, year = {2024}, author = {Montiel-Troya, M and Mohamed-Mohamed, H and Pardo-Moreno, T and González-Díaz, A and Ruger-Navarrete, A and de la Mata Fernández, M and Tovar-Gálvez, MI and Ramos-Rodríguez, JJ and García-Morales, V}, title = {Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457513}, issn = {2227-9059}, support = {PID2019-110960GB-I00//Ministry of Science and Innovation, Spain./ ; }, abstract = {(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.}, }
@article {pmid39457505, year = {2024}, author = {Seta, Y and Kimura, K and Masahiro, G and Tatsumori, K and Murakami, Y}, title = {SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis.}, journal = {Biomedicines}, volume = {12}, number = {10}, pages = {}, pmid = {39457505}, issn = {2227-9059}, abstract = {BACKGROUND/OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM).<br><br>METHODS: Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023.<br><br>RESULTS: While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant.<br><br>CONCLUSIONS: The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.}, }
@article {pmid39457470, year = {2024}, author = {Trabacca, A and Ferrante, C and Oliva, MC and Fanizza, I and Gallo, I and De Rinaldis, M}, title = {Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457470}, issn = {2073-4425}, support = {2024//The Italian Health Ministry - Ricerca Corrente/ ; }, mesh = {Humans ; *Motor Neuron Disease/genetics/pathology ; Child ; Mutation ; Muscular Atrophy, Spinal/genetics/pathology/diagnosis ; Exome Sequencing ; }, abstract = {BACKGROUND: Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype.<br><br>METHODS: We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases.<br><br>RESULTS: The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy.<br><br>CONCLUSION: This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs.}, }
@article {pmid39457468, year = {2024}, author = {Boura, I and Giannopoulou, IA and Pavlaki, V and Xiromerisiou, G and Mitsias, P and Spanaki, C}, title = {FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457468}, issn = {2073-4425}, mesh = {Humans ; *Parkinsonian Disorders/genetics/pathology/diagnostic imaging ; *Charcot-Marie-Tooth Disease/genetics/pathology ; *Flavoproteins/genetics ; Female ; Male ; Mutation, Missense ; Middle Aged ; Mutation ; Adult ; Phosphoric Monoester Hydrolases ; }, abstract = {Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.}, }
@article {pmid39457466, year = {2024}, author = {Moriyama, H and Yokota, T}, title = {Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.}, journal = {Genes}, volume = {15}, number = {10}, pages = {}, pmid = {39457466}, issn = {2073-4425}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy/therapy ; Humans ; *Superoxide Dismutase-1/genetics ; *Oligonucleotides, Antisense/therapeutic use/genetics ; *Mutation ; Animals ; Oligonucleotides/therapeutic use/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.}, }
@article {pmid39456682, year = {2024}, author = {Alshehri, RS and Abuzinadah, AR and Alrawaili, MS and Alotaibi, MK and Alsufyani, HA and Alshanketi, RM and AlShareef, AA}, title = {A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.}, journal = {International journal of molecular sciences}, volume = {25}, number = {20}, pages = {}, pmid = {39456682}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/physiopathology/diagnosis ; Humans ; *Biomarkers/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers.}, }
@article {pmid39456494, year = {2024}, author = {De Stefano, S and Tiberi, M and Salvatori, I and De Bardi, M and Gimenez, J and Pirshayan, M and Greco, V and Borsellino, G and Ferri, A and Valle, C and Mercuri, NB and Chiurchiù, V and Spalloni, A and Longone, P}, title = {Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {39456494}, issn = {2076-3921}, abstract = {Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different biochemical processes. In the central nervous system, depending on its concentration, it can be protective or damaging to neurons. In the study, we have demonstrated, in a primary mouse spinal cord cultures, that it is particularly harmful to motor neurons, is produced by glial cells, and is stimulated by inflammation. However, its role on glial cells, especially astrocytes, is still under-investigated. The present study was designed to evaluate the impact of H2S on astrocytes and their phenotypic heterogeneity, together with the functionality and homeostasis of mitochondria in primary spinal cord cultures. We found that H2S modulates astrocytes' morphological changes and their phenotypic transformation, exerts toxic properties by decreasing ATP production and the mitochondrial respiration rate, disturbs mitochondrial depolarization, and alters the energetic metabolism. These results further support the hypothesis that H2S is a toxic mediator, mainly released by astrocytes, possibly acting as an autocrine factor toward astrocytes, and probably involved in the non-cell autonomous mechanisms leading to motor neuron death.}, }
@article {pmid39456257, year = {2024}, author = {Perni, M and Mannini, B}, title = {Targeting Protein Aggregation in ALS.}, journal = {Biomolecules}, volume = {14}, number = {10}, pages = {}, pmid = {39456257}, issn = {2218-273X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy ; *Protein Aggregation, Pathological/metabolism ; Protein Aggregates ; Animals ; }, abstract = {Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.}, }
@article {pmid39456026, year = {2024}, author = {Albagli, EA and Calliari, A and Gendron, TF and Zhang, YJ}, title = {HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease.}, journal = {Molecular neurodegeneration}, volume = {19}, number = {1}, pages = {79}, pmid = {39456026}, issn = {1750-1326}, support = {P01NS084974/NS/NINDS NIH HHS/United States ; U19AG063911/AG/NIA NIH HHS/United States ; R21NS127331/NS/NINDS NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R21 NS127331/NS/NINDS NIH HHS/United States ; R01NS121125/NS/NINDS NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01NS117461/NS/NINDS NIH HHS/United States ; Target ALS//Target ALS/ ; R01 NS117461/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; R01 AG085307/AG/NIA NIH HHS/United States ; R01AG085307/AG/NIA NIH HHS/United States ; }, }
@article {pmid39455963, year = {2024}, author = {Alexander, E and Leong, KW}, title = {Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {661}, pmid = {39455963}, issn = {1477-3155}, mesh = {*Single-Domain Antibodies/chemistry ; Humans ; Animals ; *SARS-CoV-2/immunology ; COVID-19/virology/immunology ; Neurodegenerative Diseases/drug therapy ; }, abstract = {Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field.}, }
@article {pmid39455931, year = {2024}, author = {Martínez, P and Silva, M and Abarzúa, S and Tevy, MF and Jaimovich, E and Constantine-Paton, M and Bustos, FJ and van Zundert, B}, title = {Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {185}, pmid = {39455931}, issn = {1528-3658}, support = {1181645//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; DI-06-24/REG//UNAB/ ; 1221745//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 21151265//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; R01-638 EY014420//National Institute of Mental Health and Neurosciences/ ; R01-EY014074//National Institute of Mental Health and Neurosciences/ ; R03 EY014420/EY/NEI NIH HHS/United States ; 1151293//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; 13220203 explorador//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; NCN2023_32//Agencia Nacional de Investigaci&#xf3;n y Desarrollo/ ; }, mesh = {Animals ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Mitochondria/metabolism ; *Superoxide Dismutase-1/genetics/metabolism ; Mice ; Humans ; *Mice, Transgenic ; *Axonal Transport ; Cell Death ; Disease Models, Animal ; Mutation ; Cells, Cultured ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1[G93A] (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2 + transients and reactive oxygen species (i.e., H2O2). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.}, }
@article {pmid39454934, year = {2025}, author = {Takeda, T and Her, YR and Kim, JK and Jha, NN and Monani, UR}, title = {A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1[G86R] mouse model of amyotrophic lateral sclerosis.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {115024}, pmid = {39454934}, issn = {1090-2430}, support = {R01 NS104218/NS/NINDS NIH HHS/United States ; R01 NS123292/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *HSC70 Heat-Shock Proteins/metabolism/genetics ; *Superoxide Dismutase-1/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; Mutation ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8[G470R] in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.}, }
@article {pmid39451992, year = {2024}, author = {Ozdinler, PH}, title = {Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?.}, journal = {Brain sciences}, volume = {14}, number = {10}, pages = {}, pmid = {39451992}, issn = {2076-3425}, abstract = {Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.}, }
@article {pmid39451800, year = {2024}, author = {Drăgoi, MV and Nisipeanu, I and Frimu, A and Tălîngă, AM and Hadăr, A and Dobrescu, TG and Suciu, CP and Manea, AR}, title = {Real-Time Home Automation System Using BCI Technology.}, journal = {Biomimetics (Basel, Switzerland)}, volume = {9}, number = {10}, pages = {}, pmid = {39451800}, issn = {2313-7673}, abstract = {A Brain-Computer Interface (BCI) processes and converts brain signals to provide commands to output devices to carry out certain tasks. The main purpose of BCIs is to replace or restore the missing or damaged functions of disabled people, including in neuromuscular disorders like Amyotrophic Lateral Sclerosis (ALS), cerebral palsy, stroke, or spinal cord injury. Hence, a BCI does not use neuromuscular output pathways; it bypasses traditional neuromuscular pathways by directly interpreting brain signals to command devices. Scientists have used several techniques like electroencephalography (EEG) and intracortical and electrocorticographic (ECoG) techniques to collect brain signals that are used to control robotic arms, prosthetics, wheelchairs, and several other devices. A non-invasive method of EEG is used for collecting and monitoring the signals of the brain. Implementing EEG-based BCI technology in home automation systems may facilitate a wide range of tasks for people with disabilities. It is important to assist and empower individuals with paralysis to engage with existing home automation systems and gadgets in this particular situation. This paper proposes a home security system to control a door and a light using an EEG-based BCI. The system prototype consists of the EMOTIV Insight™ headset, Raspberry Pi 4, a servo motor to open/close the door, and an LED. The system can be very helpful for disabled people, including arm amputees who cannot close or open doors or use a remote control to turn on or turn off lights. The system includes an application made in Flutter to receive notifications on a smartphone related to the status of the door and the LEDs. The disabled person can control the door as well as the LED using his/her brain signals detected by the EMOTIV Insight™ headset.}, }
@article {pmid39451396, year = {2024}, author = {Yang, CH and Huang, JL and Tsai, LK and Taniar, D and Pai, TW}, title = {An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {39451396}, issn = {2306-5354}, support = {MOST 111-2221-E-027-113-414 MY2//National Science and Technology Council (Taiwan)/ ; NSTC113-2221-E-027-109//National Science and Technology Council (Taiwan)/ ; MOST104-2321-B-019-009//National Science and Technology Council (Taiwan)/ ; }, abstract = {This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3, CACNA1H, and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.}, }
@article {pmid39451238, year = {2024}, author = {Crescioli, C and Paronetto, MP}, title = {The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.}, journal = {Cells}, volume = {13}, number = {20}, pages = {}, pmid = {39451238}, issn = {2073-4409}, mesh = {Humans ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Neuroinflammatory Diseases/drug therapy/metabolism ; }, abstract = {Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.}, }
@article {pmid39449756, year = {2024}, author = {Filipi, T and Tureckova, J and Vanatko, O and Chmelova, M and Kubiskova, M and Sirotova, N and Matejkova, S and Vargova, L and Anderova, M}, title = {ALS-like pathology diminishes swelling of spinal astrocytes in the SOD1 animal model.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1472374}, pmid = {39449756}, issn = {1662-5102}, abstract = {Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.}, }
@article {pmid39449457, year = {2024}, author = {Rosa, D and Ingrande, L and Marcomini, I and Poliani, A and Villa, G and Sodano, M and Manara, DF}, title = {Perceived Pain in People Living with Amyotrophic Lateral Sclerosis-A Scoping Review.}, journal = {Nursing reports (Pavia, Italy)}, volume = {14}, number = {4}, pages = {3023-3039}, pmid = {39449457}, issn = {2039-4403}, abstract = {(1) Background: Pain is a common symptom in patients with Amyotrophic Lateral Sclerosis (ALS). There are no evidence-based pharmacological treatments for pain in ALS; recommendations are based on guidelines for chronic non-oncological pain and clinical experience. The aim is to map the literature on how people with ALS experience pain, and how this affects their daily activities and social relationships. (2) Methods: This scoping review included studies concerning patients with spinal/bulbar ALS aged ≥ 18 years who experience pain, focusing on perception, characteristics, treatment, and impact on quality of life. Temporal and linguistic criteria were applied when searching the MEDLINE, CINAHL, and SCOPUS databases. (3) Results: The management of pain in these patients is complex and involves the use of anti-inflammatory drugs, analgesics, and opioids. Pain is associated with other conditions such as depression and anxiety, which contribute to a deterioration in the quality of life. Moreover, pain may also negatively influence patient compliance with prescribed treatment regimens and the quality of care they perceive themselves to be receiving. (4) Conclusions: It is of the most importance to identify effective ways to assess and treat this issue, with health care professionals taking an active role in this process.}, }
@article {pmid39449162, year = {2024}, author = {Zhu, Y and Zhang, Y and Li, M and Bai, J and Wang, H and Pang, X and Du, R and Wang, J and Huang, X}, title = {Prognostic Value of Systemic Inflammation, Nutritional Status and Sarcopenia in Patients With Amyotrophic Lateral Sclerosis.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {15}, number = {6}, pages = {2743-2755}, pmid = {39449162}, issn = {2190-6009}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/mortality/blood ; Female ; Male ; *Nutritional Status ; *Sarcopenia/etiology/blood ; Middle Aged ; Prognosis ; *Inflammation/blood ; Aged ; Biomarkers/blood ; Proportional Hazards Models ; ROC Curve ; Kaplan-Meier Estimate ; Adult ; }, abstract = {BACKGROUND: Nutritional status, systemic inflammatory responses and muscle mass are associated with the prognosis of patients with amyotrophic lateral sclerosis (ALS). However, the optimal biomarker for predicting prognosis remains unclear. This study aimed to identify the optimal indicators of survival among the nutrition-based, inflammation-based and muscle mass-related markers for ALS patients.<br><br>METHODS: We enrolled ALS patients from January 2014 to December 2019. Experienced neurologists followed up with the participants until January 2022. This study included a total of 17 nutritional, systemic inflammatory or muscle mass-related indicators. Maximally selected rank statistics determined the cut-off points for these indicators. Kaplan-Meier estimation was used to assess survival. Uni- and multivariate Cox proportional hazards models were used to determine the effects of indicators on survival. Finally, time-dependent receiver operating characteristic (time-ROC) curves and the C-index were calculated to evaluate the predictive efficacy of different indicators.<br><br>RESULTS: A total of 506 patients with ALS were enrolled in this study, including 288 males (56.9%) and 218 females (43.1%), with a mean age of 54.2&#x2009;&#xb1;&#x2009;10.5&#x2009;years. Among these ALS patients, 334 cases (68.0%) either died or underwent tracheotomy. In univariate Cox proportional hazards regression, 11 indicators were significantly associated with ALS survival (p&#x2009;<&#x2009;0.05). And systemic immune inflammation (SII), platelet-to-lymphocyte ratio (PLR), modified geriatric nutritional risk index (mGNRI), creatinine and sarcopenia index (SI, (creatinine/cystatin C)&#x2009;&#xd7;&#x2009;100) were determined as independent predictors (p&#x2009;<&#x2009;0.05) in multivariate Cox proportional hazards regression. A higher SI predicted longer survival (hazard ratio, 0.59; 95% confidence interval [CI], 0.46-0.76; p&#x2009;<&#x2009;0.001). The results of time-ROC and C-index analyses indicated that SI had the best predictive efficacy for ALS survival, with a C-index of 0.65 (95% CI, 0.54-0.75) for 1-year, 0.61 (95% CI, 0.57-0.65) for 3-year and 0.59 (95% CI, 0.55-0.62) for 5-year survival. Across different subgroups, SI had the highest C-index in men and women, limb onset and aged <&#x2009;60&#x2009;year ALS patients, compared with other indicators. However, cystatin C was the best indicator for predicting the survival of ALS patients with bulbar onset, whereas the prognostic nutritional index (PNI) was the best for those aged &#x2265;60&#x2009;years.<br><br>CONCLUSIONS: The serum SI demonstrates superior prognostic ability compared to other inflammation-based, nutrition-based and muscle mass-related indicators for patients with ALS. Given its simplicity and availability, it is well suited for clinical use in evaluating the prognosis of ALS patients.}, }
@article {pmid39448670, year = {2024}, author = {Stankiewicz-Kosyl, M and Wińska-Krysiak, M and Wrochna, M and Haliniarz, M and Marcinkowska, K}, title = {Regional diversity of the ALS gene and hormesis due to tribenuron-methyl in Centaurea cyanus L.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25197}, pmid = {39448670}, issn = {2045-2322}, support = {BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; BIOSTRATEG 3/347445/1/NCBR/2017//The National Centre for Research and Development/ ; }, mesh = {*Acetolactate Synthase/genetics ; *Hormesis ; *Herbicides/pharmacology ; *Centaurea/genetics ; Arylsulfonates/pharmacology ; Herbicide Resistance/genetics ; Mutation ; Poland ; Plant Proteins/genetics ; Genetic Variation ; }, abstract = {Centaurea cyanus L. is a common field weed in Eastern Europe but only in Poland biotypes of this species with resistance to acetolactate synthase (ALS) inhibitors have been confirmed. This phenomenon is constantly developing and spreading to consecutive regions of Poland. This study aimed to assess the response of selected Polish C. cyanus populations to tribenuron-methyl and to analyse the genetic variability of the ALS gene of C. cyanus populations resistant to ALS inhibitors. Between 2017 and 2021, 13 seed samples were collected from eastern Poland and a dose-response study with tribenuron-methyl was performed. Eleven populations resistant to tribenuron-methyl were identified. All populations from this study as well as 6 additional resistant populations characterised in the previous dose-response studies were subjected to molecular analysis of the ALS gene. Target-site resistance due to mutations P197S, P197Q, P197T and P197A were identified in 8 populations from Warmia-Masuria and Podlaskie provinces. This is the first case of target-site resistance (TSR) in C. cyanus confirmed by sequencing of the ALS gene. Moreover in some resistant plants, ten changes in the amino acid ALS sequence were identified in comparison to those in the susceptible ones. In none of the populations were all mutations detected in the same individual. The highest frequency of mutations was detected in Warmia-Masuria province. Some C. cyanus populations resistant to ALS inhibitors showed hormesis effect concerning shoot fresh weight after tribenuron-methyl treatment. Stimulation due to half the recommended dose of tribenuron-methyl was the highest and the difference between untreated and treated plants was statistically significant in two populations from Warmia-Masuria and in one from Podlaskie province.}, }
@article {pmid39447539, year = {2024}, author = {Zhu, H}, title = {Interference of nuclear speckles: A nexus of RNA foci, dipeptide repeats, and mis-splicing in C9ORF72 ALS/FTD.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3375-3377}, doi = {10.1016/j.neuron.2024.10.001}, pmid = {39447539}, issn = {1097-4199}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *C9orf72 Protein/genetics ; *Frontotemporal Dementia/genetics/metabolism ; *RNA Splicing/genetics ; Dipeptides/metabolism ; DNA Repeat Expansion/genetics ; Proteins/genetics/metabolism ; RNA/genetics ; }, abstract = {In this issue of Neuron, Wu et al.[1] show that nuclear speckle proteins are sequestered by both nuclear RNA foci and cytoplasmic dipeptide repeat aggregates in C9ORF72-ALS/FTD. Consequently, dysregulation of splicing induces widespread splicing alterations and contributes to neurodegeneration.}, }
@article {pmid39444183, year = {2025}, author = {Alici, H and Uversky, VN and Kang, DE and Woo, JA and Coskuner-Weber, O}, title = {Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.}, journal = {Current protein &amp; peptide science}, volume = {26}, number = {3}, pages = {201-212}, pmid = {39444183}, issn = {1875-5550}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Mutation ; }, abstract = {INTRODUCTION: The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10[Q108P] proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.<br><br>METHODS: This study presents the foundational characterization of the structural features of CHCHD10[Q108P] and compares them with those of the wild-type counterpart. We conducted multiple run molecular dynamics simulations and bioinformatics analyses.<br><br>RESULTS: Our findings reveal distinct differences in structural properties, free energy surfaces, and the outputs of principal component analysis between these two proteins. These results contribute significantly to the comprehension of CHCHD10 and its Q108P variant in terms of pathology, biochemistry, and structural biology.<br><br>CONCLUSION: The reported structural properties hold promise for informing the development of more effective treatments for ALS.}, }
@article {pmid39444004, year = {2024}, author = {Hoshino, T and Mukai, A and Yamashita, H and Misawa, H and Urushitani, M and Tashiro, Y and Matsuzawa, SI and Takahashi, R}, title = {NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.}, journal = {Molecular brain}, volume = {17}, number = {1}, pages = {77}, pmid = {39444004}, issn = {1756-6606}, support = {16H01695//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Up-Regulation/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Proteasome Endopeptidase Complex/metabolism ; Mice ; *Ubiquitin/metabolism ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Cell Line, Tumor ; Motor Neurons/metabolism/pathology ; Nerve Degeneration/pathology ; Cell Death ; Humans ; }, abstract = {Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.}, }
@article {pmid39443862, year = {2024}, author = {Paulin, J and Lahti, M and Riihimäki, H and Hänninen, J and Vesanen, T and Koivisto, M and Peltonen, LM}, title = {The rate and predictors of violence against EMS personnel.}, journal = {BMC emergency medicine}, volume = {24}, number = {1}, pages = {200}, pmid = {39443862}, issn = {1471-227X}, mesh = {Humans ; Male ; Retrospective Studies ; Female ; Finland ; Adult ; Middle Aged ; *Emergency Medical Technicians/statistics &amp; numerical data ; Emergency Medical Services/statistics &amp; numerical data ; Workplace Violence/statistics &amp; numerical data ; Violence/statistics &amp; numerical data ; Logistic Models ; Electronic Health Records ; }, abstract = {BACKGROUND: Violence against Emergency Medical Services (EMS) personnel vary between studies. Current studies are mainly based on self-reporting, thus other designs are needed to provide more perspective. The purpose of this study was to explore the rate and predictors of violent behavior targeted at EMS personnel by exploring the Electronic patient care records (ePCR) documentation by EMS personnel.<br><br>METHODS: This was a retrospective cohort study of EMS patients in Finland. The data were collected from three regions between 1st June and 30th November 2018. Text mining and manual evaluation were used to identify and explore predictors of violence targeted at EMS personnel from the ePCR narratives. Multivariable logistic regressions were used to determine factors that were independently associated with violent behavior. The results are presented with odds ratios (ORs) with 95% confidence intervals (CIs).<br><br>RESULTS: The EMS personnel reported experiences of violence in a total of 297 identified missions (0.7%) of all EMS missions (n&#x2009;=&#x2009;40,263). The violence was mostly verbal (62.3%) and the most common violence perpetrator was the patient (98.0%). The police were alarmed to many missions where violence was reported (40.7%). Sometimes violence occurred suddenly although the police were present. The multivariable logistic regression model indicates that violence occurred typically in urban areas (OR 1.699; 95% CI 1.283 to 2.248), at weekend nights (OR 1.357; 95% CI 1.043 to 1.765), by male (OR 1.501; 95% CI 1.160 to 1.942), and patients influenced by alcohol (OR 3.464; 95% CI 2.644 to 4.538). A NEWS2 score of 3 in any parameter (vs. score 0-4, OR 2.386; 95% CI: 1.788 to 3.185) and ALS unit type (vs. BLS, OR 1.373; 95% CI: 1.009 to 1.866) increased the likelihood as well.<br><br>CONCLUSIONS: The documentation in ePCRs show low rates of violence targeted at EMS personnel. However, violence is a multidimensional phenomenon connected to unfamiliar patients, rushed situations, and an uncontrolled environment. This means that the EMS personnels' safety cannot be ensured in all situations. Therefore, a balance between safety margins and treating patients needs to be considered.}, }
@article {pmid39443410, year = {2024}, author = {Zhang, T and Rui, W and Sun, Y and Tian, Y and Li, Q and Zhang, Q and Zhao, Y and Liu, Z and Wang, T}, title = {Identification of nitric oxide-mediated necroptosis as the predominant death route in Parkinson's disease.}, journal = {Molecular biomedicine}, volume = {5}, number = {1}, pages = {44}, pmid = {39443410}, issn = {2662-8651}, mesh = {*Necroptosis ; *Parkinson Disease/pathology/metabolism/genetics ; *Nitric Oxide/metabolism ; Humans ; Animals ; Mice ; Neurons/metabolism/pathology ; Signal Transduction ; Male ; Brain/pathology/metabolism ; Alzheimer Disease/pathology/metabolism/genetics ; Amyotrophic Lateral Sclerosis/pathology/metabolism/genetics ; Membrane Potential, Mitochondrial ; }, abstract = {Parkinson's disease (PD) involves multiple forms of neuronal cell death, but the dominant pathway involved in disease progression remains unclear. This study employed RNA sequencing (RNA-seq) of brain tissue to explore gene expression patterns across different stages of PD. Using the Scaden deep learning algorithm, we predicted neurocyte subtypes and modelled dynamic interactions for five classic cell death pathways to identify the predominant routes of neuronal death during PD progression. Our cell type-specific analysis revealed an increasing shift towards necroptosis, which was strongly correlated with nitric oxide synthase (NOS) expression across most neuronal subtypes. In vitro experiments confirmed that nitric oxide (NO) is a key mediator of necroptosis, leading to nuclear shrinkage and decreased mitochondrial membrane potential via phosphorylation of the PIP1/PIP3/MLKL signalling cascade. Importantly, specific necroptosis inhibitors significantly mitigated neuronal damage in both in vitro and in vivo PD models. Further analysis revealed that NO-mediated necroptosis is prevalent in early-onset Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and across multiple brain regions but not in brain tumours. Our findings suggest that NO-mediated necroptosis is a critical pathway in PD and other neurodegenerative disorders, providing potential targets for therapeutic intervention.}, }
@article {pmid39441150, year = {2024}, author = {Hamad, AA and Alkhawaldeh, IM and Abbas, A and Elaraby, A and Meshref, M}, title = {Incidence and risk factors of venous thromboembolism in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {La Tunisie medicale}, volume = {102}, number = {10}, pages = {610-515}, pmid = {39441150}, issn = {2724-7031}, mesh = {*Amyotrophic Lateral Sclerosis/epidemiology/complications ; Humans ; *Venous Thromboembolism/epidemiology/etiology ; Incidence ; Risk Factors ; Male ; Female ; }, abstract = {AIMS: This systematic review and meta-analysis aimed to determine the annual incidence rate of venous thromboembolism (VTE) and identify risk factors of VTE in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: A comprehensive search of three databases was conducted up to April 8, 2024, to identify longitudinal studies reporting VTE incidence in ALS patients. The included studies were either prospective or retrospective, following up with ALS patients. Quality assessment was performed using the NIH tool for observational cohort studies. Meta-analysis was conducted using Open Meta Analyst, employing a random-effect model. Subgroup, Meta-regression, and sensitivity analyses were also carried out.<br><br>RESULTS: Our analysis included eight studies comprising a total of 26,758 ALS patients that met the inclusion criteria. The pooled annual incidence of VTE across all studies was found to be 22 cases per 1,000 person-year (95% CI = 18 to 27). Subgroup analysis revealed that the annual incidence of VTE in males was 19 cases per 1,000 person-year (95% CI = 15 to 22), while in females, it was 20 cases per 1,000 person-year (95% CI = 16 to 25). Leave-one-out analysis demonstrated that the incidence ranged from 21 to 28 cases per 1,000 person-year when excluding each study individually. Meta-regression analysis did not find a significant association between age and the risk of VTE (P = 0.079). Based on the included studies, risk factors of VTE in ALS patients included a history of VTE, non-invasive ventilation, immobility, and decreased functional status.<br><br>CONCLUSION: Patients with ALS face a higher risk of developing VTE compared to individuals of the same age. These findings underscore the importance of implementing preventive measures and closely monitoring VTE in ALS patients.}, }
@article {pmid39441015, year = {2024}, author = {Liu, Y and Li, Y and Zhang, P}, title = {Stress granules and organelles: Coordinating cellular responses in health and disease.}, journal = {Protein &amp; cell}, volume = {}, number = {}, pages = {}, doi = {10.1093/procel/pwae057}, pmid = {39441015}, issn = {1674-8018}, abstract = {Membrane-bound organelles and membraneless organelles (MLOs) coordinate various biological processes within eukaryotic cells. Among these, stress granules (SGs) are significant cytoplasmic MLOs that form in response to cellular stress, exhibiting liquid-like properties alongside stable substructures. SGs interact with diverse organelles, thereby influencing cellular pathways that are critical in both health and disease contexts. This review discusses the interplay between SGs and organelles and explores the methodologies employed to analyze interactions between SGs and other MLOs. Furthermore, it highlights the pivotal roles SGs play in regulating cellular responses and the pathogenesis of ALS. Gaining insights into these interactions is essential for deciphering the mechanisms underlying both physiological processes and pathological conditions.}, }
@article {pmid39440770, year = {2024}, author = {Allowitz, K and Taylor, J and Harames, K and Yoo, J and Baloch, O and Ramana, KV}, title = {Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X342720241014164650}, pmid = {39440770}, issn = {1875-6190}, abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.}, }
@article {pmid39440303, year = {2024}, author = {Dafinca, R and Tosat-Bitrian, C and Carroll, E and Vahsen, BF and Gilbert-Jaramillo, J and Scaber, J and Feneberg, E and Johnson, E and Talbot, K}, title = {Dynactin-1 mediates rescue of impaired axonal transport due to reduced mitochondrial bioenergetics in amyotrophic lateral sclerosis motor neurons.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae350}, pmid = {39440303}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43[M337V] mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43[M337V] with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.}, }
@article {pmid39439710, year = {2024}, author = {Kelser, BM and Teichner, EM and Subtirelu, RC and Hoss, KN}, title = {A review of proposed mechanisms for neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {16}, number = {}, pages = {1370580}, pmid = {39439710}, issn = {1663-4365}, abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.}, }
@article {pmid39437787, year = {2024}, author = {Saez-Atienzar, S and Souza, CDS and Chia, R and Beal, SN and Lorenzini, I and Huang, R and Levy, J and Burciu, C and Ding, J and Gibbs, JR and Jones, A and Dewan, R and Pensato, V and Peverelli, S and Corrado, L and van Vugt, JJFA and van Rheenen, W and Tunca, C and Bayraktar, E and Xia, M and ,  and ,  and ,  and ,  and Iacoangeli, A and Shatunov, A and Tiloca, C and Ticozzi, N and Verde, F and Mazzini, L and Kenna, K and Al Khleifat, A and Opie-Martin, S and Raggi, F and Filosto, M and Piccinelli, SC and Padovani, A and Gagliardi, S and Inghilleri, M and Ferlini, A and Vasta, R and Calvo, A and Moglia, C and Canosa, A and Manera, U and Grassano, M and Mandrioli, J and Mora, G and Lunetta, C and Tanel, R and Trojsi, F and Cardinali, P and Gallone, S and Brunetti, M and Galimberti, D and Serpente, M and Fenoglio, C and Scarpini, E and Comi, GP and Corti, S and Del Bo, R and Ceroni, M and Pinter, GL and Taroni, F and Bella, ED and Bersano, E and Curtis, CJ and Lee, SH and Chung, R and Patel, H and Morrison, KE and Cooper-Knock, J and Shaw, PJ and Breen, G and Dobson, RJB and Dalgard, CL and ,  and Scholz, SW and Al-Chalabi, A and van den Berg, LH and McLaughlin, R and Hardiman, O and Cereda, C and Sorarù, G and D'Alfonso, S and Chandran, S and Pal, S and Ratti, A and Gellera, C and Johnson, K and Doucet-O'Hare, T and Pasternack, N and Wang, T and Nath, A and Siciliano, G and Silani, V and Başak, AN and Veldink, JH and Camu, W and Glass, JD and Landers, JE and Chiò, A and Sattler, R and Shaw, CE and Ferraiuolo, L and Fogh, I and Traynor, BJ}, title = {Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100679}, pmid = {39437787}, issn = {2666-979X}, support = {R35 NS127253/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Drug Repositioning ; *Frontotemporal Dementia/genetics/drug therapy ; Genomics/methods ; Riluzole/therapeutic use ; Male ; Female ; Neuroprotective Agents/therapeutic use/pharmacology ; DNA Repeat Expansion/genetics ; }, abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.}, }
@article {pmid39436867, year = {2025}, author = {Firozjae, AA and Shiran, MR and Rashidi, M}, title = {The neuropharmacological and clinical effects of lutein: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {27-38}, pmid = {39436867}, issn = {1868-1891}, mesh = {*Lutein/pharmacology/therapeutic use ; Humans ; *Neurodegenerative Diseases/drug therapy ; Alzheimer Disease/drug therapy ; }, abstract = {OBJECTIVES: Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.<br><br>METHODS: A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.<br><br>RESULTS: We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.<br><br>CONCLUSIONS: 4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in&#xa0;the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.}, }
@article {pmid39436522, year = {2025}, author = {Ma, J and Wen, Q and Pang, X and Huang, S and Zhang, J and Wang, J and Chang, X and Guo, J and Zhang, W}, title = {Correction to: Fasciculation score: a sensitive biomarker in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {525-526}, doi = {10.1007/s10072-024-07807-y}, pmid = {39436522}, issn = {1590-3478}, }
@article {pmid39435791, year = {2024}, author = {Brylev, LV and Bryukhov, VV and Druzhinina, ES and Kovalchuk, MO}, title = {[Lower motor neuron disease with MRI «snake eyes» pattern].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {124}, number = {9}, pages = {141-144}, doi = {10.17116/jnevro2024124091141}, pmid = {39435791}, issn = {1997-7298}, mesh = {Humans ; *Magnetic Resonance Imaging ; *Motor Neuron Disease/diagnostic imaging/diagnosis ; Motor Neurons/pathology ; *Pyramidal Tracts/diagnostic imaging ; }, abstract = {Motor neuron disease with isolated or predominant lesion of the lower motor neuron at one level of the pyramidal tract is a rare diagnostic finding. In the article, we analyze the case of a patient with asymmetric lesion of the inferior motor neuron at the cervical level: clinical manifestations, results of additional studies and dynamic observation of the patient. Special attention is paid to the MRI picture of changes in the pyramidal tracts in the cervical region, which have been called the «snake eyes» in the literature, and the impact of this finding on the diagnosis and prognosis of the disease.}, }
@article {pmid39435635, year = {2025}, author = {Yang, X and Gao, X and Jiang, X and Yue, K and Luo, P}, title = {Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases.}, journal = {Neural regeneration research}, volume = {20}, number = {11}, pages = {3076-3094}, pmid = {39435635}, issn = {1673-5374}, abstract = {Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.}, }
@article {pmid39434139, year = {2024}, author = {Agah, E and Mojtabavi, H and Behkar, A and Heidari, A and Ajdari, A and Shaka, Z and Mousavi, SV and Firoozeh, N and Tafakhori, A and Rezaei, N}, title = {CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {953}, pmid = {39434139}, issn = {1479-5876}, mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *Amyotrophic Lateral Sclerosis/blood/cerebrospinal fluid/diagnosis ; Biomarkers/blood/cerebrospinal fluid ; Neurofilament Proteins/blood/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid/blood ; Phosphorylation ; Publication Bias ; *tau Proteins/cerebrospinal fluid/blood ; }, abstract = {Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.}, }
@article {pmid39434103, year = {2024}, author = {Sun, S and Chen, Y and Yun, Y and Zhao, B and Ren, Q and Sun, X and Meng, X and Yan, C and Lin, P and Liu, S}, title = {Elevated peripheral inflammation is associated with choroid plexus enlargement in independent sporadic amyotrophic lateral sclerosis cohorts.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {83}, pmid = {39434103}, issn = {2045-8118}, support = {qnts202306347//Taishan Young Scholar Program/ ; ZR2024MH178//Shandong Provincial Natural Science Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnostic imaging/pathology ; Male ; *Choroid Plexus/diagnostic imaging/pathology ; Female ; Middle Aged ; *Inflammation/blood/diagnostic imaging ; *Magnetic Resonance Imaging ; Cohort Studies ; Aged ; Adult ; }, abstract = {BACKGROUND: Using neuroimaging techniques, growing evidence has suggested that the choroid plexus (CP) volume is enlarged in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, the CP has been suggested to play an important role in inflammation-induced CNS damage under disease conditions. However, to our knowledge, no study has investigated the relationships between peripheral inflammation and CP volume in sporadic ALS patients. Thus, in this study, we aimed to verify CP enlargement and explore its association with peripheral inflammation in vivo in independent ALS cohorts.<br><br>METHODS: Based on structural MRI data, CP volume was measured using Gaussian mixture models and further manually corrected in two independent cohorts of sporadic ALS patients and healthy controls (HCs). Serum inflammatory protein levels were measured using a novel high-sensitivity Olink proximity extension assay (PEA) technique. Xtreme gradient boosting (XGBoost) was used to explore the contribution of peripheral inflammatory factors to CP enlargement. Then, partial correlation analyses were performed.<br><br>RESULTS: CP volumes were significantly higher in ALS patients than in HCs in the independent cohorts. Compared with HCs, serum levels of CRP, IL-6, CXCL10, and 35 other inflammatory factors were significantly increased in ALS patients. Using the XGBoost approach, we established a model-based importance of features, and the top three predictors of CP volume in ALS patients were CRP, IL-6, and CXCL10 (with gains of 0.24, 0.18, and 0.15, respectively). Correlation analyses revealed that CRP, IL-6, and CXCL10 were significantly associated with CP volume in ALS patients (r&#x2009;=&#x2009;0.462&#x2009;&#x223c;&#x2009;0.636, p&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: Our study is the first to reveal a consistent and replicable contribution of peripheral inflammation to CP enlargement in vivo in sporadic ALS patients. Given that CP enlargement has been recently detected in other brain diseases, these findings should consider extending to other disease conditions with a peripheral inflammatory component.}, }
@article {pmid39433597, year = {2024}, author = {Candrea, DN and Shah, S and Luo, S and Angrick, M and Rabbani, Q and Coogan, C and Milsap, GW and Nathan, KC and Wester, BA and Anderson, WS and Rosenblatt, KR and Uchil, A and Clawson, L and Maragakis, NJ and Vansteensel, MJ and Tenore, FV and Ramsey, NF and Fifer, MS and Crone, NE}, title = {A click-based electrocorticographic brain-computer interface enables long-term high-performance switch scan spelling.}, journal = {Communications medicine}, volume = {4}, number = {1}, pages = {207}, pmid = {39433597}, issn = {2730-664X}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Brain-computer interfaces (BCIs) can restore communication for movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command click detectors provide a basic yet highly functional capability.<br><br>METHODS: We sought to test the performance and long-term stability of click decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis. We trained the participant's click detector using a small amount of training data (<44&#x2009;min across 4&#x2009;days) collected up to 21&#x2009;days prior to BCI use, and then tested it over a period of 90&#x2009;days without any retraining or updating.<br><br>RESULTS: Using a click detector to navigate a switch scanning speller interface, the study participant can maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation can interrupt usage of a fixed model, a new click detector can achieve comparable performance despite being trained with even less data (<15&#x2009;min, within 1&#x2009;day).<br><br>CONCLUSIONS: These results demonstrate that a click detector can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.}, }
@article {pmid39432543, year = {2024}, author = {Liu, X and Dong, L and Li, S and Li, Z and Wang, Y and Mao, Z and Deng, L}, title = {Improving AGB estimations by integrating tree height and crown radius from multisource remote sensing.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0311642}, pmid = {39432543}, issn = {1932-6203}, mesh = {*Biomass ; *Trees/growth &amp; development ; *Remote Sensing Technology/methods ; *Forests ; }, abstract = {Precise estimation of forest above ground biomass (AGB) is essential for assessing its ecological functions and determining forest carbon stocks. It is difficult to directly obtain diameter at breast height (DBH) based on remote sensing imagery. Therefore, it is crucial to accurately estimate the AGB with features extracted directly from RS. This paper demonstrates the feasibility of estimating AGB from crown radius (R) and tree height (H) features extracted from multi-source RS data. Accurate information on tree height (H), crown radius (R), and diameter at breast height (DBH) can be obtained through point clouds generated by airborne laser scanning (ALS) and terrestrial laser scanning (TLS), respectively. Nine allometric growth equations were used to fit coniferous forests (Larix principis-rupprechtii) and broadleaf forests (Fraxinus chinensis and Sophora japonica). The fitting performance of models constructed using only "H" or "R" was compared with that of models constructed using both combined. The results showed that the quadratic polynomial model constructed with "H+R" fitted the AGB estimation better in each vegetation type, especially in the scenario of mixed tall and short coniferous forests, in which the R2 and RMSE were 0.9282 and 25.30 kg (rRMSE 17.31%), respectively. Therefore, using high-resolution data to extract crown radius and tree height can achieve high-precision, global-scale estimation of forest above ground biomass.}, }
@article {pmid39432435, year = {2024}, author = {Anjaneyulu, J and Godbole, A}, title = {Small organism models for mode of action research on anti-ageing and nootropic herbs, foods, and formulations.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/1028415X.2024.2409128}, pmid = {39432435}, issn = {1476-8305}, abstract = {With global increase in ageing population along with increasing age-related neurodegenerative diseases (NDs), development of sustainable, safe and effective solutions for promoting healthy ageing and preventing diseases has become a priority. Traditional healthcare systems/medicines prescribe several herbs, foods and formulations to promote healthy ageing and prevent and/or treat age-related diseases. However, the scientific data elucidating their mechanism of action is very limited and deeper research using different models is warranted for timely and wider use. The clinical studies and research with higher model organisms, although useful, have several practical, technical, and financial limitations. Conversely, small organism models like Yeast, Roundworm, Fruit fly, and Zebrafish, which have genetic similarities to humans, can replicate the disease features and provide behavioural, cellular and molecular insights. The common features of ageing and NDs, like amyloid protein aggregations, oxidative stress, energy dysregulation, inflammation and neurodegeneration can be mimicked in the small organism models for Alzheimer's, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis. This review focuses on small organism model- based research unveiling interesting modes of action and synergistic effects of herbal extracts, foods, and formulations, which are indicated especially for healthy ageing and management of NDs. This will provide leads for the quick and sustainable development of scientifically evaluated solutions for clinically relevant, age-related conditions.}, }
@article {pmid39431591, year = {2024}, author = {Sheers, NL and Hannan, LM and Rautela, L and Graco, M and Jones, J and Retica, S and Saravanan, K and Burgess, N and McGaw, R and Donovan, A and Clohessy, T and Chao, C and Charles, C and Howard, ME and Berlowitz, DJ}, title = {NIV@Home: a pilot randomized controlled trial of in-home noninvasive ventilation initiation compared to a single-day admission model.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/21678421.2024.2416668}, pmid = {39431591}, issn = {2167-9223}, abstract = {Objective: Noninvasive ventilation (NIV) is the primary treatment for respiratory insufficiency in neuromuscular disease. NIV implementation is usually conducted within hospitals; however, in-home implementation with intensive follow-up is an effective alternative. This pilot study aimed to assess model feasibility, acceptability, and NIV usage at 12-weeks after a single visit in-home implementation of NIV with remote monitoring follow-up (NIV@Home) compared to an in-hospital day admission NIV initiation plus planned polysomnography (Usual care). Methods: A single-blinded randomized controlled trial (www.anzctr.org.au ACTRN12620000682943) of adults with neuromuscular disease referred for NIV implementation. Participants were stratified by disease (MND or Other diagnoses) and bulbar symptoms before randomization to NIV@Home or Usual care, with follow-up at 12-weeks. The primary outcome was NIV usage. Secondary outcomes included feasibility, health-related quality of life, symptoms, carer burden, and NIV experience (semi-structured qualitative interviews). Results: Twenty-three participants (MND bulbar = 9, MND non-bulbar = 11, Other = 3) were randomized (NIV@Home = 9). No statistical differences were observed in the percentage of MND participants using NIV for >4 hours/day (NIV@Home = 33% vs. Usual care = 60%, p = 0.370), average use (NIV@Home = 2.4 [1.5-9.3] vs. 5.3 [1.8-7.0] hours/day, p = 0.568), or secondary outcomes. In-home NIV implementation was feasible and safe but took more therapist time (NIV@Home = 278 [270-305] vs. 172 [130-200] minutes, p < 0.001). Participants in the NIV@Home group reported substantial advantages to receiving care in home. Conclusion: In-home NIV implementation is feasible and acceptable to people with MND but requires more therapist time. Larger studies are required to determine whether there are clinically important differences between this model of NIV initiation and a traditional hospital-based model.}, }
@article {pmid39431590, year = {2024}, author = {Correa-Arrieta, C and Castellar-Leones, S and Forero Diaz, JJ and Peña-Preciado, M and Ortiz-Corredor, F}, title = {Slowly progressing Amyotrophic lateral sclerosis associated with the F21L variant in the SOD1 gene: Demographic and clinical characteristics.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2416669}, pmid = {39431590}, issn = {2167-9223}, abstract = {INTRODUCTION/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which genetic variants can significantly influence clinical presentation and prognosis. This study aims to describe the demographic and clinical characteristics of ALS patients carrying the SOD1: c.63C > G (p.Phe21Leu) [NM_000454.4] variant, as treated at a national reference center in Colombia.<br><br>METHODS: A descriptive study was conducted on patients identified with the SOD1: c.63C&#x2009;>&#x2009;G (p.Phe21Leu) [NM_000454.4] variant, selected from the database of a neuromuscular disease center in Colombia. Demographic and clinical data were collected through medical records and patient interviews. Molecular analysis was performed using PCR and automated sequencing to confirm the presence of the variant.<br><br>RESULTS: Eleven patients with SOD1: c.63C&#x2009;>&#x2009;G (p.Phe21Leu) [NM_000454.4] variant were identified. The mean age at onset was 48.4 years, with a mean disease duration of 76.7 months. The majority (90.9%) exhibited a slowly progressive course, predominantly with spinal onset and no cognitive impairment. Bulbar symptoms developed in 72.2% of the patients, and 81.8% required noninvasive ventilation. A family history of ALS or other neurodegenerative disorders was present in 54.5% of the patients.<br><br>CONCLUSIONS: The SOD1: c.63C&#x2009;>&#x2009;G (p.Phe21Leu) [NM_000454.4] variant is associated with a slowly progressive ALS phenotype, characterized by predominant lower motor neuron involvement and delayed onset of bulbar and respiratory symptoms. This variant appears to be predominantly distributed in central Colombia. Early detection of this variant may enable timely interventions and personalized care plans. Further research is required to establish a definitive causal relationship between this variant and the observed clinical course.}, }
@article {pmid39428513, year = {2024}, author = {Shibasaki, N and Konishi, K and Nishiyama, Y and Miyagawa, T and Numayama, T}, title = {[A case of amyotrophic lateral sclerosis managed by tracheostomy and invasive ventilation in which air leaks occurred at the cuff].}, journal = {Rinsho shinkeigaku = Clinical neurology}, volume = {64}, number = {11}, pages = {789-793}, doi = {10.5692/clinicalneurol.cn-001990}, pmid = {39428513}, issn = {1882-0654}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/therapy ; Middle Aged ; *Tracheostomy ; *Respiration, Artificial ; Tomography, X-Ray Computed ; Trachea/diagnostic imaging ; Air ; Pressure ; Treatment Outcome ; }, abstract = {The patient was a 64-year-old woman who had been diagnosed with amyotrophic lateral sclerosis 8 years ago, and had been under artificial ventilation with tracheotomy for 6 years. Computed tomography indicated a dilated tracheal diameter of 29.6 ‍mm at the cuff, and a high cuff pressure of 80 ‍cmH2O. An adjustable flange tracheostomy tube with an optional length setting was used to extend the effective length by 28 ‍mm. A previously evident air leak disappeared with the change in cuff level, and cuff pressure decreased to 25 ‍cmH2O. X-ray images indicated a reduction in the size of the previous cuff area. Tracheal dilatation due to improper management of cuff pressure is a contributing factor to air leakage at the cuff area, and using an adjustable flange tracheostomy tube in an effort to resolve such air leaks is a valid option.}, }
@article {pmid39428436, year = {2024}, author = {Assialioui, A and Marco-Pascual, C and Torrente-Segarra, V and Domínguez, R and Santos, N and Peñafiel, J and Juanola, X and Povedano, M and Ferrer, I}, title = {Microvascular abnormalities in skin capillaries of individuals with amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24648}, pmid = {39428436}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Middle Aged ; Male ; *Capillaries/pathology ; Female ; *Skin/blood supply/pathology ; Aged ; Microscopic Angioscopy ; Case-Control Studies ; Adult ; }, abstract = {This is the first study aimed to detect morphological abnormalities in vivo in the skin capillaries of amyotrophic lateral sclerosis patients (ALS). Videocapillaroscopy assessed subungueal capillaries in 28 ALS patients (cases) and 35 controls (p = 0.42). The mean age was 61.46 and 61.23 years, respectively (p > 0.99). No statistically significant differences were observed between the groups regarding dominant hand, arterial hypertension, dyslipidemia, diabetes mellitus, active smoker, and former smoker variables. 78.57% of cases had spinal onset and 21.43% bulbar. The median disease duration (time between the onset of symptoms and the date of videocapillarscopy) was 29.71 months. Dilated capillaries were detected in 17.8% of cases and 11.43% of controls (p = 0.49). The median of capillary diameter in cases was 10.15 µm and 8.72 µm in controls (p = 0.011). 35.71% of cases and 2.86% of controls had severe capillary tortuosities (p < 0.001). Ramified capillaries were observed in 46.43% of cases and 11.43% of controls (p < 0.002). Micro-hemorrhages were only observed in 10.71% of cases. No significant correlations were observed between disease duration and dilated capillaries, tortuosity, ramified capillaries, and micro-hemorrhages. The present in vivo study shows abnormalities in the skin capillaries of ALS patients that do not depend on disease duration.}, }
@article {pmid39428248, year = {2024}, author = {Luo, N and Wang, J and Zhang, ZY and Zhao, XY and Huang, RR and Wu, QY}, title = {[Research progress on Pb-induced neurotoxicity through glial cells].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {58}, number = {10}, pages = {1610-1615}, doi = {10.3760/cma.j.cn112150-20240513-00382}, pmid = {39428248}, issn = {0253-9624}, support = {8217348282, 82173554, 82101593//National Natural Science Foundation of China/ ; }, mesh = {*Neuroglia/drug effects ; Humans ; *Lead/toxicity ; }, abstract = {Lead is one of the most important occupational hazards in China, and occupational exposure is the leading cause of lead poisoning. Lead can be absorbed by the body through air, food, drinking water and skin, and accumulate in multiple organs in the body, posing health risks to humans, especially to lead workers. Many previous studies have shown that lead can affect the function of glial cells such as microglia, astrocytes and oligodendrocytes, resulting in irreversible neurological damage. This article provides an overview of the neurotoxic mechanism induced by lead through glial cells, elucidates that lead can induce neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and reviews the relationship between lead and glial cells, in order to provide reference for further research on the neurotoxic mechanism of lead on glial cells.}, }
@article {pmid39428001, year = {2025}, author = {Simoes, FA and Christoforidou, E and Cassel, R and Dupuis, L and Hafezparast, M}, title = {Severe dynein dysfunction in cholinergic neurons exacerbates ALS-like phenotypes in a new mouse model.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1871}, number = {1}, pages = {167540}, doi = {10.1016/j.bbadis.2024.167540}, pmid = {39428001}, issn = {1879-260X}, mesh = {Animals ; *Disease Models, Animal ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Phenotype ; *Cholinergic Neurons/metabolism/pathology ; Cytoplasmic Dyneins/metabolism/genetics ; Neuromuscular Junction/metabolism/pathology ; DNA-Binding Proteins/genetics/metabolism ; Mice, Knockout ; Male ; Dyneins/metabolism/genetics ; Point Mutation ; }, abstract = {Cytoplasmic dynein 1, a motor protein essential for retrograde axonal transport, is increasingly implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this study, we developed a novel mouse model that combines the Legs at odd angles (Loa, F580Y) point mutation in the dynein heavy chain with a cholinergic neuron-specific knockout of the dynein heavy chain. This model, for the first time, allows us to investigate the impact of Loa allele exclusivity in these neurons into adulthood. Our findings reveal that this selective increase in dynein dysfunction exacerbated the phenotypes observed in heterozygous Loa mice including pre-wean survival, reduced body weight and grip strength. Additionally, it induced ALS-like pathology in neuromuscular junctions (NMJs) not seen in heterozygous Loa mice. Notably, we also found a previously unobserved significant increase in neurons displaying TDP-43 puncta in both Loa mutants, suggesting early TDP-43 mislocalisation - a hallmark of ALS. The novel model also exhibited a concurrent rise in p62 puncta that did not co-localise with TDP-43, indicating broader impairments in autophagic clearance mechanisms. Overall, this new model underscores the fact that dynein impairment alone can induce ALS-like pathology and provides a valuable platform to further explore the role of dynein in ALS.}, }
@article {pmid39427550, year = {2024}, author = {Pan, Y and Sun, X and Tian, Y and Yu, M and Luo, Y and Sun, X}, title = {L-NRB alleviates amyotrophic lateral sclerosis by regulating P11-Htr4 signaling pathway.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {180}, number = {}, pages = {117588}, doi = {10.1016/j.biopha.2024.117588}, pmid = {39427550}, issn = {1950-6007}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; *Signal Transduction/drug effects ; Mice ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Male ; Benzofurans/pharmacology/therapeutic use ; Disease Models, Animal ; Motor Neurons/drug effects/pathology/metabolism ; Apoptosis/drug effects ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: L-NRB is a compound formed as a ring cleavage product of butylphthalide and borneol in a molar ratio 1:2. This study aimed to explore the therapeutic effect of L-NRB on amyotrophic lateral sclerosis (ALS) and its possible mechanism.<br><br>METHODS: SOD1-G93A mice were used as an ALS model. Behavioral tests, histopathological staining, Nissl staining, immunohistochemistry, enzyme-linked immunosorbent assays, and Western blotting were used to analyze the therapeutic effect. The underlying mechanism of L-NRB in treating ALS was investigated using transcriptomic analyses.<br><br>RESULTS: It was found that L-NRB alleviated motor dysfunction, pathological changes in the gastrocnemius muscle, and motor neuron injuries. The results indicated that L-NRB had a neuroprotective function associated with the inhibition of neuroinflammation. The anti-apoptotic effect of L-NRB was found to be related to the regulation of the P11-Htr4 signaling pathway.<br><br>CONCLUSION: In summary, the results demonstrated the therapeutic effect of L-NRB on ALS and suggest a promising new therapeutic candidate for ALS.}, }
@article {pmid39426615, year = {2024}, author = {Mackness, BC and Morgan, BR and Deveau, LM and Kathuria, SV and Zitzewitz, JA and Massi, F}, title = {A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168823}, doi = {10.1016/j.jmb.2024.168823}, pmid = {39426615}, issn = {1089-8638}, support = {P41 GM103622/GM/NIGMS NIH HHS/United States ; R01 GM137529/GM/NIGMS NIH HHS/United States ; }, mesh = {*Protein Folding ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Hydrophobic and Hydrophilic Interactions ; *Molecular Dynamics Simulation ; Protein Structure, Secondary ; Protein Stability ; RNA Recognition Motif/genetics ; Protein Conformation ; Models, Molecular ; }, abstract = {Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43 (TAR DNA-binding protein-43), using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.}, }
@article {pmid39425598, year = {2024}, author = {Zhang, L and Zhou, X and Cha, S}, title = {Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression.}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1028}, doi = {10.1002/ana.27092}, pmid = {39425598}, issn = {1531-8249}, }
@article {pmid39425590, year = {2025}, author = {Zhu, L and Li, Y and Yu, X and Chen, Y and Zhang, J and Pang, C and Xie, J and Gao, L and Du, L and Cao, W and Fan, D and Cui, C and Yu, H and Deng, B}, title = {Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.}, journal = {Annals of neurology}, volume = {97}, number = {2}, pages = {270-280}, doi = {10.1002/ana.27115}, pmid = {39425590}, issn = {1531-8249}, support = {12101460//National Natural Science Foundation of China/ ; 81901273//National Natural Science Foundation of China/ ; ZCLY24H0903//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnostic imaging ; Female ; Male ; Middle Aged ; Aged ; Prospective Studies ; Magnetic Resonance Imaging ; Liver Diseases/epidemiology ; Adult ; Risk Factors ; Cohort Studies ; Liver/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.<br><br>METHODS: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan&#xae; software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.<br><br>RESULTS: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6&#x2009;years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p&#x2009;<&#x2009;0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.<br><br>INTERPRETATION: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2025;97:270-280.}, }
@article {pmid39424779, year = {2024}, author = {Wu, H and Wang, LC and Sow, BM and Leow, D and Zhu, J and Gallo, KM and Wilsbach, K and Gupta, R and Ostrow, LW and Yeo, CJJ and Sobota, RM and Li, R}, title = {TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9026}, pmid = {39424779}, issn = {2041-1723}, support = {A-0007081-00-00//Ministry of Education - Singapore (MOE)/ ; NRF-MSG-2023-0001//National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore)/ ; NRF-SIS "SingMass"//A*STAR | Singapore Institute of Manufacturing Technology (Singapore Institute of Manufacturing Technology - A STAR)/ ; }, mesh = {Humans ; *Golgi Apparatus/metabolism ; *Endoplasmic Reticulum/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *DNA-Binding Proteins/metabolism/genetics ; Protein Transport ; Protein Aggregates ; Motor Neurons/metabolism ; HeLa Cells ; HEK293 Cells ; }, abstract = {Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.}, }
@article {pmid39424648, year = {2024}, author = {Chartier, C and Godard, J and Durand, S and Humeau-Heurtier, A and Menetrier, E and Allain, P and Besnard, J}, title = {Combinations of physical and cognitive training for subcortical neurodegenerative diseases with physical, cognitive and behavioral symptoms: a systematic review.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {45}, number = {12}, pages = {5571-5589}, pmid = {39424648}, issn = {1590-3478}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Behavioral Symptoms/therapy/etiology ; Cognitive Behavioral Therapy/methods ; Exercise Therapy/methods ; Cognitive Dysfunction/therapy/rehabilitation/etiology ; Cognitive Training ; }, abstract = {BACKGROUND: The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies.<br><br>METHODS: We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal.<br><br>RESULTS: Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training.<br><br>DISCUSSION: Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data.<br><br>CONCLUSIONS: Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training.}, }
@article {pmid39424561, year = {2024}, author = {Crow, YJ}, title = {CNS disease associated with enhanced type I interferon signalling.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1158-1168}, pmid = {39424561}, issn = {1474-4465}, support = {786142/ERC_/European Research Council/International ; MC_UU_00035/11/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Interferon Type I/metabolism/immunology ; *Signal Transduction ; Animals ; Central Nervous System Diseases/immunology/metabolism ; }, abstract = {The ability to mount an interferon-mediated innate immune response is essential in protection against neurotropic viruses, but antiviral type I interferons also have neurotoxic potential. The production of type I interferons can be triggered by self-derived nucleic acids, and the brain can be susceptible to inappropriate upregulation of type I interferon signalling. Homoeostatic dysregulation of type I interferons has been implicated in rare inborn errors of immunity (referred to as type I interferonopathies) and more common neurodegenerative disorders (eg, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Recent developments include new insights into the pathogenesis of these disorders that involve dysregulated type I interferon signalling, as well as advances in their diagnosis and management. The role of type I interferons in brain cellular health suggests the future therapeutic potential of approaches that target these interferons and their signalling.}, }
@article {pmid39424560, year = {2024}, author = {Koch, JC and Leha, A and Bidner, H and Cordts, I and Dorst, J and Günther, R and Zeller, D and Braun, N and Metelmann, M and Corcia, P and De La Cruz, E and Weydt, P and Meyer, T and Großkreutz, J and Soriani, MH and Attarian, S and Weishaupt, JH and Weyen, U and Kuttler, J and Zurek, G and Rogers, ML and Feneberg, E and Deschauer, M and Neuwirth, C and Wuu, J and Ludolph, AC and Schmidt, J and Remane, Y and Camu, W and Friede, T and Benatar, M and Weber, M and Lingor, P and , }, title = {Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1133-1146}, doi = {10.1016/S1474-4422(24)00373-9}, pmid = {39424560}, issn = {1474-4465}, mesh = {Humans ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs &amp; derivatives/therapeutic use/pharmacology/adverse effects ; Middle Aged ; Male ; Double-Blind Method ; Female ; *Amyotrophic Lateral Sclerosis/drug therapy ; Aged ; Adult ; *rho-Associated Kinases/antagonists &amp; inhibitors ; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration &amp; dosage ; Treatment Outcome ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis.<br><br>METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed.<br><br>FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1&#xb7;00 (95% CI 0&#xb7;91 to 1&#xb7;00) with placebo, 1&#xb7;00 (0&#xb7;89 to 1&#xb7;00) with fasudil 30 mg, and 1&#xb7;00 (0&#xb7;90 to 1&#xb7;00) with fasudil 60 mg; the difference in proportions was 0&#xb7;00 (95% CI -0&#xb7;11 to 0&#xb7;10; p>0&#xb7;99) for fasudil 30 mg versus placebo and 0&#xb7;00 (-0&#xb7;10 to 0&#xb7;10; p>0&#xb7;99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0&#xb7;93 (95% CI 0&#xb7;81 to 0&#xb7;99) with placebo, 1&#xb7;00 (0&#xb7;90 to 1&#xb7;00) with fasudil 30 mg, and 0&#xb7;90 (0&#xb7;76 to 0&#xb7;97) with fasudil 60 mg; the difference in proportions was 0&#xb7;07 (95% CI -0&#xb7;05 to 0&#xb7;20; p=0&#xb7;25) for fasudil 30 mg versus placebo, and -0&#xb7;03 (-0&#xb7;18 to 0&#xb7;10; p=0&#xb7;70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group.<br><br>INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug.<br><br>FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".}, }
@article {pmid39424548, year = {2024}, author = {Andrews, JA}, title = {A new era of drug discovery for amyotrophic lateral sclerosis.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1070-1072}, doi = {10.1016/S1474-4422(24)00407-1}, pmid = {39424548}, issn = {1474-4465}, }
@article {pmid39424348, year = {2025}, author = {Yoganathan, S and Kumar, M and Aaron, R and Rangan, SR and Umakant, BS and Thomas, M and Oommen, SP and Danda, S}, title = {Phenotype and Genotype of Children with ALS2 gene-Related Disorder.}, journal = {Neuropediatrics}, volume = {56}, number = {1}, pages = {20-28}, doi = {10.1055/s-0044-1791256}, pmid = {39424348}, issn = {1439-1899}, mesh = {Humans ; *Phenotype ; *Guanine Nucleotide Exchange Factors/genetics ; Male ; Female ; *Genotype ; Child ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Child, Preschool ; Adolescent ; Pedigree ; Mutation ; Spastic Paraplegia, Hereditary ; }, abstract = {INTRODUCTION: The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder.<br><br>METHODS: The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval.<br><br>RESULTS: One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families.<br><br>CONCLUSION: ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype-phenotype correlation in patients with ALS2 gene-related disorder.}, }
@article {pmid39423873, year = {2024}, author = {Thapa, R and Moglad, E and Afzal, M and Gupta, G and Bhat, AA and Hassan Almalki, W and Kazmi, I and Alzarea, SI and Pant, K and Singh, TG and Singh, SK and Ali, H}, title = {The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102545}, doi = {10.1016/j.arr.2024.102545}, pmid = {39423873}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Sirtuin 1/metabolism ; *Aging/metabolism/genetics ; Animals ; Oxidative Stress/physiology ; }, abstract = {Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications.}, }
@article {pmid39422938, year = {2024}, author = {Pappolla, MA and Wu, P and Fang, X and Poeggeler, B and Sambamurti, K and Wisniewski, T and Perry, G}, title = {Stem Cell Interventions in Neurology: From Bench to Bedside.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {s1}, pages = {S395-S416}, doi = {10.3233/JAD-230897}, pmid = {39422938}, issn = {1875-8908}, mesh = {Humans ; Animals ; *Stem Cell Transplantation/methods/trends ; Nervous System Diseases/therapy ; Neurology/trends/methods ; Translational Research, Biomedical/trends ; Neural Stem Cells/transplantation ; }, abstract = {Stem cell therapies are progressively redefining the treatment landscape for a spectrum of neurological and age-related disorders. This review discusses the molecular and functional attributes of stem cells, emphasizing the roles of neural stem cells and mesenchymal stem cells in the context of neurological diseases such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. The review also explores the potential of stem cells in addressing the aging process. The paper analyzes stem cells' intrinsic properties of self-renewal, differentiation, and paracrine effects, alongside the importance of laboratory-modified stem cells like induced pluripotent stem cells and transgenic stem cells. Insights into disease-specific stem cell treatments are offered, reviewing both successes and challenges in the field. This includes the translational difficulties from rodent studies to human trials. The review concludes by acknowledging the uncharted territories that warrant further investigation, emphasizing the potential roles of stem cell-derived exosomes and indole-related molecules, and aiming at providing a basic understanding of stem cell therapies.}, }
@article {pmid39420987, year = {2024}, author = {Sun, H and Tang, Q and Yan, X and Xie, W and Xu, Y and Zhang, W}, title = {Cathepsins and neurological diseases: a Mendelian randomization study.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1454369}, pmid = {39420987}, issn = {1662-4548}, abstract = {BACKGROUND: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases.<br><br>METHODS: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis.<br><br>RESULTS: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p&#x2009;=&#x2009;0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p&#x2009;=&#x2009;0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p&#x2009;=&#x2009;0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p&#x2009;=&#x2009;0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p&#x2009;=&#x2009;0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases.<br><br>CONCLUSION: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions.}, }
@article {pmid39419765, year = {2024}, author = {Johns, AE and Taga, A and Charalampopoulou, A and Gross, SK and Rust, K and McCray, BA and Sullivan, JM and Maragakis, NJ}, title = {Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.}, journal = {Stem cells translational medicine}, volume = {13}, number = {12}, pages = {1198-1212}, pmid = {39419765}, issn = {2157-6580}, mesh = {Humans ; *Motor Neurons/metabolism/drug effects ; *Receptors, Purinergic P2X7/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Purinergic P2X Receptor Antagonists/pharmacology ; Animals ; Adenosine Triphosphate/metabolism ; Neuroprotection/drug effects ; Mice ; Rats ; }, abstract = {ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.}, }
@article {pmid39419433, year = {2025}, author = {Majumder, P and Hsu, TI and Hu, CJ and Huang, JK and Lee, YC and Hsieh, YC and Ahsan, A and Huang, CC}, title = {Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease.}, journal = {Experimental neurology}, volume = {383}, number = {}, pages = {114999}, doi = {10.1016/j.expneurol.2024.114999}, pmid = {39419433}, issn = {1090-2430}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; Female ; *Disease Models, Animal ; Male ; *DNA-Binding Proteins/metabolism/genetics ; *Estrogen Replacement Therapy/methods ; *Curcumin/pharmacology/administration &amp; dosage/therapeutic use ; Mice, Transgenic ; Aromatase/metabolism ; Estradiol/pharmacology ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS.<br><br>METHODS: Prp-TDP-43[A315T] mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43[A315T] mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43[A315T] mice with or without SLCP were determined.<br><br>RESULTS: We found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43[A315T] mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43[A315T] mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes.<br><br>CONCLUSIONS: Our results showed that Prp-TDP-43[A315T] mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.}, }
@article {pmid39419034, year = {2025}, author = {Wijegunawardana, D and Nayak, A and Vishal, SS and Venkatesh, N and Gopal, PP}, title = {Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.}, journal = {Developmental cell}, volume = {60}, number = {2}, pages = {253-269.e5}, doi = {10.1016/j.devcel.2024.09.023}, pmid = {39419034}, issn = {1878-1551}, mesh = {Animals ; *Ataxin-2/metabolism/genetics ; *Peptides/metabolism/genetics ; *RNA, Messenger/genetics/metabolism ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; *Motor Neurons/metabolism ; Protein Biosynthesis ; Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Rats ; Ribonucleoproteins/metabolism/genetics ; Axons/metabolism ; RNA Transport ; Humans ; }, abstract = {Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo. We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within RNP condensates and disrupt both its motility along the axon and liquid-like properties. We provide evidence that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localization, and/or translation of critical axonal and cytoskeletal mRNAs, particularly important for motor neuron integrity.}, }
@article {pmid39418491, year = {2025}, author = {Kumar, R and Ghai, S and Finelli, A and Klotz, L and Kinnaird, A and Mannas, M and Bhindi, B and Sanchez-Salas, R and Anidjar, M and Ahmad, A and Chin, J and Inman, B and Perlis, N}, title = {The use of focal therapy for the treatment of prostate cancer in Canada Where are we, how did we get here, and where are we going?.}, journal = {Canadian Urological Association journal = Journal de l'Association des urologues du Canada}, volume = {19}, number = {2}, pages = {63-72}, pmid = {39418491}, issn = {1911-6470}, abstract = {INTRODUCTION: Focal therapy is an emerging treatment for localized prostate cancer (PCa). The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada.<br><br>METHODS: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up to 2020. We focused on studies reporting functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrials.gov.<br><br>RESULTS: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation, or transurethral ultrasound ablation.<br><br>CONCLUSIONS: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.}, }
@article {pmid39416141, year = {2024}, author = {Winkelsas, A and Apfel, A and Johnson, B and Harmison, G and Li, D and Cheung, V and Grunseich, C}, title = {Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416141}, issn = {2692-8205}, support = {R21 ES034919/ES/NIEHS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.}, }
@article {pmid39416104, year = {2024}, author = {Gunner, G and Basu, H and Lu, Y and Bergstresser, M and Neel, D and Choi, SY and Chiu, IM}, title = {Gasdermin D is activated but does not drive neurodegeneration in SOD1 [G93A] model of ALS: Implications for targeting pyroptosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.10.10.617609}, pmid = {39416104}, issn = {2692-8205}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1 [G93A] mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1 [G93A] animals across two strain backgrounds, with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred B6.SOD1 [G93A] mice onto a GSDMD - deficient background. In comparing SOD1 [G93A] ; Gsdmd +/+ and SOD1 [G93A] ; Gsdmd -/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1 [G93A] mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.}, }
@article {pmid39415649, year = {2024}, author = {Kim, Y and O, JH and Cho, H and Ye, S}, title = {Recognized cases of amyotrophic lateral sclerosis in automobile workers by the Korean Epidemiologic Investigation Evaluation Committee.}, journal = {Annals of occupational and environmental medicine}, volume = {36}, number = {}, pages = {e28}, pmid = {39415649}, issn = {2052-4374}, abstract = {BACKGROUND: Three automobile company workers (one from Factory D and two from Factory E) were diagnosed with amyotrophic lateral sclerosis. The Korean Epidemiologic Investigation and Evaluation Committee determined that there is considerable scientific evidence supporting the association between amyotrophic lateral sclerosis and combined exposure to heavy metals, organic solvents, and diesel exhaust at the manufacturing plant.<br><br>CASE PRESENTATION: Patient A, who primarily engaged in engine processing and completed vehicle inspection at Factory D, was exposed to considerable amounts of heavy metals and organic solvents during medium- and large-engine processing, welding, and painting for over 23 years. Additionally, the patient was likely exposed to diesel exhaust for 33 years from forklifts delivering engines in the workshop. Patients B and C, who were responsible for engine assembly, ignition testing, and engine shipment at Factory E since around 1990, were exposed to lead and benzene from gasoline during engine ignition tests in the engine department for 15 and 16 years, respectively. They also encountered welding fumes, heavy metals, and organic solvents during welding and painting tasks. In addition, Patients B and C were continuously exposed to diesel exhaust from logistics vehicles on standby during work hours for 25 and 30 years, respectively.<br><br>CONCLUSIONS: Although the specific level of lead exposure causing amyotrophic lateral sclerosis remains undetermined, numerous studies have consistently reported a relationship between lead exposure and disease development. Limited evidence suggests that exposure to organic solvents and diesel exhaust may increase the risk of amyotrophic lateral sclerosis. Therefore, the Epidemiological Investigation and Evaluation Committee concluded that the three patients' work-related exposure to heavy metals, organic solvents, and diesel exhaust is significantly supported by scientific evidence as a cause of their amyotrophic lateral sclerosis.}, }
@article {pmid39415277, year = {2024}, author = {Abdelnaby, R and Shabib, AS and El Din Moawad, MH and Salem, T and Wagih Youssef Awad, M and Awad, PD and Maallem, I and Atwan, H and Rabie, SA and Mohamed, KA and Abdelmageed, H and Karkour, AM and Elsayed, M and Cartwright, MS}, title = {Nerve ultrasound in amyotrophic lateral sclerosis: systematic review and meta-analysis.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {47}, pmid = {39415277}, issn = {2524-3489}, abstract = {BACKGROUND/ AIM: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, causing progressive atrophy of muscles, hypertonia, and paralysis. This study aimed to evaluate the current evidence and effectiveness of ultrasound in investigating nerve cross-sectional area (CSA) of peripheral nerves, vagus and cervical roots in those with ALS compared with healthy controls and to pool the CSA measurements.<br><br>METHODS: A systematic search was conducted on Cochrane, Clarivate Web of Science, PubMed, Scopus, and Embase for the mesh terms nerve, ultrasonography, and amyotrophic lateral sclerosis. A quality assessment was performed using the New-Ottawa scale. In addition, a double-arm meta-analysis using Review Manager 5 software version 5.4 was performed.<br><br>RESULTS: From the seventeen studies included in this review, the overall mean difference showed that individuals with ALS had a significantly smaller CSA in comparison to healthy controls for median, ulnar, C6 root, and phrenic nerves. However, no significant difference in the CSA was found in radial, vagal, sural, and tibial nerves.<br><br>DISCUSSION: This study confirmed results of some of the included studies regards the anatomic sites, where nerve atrophy in ALS could be detected to potentially support the diagnosis of ALS. However, we recommend further large, prospective studies to assess the diagnostic value of these anatomical sites for the diagnosis of ALS.<br><br>CONCLUSIONS: Our findings confirmed specific anatomic sites to differentiate ALS patients from healthy controls through ultrasound. However, these findings cannot be used to confirm the ALS diagnosis, but rather assist in differentiating it from other diagnoses.<br><br>TRIAL REGISTRATION: Retrospectively registered on July 30th 2024 in PROSPERO (PROSPERO (york.ac.uk)) with ID574702.}, }
@article {pmid39414899, year = {2024}, author = {Kawata, S and Seki, S and Nishiura, A and Kitaoka, Y and Iwamori, K and Fukada, SI and Kogo, M and Tanaka, S}, title = {Preservation of masseter muscle until the end stage in the SOD1G93A mouse model for ALS.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24279}, pmid = {39414899}, issn = {2045-2322}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics ; *Masseter Muscle/pathology ; *Disease Models, Animal ; Mice ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Satellite Cells, Skeletal Muscle/pathology/metabolism ; Motor Neurons/pathology/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) progressively impairs motor neurons, leading to muscle weakness and loss of voluntary muscle control. This study compared the effects of SOD1 mutation on masticatory and limb muscles from disease onset to death in ALS model mice. Notably, limb muscles begin to atrophy soon after ALS-like phenotype appear, whereas masticatory muscles maintain their volume and function in later stages. Our analysis showed that, unlike limb muscles, masticatory muscles retain their normal structure and cell makeup throughout most of the disease course. We found an increase in the number of muscle satellite cells (SCs), which are essential for muscle repair, in masticatory muscles. In addition, we observed no reduction in the number of muscle nuclei and no muscle fibre-type switching in masticatory muscles. This indicates that masticatory muscles have a higher resistance to ALS-related damage than limb muscles, likely because of differences in cell composition and repair mechanisms. Understanding why masticatory muscles are less affected by ALS could lead to the development of new treatments. This study highlights the importance of studying different muscle groups in ALS to clarify disease aetiology and mechanisms.}, }
@article {pmid39413009, year = {2024}, author = {Ralbovsky, NM and Zhang, Y and Williams, DM and McKelvey, CA and Smith, JP}, title = {Machine Learning and Hyperspectral Imaging for Analysis of Human Papillomaviruses (HPV) Vaccine Self-Healing Particles.}, journal = {Analytical chemistry}, volume = {96}, number = {43}, pages = {17118-17127}, doi = {10.1021/acs.analchem.4c02327}, pmid = {39413009}, issn = {1520-6882}, mesh = {*Papillomavirus Vaccines/immunology ; *Machine Learning ; Humans ; Vaccines, Virus-Like Particle ; Human Papillomavirus Viruses ; }, abstract = {Human papillomaviruses (HPV) are known to cause a variety of diseases, including cervical cancer and genital warts. HPV is a highly prevalent virus and is considered the most common sexually transmitted disease. Because of the risks associated with HPV, Gardasil, a quadrivalent recombinant vaccine, was developed by Merck &amp; Co., Inc., Rahway, NJ, USA, and approved by the Food and Drug Administration (FDA) in 2006. The second generation of the vaccine, Gardasil9, was subsequently approved by the FDA in 2014, providing significant protection against HPV. The HPV vaccine may be given as 2 or 3 doses; however, vaccine administration as a single dose with a sustained release mechanism may potentially offer benefits to meet emerging health needs. To explore this, HPV vaccines were formulated within microporous self-healing particles (SHPs) to enable potential controlled release of HPV virus-like particle (VLP) antigen. Machine learning, in the form of multivariate curve resolution-alternating least-squares (MCR-ALS), with Raman hyperspectral imaging was used to determine the molecular identity and spatial distribution of all relevant species within this HPV vaccine formulation. The results indicate that machine learning with Raman hyperspectral imaging was able to spatially resolve HPV VLP antigens within SHP vaccines for the first time, providing crucial information necessary for vaccine development.}, }
@article {pmid39412921, year = {2024}, author = {Bahador, M and Soltaninejad, S and Mobasheri, M}, title = {Correlation of new two-dimensional geometrical parameters to lung and heart dose-volume parameters in breast cancer radiation therapy.}, journal = {Journal of cancer research and therapeutics}, volume = {20}, number = {5}, pages = {1570-1577}, doi = {10.4103/jcrt.jcrt_2351_23}, pmid = {39412921}, issn = {1998-4138}, mesh = {Humans ; Female ; *Heart/radiation effects/diagnostic imaging ; *Radiotherapy Dosage ; *Radiotherapy Planning, Computer-Assisted/methods ; *Lung/radiation effects/diagnostic imaging/pathology ; *Breast Neoplasms/radiotherapy/pathology ; *Organs at Risk/radiation effects ; Tomography, X-Ray Computed/methods ; ROC Curve ; Middle Aged ; }, abstract = {OBJECTIVE: To develop new two-dimensional geometric parameters for pulmonary and cardiac dose estimation in left-sided breast cancer radiation therapy without dose-volume histogram (DVH).<br><br>METHODS: On the CT image of 90 patients with left breast cancer, treatment planning was performed using two opposed tangent fields with/without supraclavicular. The field-in-field technique and 6MV photons were used. From DVH dosimetric parameters of mean dose, Vx (x (Gy) =5, 10, 15, 20, 30, 40, 50) were calculated, and from heart and lung outlines on the beam's eye view, new geometric parameters of percent of lung area in tangent and supraclavicular fields (%area of the lung in the tangent (ALT), %ALS) and percent of heart in tangent field (%area of the heart in the tangent (AHT)) were measured. Correlation, regression, and diagnostic performance by receiver operating characteristic curve (ROC) were investigated for statistical analysis.<br><br>RESULTS: The Pearson coefficient between %ALT and Vx (x = 10, 15, 20, 30, 40) show strong correlation in patient treatment with only opposed tangents (>0.85) and weaker in treatment by opposed tangents with supraclavicular (0.56-0.88), the %ALS indicate weak correlation (<0.5) and %AHT show strong correlation (0.93-0.98). The regression analysis shows a positive relation between %ALT and mean dose (R2 = 0.8), V20Gy (R2 = 0.9) in the lung (tangent treatment), and between %AHT and mean dose (R2 = 0.9), V20Gy (R2 = 1.0) in the heart. The ROC analysis shows by %ALT <20.3 for treatment by just opposed fields, %ALT <22.1% for treatment tangents with supra, and %AHT <11.6%, practical lung and heart dose constraints are addressed.<br><br>CONCLUSION: The proposed geometric parameters could replace previous one-dimensional maximum and central distances for predicting doses to lung and heart.<br><br>ADVANCES IN KNOWLEDGE: This study presents simple geometric parameters that could estimate pulmonary and cardiac dose in left breast cancer treatment from a 2D radiograph.}, }
@article {pmid39412565, year = {2024}, author = {Sangari, S and Lackmy-Vallee, A and Preuilh, A and Peyre, I and Pradat, PF and Marchand-Pauvert, V}, title = {Synaptic dynamics linked to widespread elevation of H-reflex before peripheral denervation in amyotrophic lateral sclerosis.}, journal = {Journal of neurophysiology}, volume = {132}, number = {5}, pages = {1541-1560}, doi = {10.1152/jn.00144.2024}, pmid = {39412565}, issn = {1522-1598}, support = {VMarchand/2013//ARSLA/ ; DdT1 2015- 2; CTL/SS/2016-0029/no 16597//AFM-Telethon/ ; FTL AAP7/2015//Fondation Thierry Latran (Thierry Latran Foundation)/ ; }, mesh = {Humans ; *H-Reflex/physiology ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Middle Aged ; *Evoked Potentials, Motor/physiology ; *Muscle, Skeletal/physiopathology/physiology ; Aged ; Adult ; Excitatory Postsynaptic Potentials/physiology ; Riluzole/pharmacology ; Motor Neurons/physiology ; }, abstract = {Changes in Hoffmann reflex (H-reflex) exhibit heterogeneity among patients with amyotrophic lateral sclerosis (ALS), likely due to phenotype diversity. Current knowledge primarily focuses on soleus H-reflex, which may demonstrate an initial increase before subsequent decline throughout the disease course. The main objective was to investigate other muscles, to determine whether H-reflex changes could be associated with patient phenotype (onset site, functional disabilities). Additional experiments were performed to elucidate the neurophysiological mechanisms underlying H-reflex modifications. In age- and sex-matched groups of control subjects and patients, we compared H-reflex recruitment curves in soleus, quadriceps, and forearm flexors. Additionally, we examined H-reflex and motor evoked potential (MEP) recruitment curves in quadriceps. Last, to assess potential changes in monosynaptic excitatory postsynaptic potentials (EPSPs) of both peripheral and cortical origins, we analyzed peristimulus time histograms (PSTHs) and peristimulus frequencygrams (PSFs) of single motor units, along with H-reflex occurrence after paired-pulse stimuli. The ratio between maximal amplitudes of H-reflex and direct motor response increased in all muscles, irrespective of disease onset, and was found positively correlated with exaggerated osteotendinous reflexes and spasticity but depressed in patients on riluzole. This finding was accompanied by a reduction in MEP size and no changes in PSTH, PSF, and paired-pulse H-reflex probability. It is speculated that spinal interneurons may compensate for potential depression of monosynaptic EPSPs in ALS. From a clinical perspective, although the added value of H-reflex to osteotendinous reflex evaluation may be limited, it can serve as a valuable quantitative biomarker of pyramidal dysfunction in clinical trials.NEW &amp; NOTEWORTHY Without significant evidence of peripheral denervation, H-reflex enhancement appears to be a widespread phenomenon, regardless of disease onset site. This increase is likely associated with a decrease in inhibitory control over presynaptic transmission of the synapse between muscle group Ia afferents and motoneurons. Although the link to exaggerated osteotendinous reflexes and spasticity implies a restricted role in identifying a pyramidal syndrome, its quantitative aspect positions the H-reflex as a valuable biomarker in clinical trials.}, }
@article {pmid39412227, year = {2024}, author = {Mascías Cadavid, J and Radakovic, R and Radakovic, C and Moran Benito, Y and Marín Esteban, S and Rodríguez-Santos, F and Salas Campos, T}, title = {Spanish adaptation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS).}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/21678421.2024.2416665}, pmid = {39412227}, issn = {2167-9223}, abstract = {Amyotrophic lateral sclerosis (ALS) is characterized functional decline, traditionally measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is an alternative comprehensive, detailed functional disability measure for people with ALS (pwALS), not yet translated to Spanish. The aim of this study was to translate and validate the Spanish ROADS. 53 Spanish speaking pwALS were recruited. They completed the ALSFRS-R and Spanish ROADS. Reliability (internal consistency, intra-class correlation) and validity (ALSFRS-R total and item-total correlations) were determined. The Spanish ROADS internal consistency reliability was excellent (Cronbach's standardized alpha = 0.94), the test-retest reliability intra-class correlation value was 0.93. There was a strong significant correlation between the Spanish ROADS and ALSFRS-R totals (rs(52) = .89, p < .001). Additionally, the ALSFRS-R subscales and ROADS items correlations showed domain-to-item specific expected significant correlations. The Spanish ROADS is a psychometrically robust, valid and reliable measure for quantifying functional disability for pwALS.}, }
@article {pmid39411168, year = {2024}, author = {An, D and Han, J and Fang, P and Bu, Y and Ji, G and Liu, M and Deng, J and Song, X}, title = {Evidence for the potential role of m6A modification in regulating autophagy in models of amyotrophic lateral sclerosis.}, journal = {CytoJournal}, volume = {21}, number = {}, pages = {33}, pmid = {39411168}, issn = {0974-5963}, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Research indicates that N6-methyladenosine (m6A) modification plays a crucial role in cellular autophagy during ALS development. This study investigates the role of autophagy in ALS, with a focus on the effect of messenger ribonucleic acid m6A methylation modification on disease progression.<br><br>MATERIAL AND METHODS: We compared m6A levels and regulatory molecule expressions in transgenic superoxide dismutase (SOD1)-G93A and non-transgenic mice, categorized into end-stage and control groups, using quantitative polymerase chain reaction and Western blotting. The NSC-34 cell line, which was modified to model ALS, enabled the investigation of apoptosis, autophagy, and autophagy disruption through terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assays, Western blotting, and fluorescent staining.<br><br>RESULTS: Our findings indicate significantly elevated m6A methylation levels in ALS mice (0.262 &#xb1; 0.005) compared with the controls (0.231 &#xb1; 0.003) and in the ALS model cells (0.242&#xb1;0.005) relative to those belonging to the wild-type control group (0.183 &#xb1; 0.007). Furthermore, the proteins involved in m6A RNA modification differed between groups, which suggest impaired autophagy flux in the ALS models.<br><br>CONCLUSION: These results suggest that m6A methylation may accelerate ALS progression through the disruption of autophagic processes. Our study underscores the role of m6A methylation in the pathology of ALS and proposes the targeting of m6A methylation as a potential therapeutic strategy for disease treatment. Although this study primarily used transgenic SOD1-G93A mice and NSC-34 cell models to investigate ALS pathology, potential differences in disease mechanisms between animal models and humans must be considered. Although a correlation was detected between m6A methylation levels and autophagy disruption in ALS, the study primarily established an association rather than provided detailed mechanistic insights.}, }
@article {pmid39410995, year = {2024}, author = {Zaninotto, AL and Makary, MM and Rowe, HP and Eshghi, M and Tseng, CJ and Chan, J and Zürcher, NR and Hooker, J and Lewis, A and Keegan, M and Gifford, RF and Green, JR and Babu, S}, title = {Speech motor impairment in ALS is associated with multiregional cortical thinning beyond primary motor cortex.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1451177}, pmid = {39410995}, issn = {1664-2295}, abstract = {INTRODUCTION: Cortical thinning is well-documented in individuals with amyotrophic lateral sclerosis (ALS), yet its association with speech deterioration remains understudied. This study characterizes anatomical changes in the brain within the context of speech impairment patterns in individuals with ALS, providing insight into the disease's multiregional spread and biology.<br><br>METHODS: To evaluate patterns of cortical thickness in speakers with ALS with and without functional speech changes compared to healthy controls (HCs) using whole-brain and region of interest (ROI) analyses. Forty individuals with ALS and 22 HCs underwent a T1-weighted 3-Tesla magnetic resonance imaging (MRI). Individuals with ALS were divided into two groups based on the preserved speech [ps-ALS] (n = 18) or deteriorated speech [ds-ALS] (n = 22) as measured by the ALSFRSF-R speech subscore (=4 or <4 points, respectively). Sixteen a priori-defined and automatically segmented cortical and subcortical brain ROIs were selected based on their previously documented roles in speech production. Two cortical thickness analyses were performed: (1) group-level whole-brain surface-based analyses and (2) group-level ROI analyses. A case study of 6 ALS individuals examined the cortical thickness, and their speech was characterized using quantitative and qualitative measures.<br><br>RESULTS: Based on the group-level whole-brain surface-based analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in the left primary motor and somatosensory cortices and the right inferior parietal lobe with its adjacent lateral occipital cortical regions. The ps-ALS group demonstrated no significant cortical thinning compared to HCs. Based on the group-level ROI analyses, the ds-ALS group demonstrated significant cortical thinning compared to HCs in bilateral middle motor cortices, right posterior dorsal premotor cortex, and left anterior cingulate cortex. The case study analysis revealed that ALS speakers with speech features characteristic of spastic dysarthria exhibited cortical thinning, while those with speech features characteristic of flaccid dysarthria did not.<br><br>DISCUSSION: Individuals with ALS have anatomical changes involving multiregional neocortical areas beyond the primary motor cortex that may manifest as subjective (i.e., clinical judgment) and objective (i.e., speaking rate) changes in speech production. Further longitudinal work in ALS is needed to better understand the link between MRI cortical thickness changes and bulbar dysfunction.}, }
@article {pmid39408720, year = {2024}, author = {Du, X and Dong, Q and Zhu, J and Li, L and Yu, X and Liu, R}, title = {Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39408720}, issn = {1422-0067}, support = {XDB39050600//Strategic Priority Research Program of Chinese Academy of Sciences/ ; 82150107//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Rutin/pharmacology/therapeutic use ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology/genetics ; Mice ; *Superoxide Dismutase-1/metabolism/genetics ; *Disease Models, Animal ; *Mice, Transgenic ; *Spinal Cord/drug effects/metabolism/pathology ; Motor Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Protein Aggregation, Pathological/drug therapy/metabolism ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of motor neurons, with limited effective treatments. Recently, the exploration of natural products has unveiled their potential in exerting neuroprotective effects, offering a promising avenue for ALS therapy. In this study, the therapeutic effects of rutin, a natural flavonoid glycoside with neuroprotective properties, were evaluated in a superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. We showed that rutin reduced the level of SOD1 aggregation and diminished glial cell activation in spinal cords and brainstems, resulting in significantly improved motor function and motor neuron restoration in SOD1-G93A mice. Our findings indicated that rutin's multi-targeted approach to SOD1-related pathology makes it a promising candidate for the treatment of ALS.}, }
@article {pmid39408173, year = {2024}, author = {Rolling, J and Fath, M and Zanfonato, T and Durpoix, A and Mengin, AC and Schröder, CM}, title = {EMDR-Teens-cPTSD: Efficacy of Eye Movement Desensitization and Reprocessing in Adolescents with Complex PTSD Secondary to Childhood Abuse: A Case Series.}, journal = {Healthcare (Basel, Switzerland)}, volume = {12}, number = {19}, pages = {}, pmid = {39408173}, issn = {2227-9032}, abstract = {Background: Mental healthcare for children and adolescents with a history of childhood abuse constitutes a major public health issue. Indeed, abuse exposes children to severe and complex post-traumatic stress disorder (cPTSD) but also to neurodevelopmental and psychological repercussions impacting the developmental trajectory. Trauma-focused care is essential to avoid the chronicization of symptoms and disorders. Objective: The aim of this prospective case series study was to investigate the efficacy of eye movement desensitization and reprocessing (EMDR) on complex post-traumatic symptoms and associated psychiatric disorders in adolescents with a history of abuse. Method: Twenty-two adolescents, aged 12 to 17, who had been abused during childhood were included. All adolescents met ICD-11 criteria for complex PTSD. Subjective measures of PTSD and associated psychiatric disorders were taken before (T0) and after 3 months of EMDR therapy (T1). Results: The average PTSD symptom score on the CPTS-RI significantly decreased from 40.2 to 34.4 after EMDR, indicating improvement in post-traumatic symptoms. A significant decrease in the average depression score (CDI from 18.2 at T0 to 10.6 at T1), anxiety score (R-CMAS from 21.3 at T0 to 13.3 at T1), emotional regulation score (ALS from 29 at T0 to 10.8 at T1), insomnia score (ISI from 18.5 at T0 to T1 of 9.2 at T1), and harmful use of alcohol and drugs score (ADOSPA from 2.3 at T0 to 0.3 at T1) was observed after EMDR therapy, as well as an increase in quality of life (CBCL 4-16 score from 57.9 at T0 to 77.4 at T1). Conclusions: The results of this study are encouraging and suggest that EMDR may be effective in the symptom management reducing post-traumatic symptoms and certain comorbid disorders frequently seen in adolescents who have experienced childhood abuse. Further research is needed on adolescent populations suffering from cPTSD (e.g., randomized controlled trials with control groups and other therapies or evaluating the action of the different phases of the study).}, }
@article {pmid39407861, year = {2024}, author = {Proaño, B and Cuerda-Ballester, M and Daroqui-Pajares, N and Del Moral-López, N and Seguí-Sala, F and Martí-Serer, L and Calisaya Zambrana, CK and Benlloch, M and de la Rubia Ortí, JE}, title = {Clinical and Sociodemographic Factors Related to Amyotrophic Lateral Sclerosis in Spain: A Pilot Study.}, journal = {Journal of clinical medicine}, volume = {13}, number = {19}, pages = {}, pmid = {39407861}, issn = {2077-0383}, support = {2021-203-003//Catholic University of Valencia San Vicente M&#xe1;rtir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknow etiology. Male sex is a well stablished risk factor, but other factors such as early and adult life expositions show contradictory evidence. Aim: to explore the link of clinical, sociodemographic, and occupational factors with ALS patients in Spain and the impact of these factors in functionality. Methods: A cross-sectional study was conducted with ALS patients and healthy controls. Registered variables were smoking, arterial hypertension, diabetes mellitus type 2, previous cancer to reproductive organs or breast, occupational exposure, and early life exposures. Functionality in ALS patients was compared according to each exposure. Results: The ALS group consisted of 59 participants and the control group of 90 participants. ALS patients showed a significant association with previous cancer (p = 0.011), occupational exposure (p < 0.001), and older siblings (p = 0.029). ALS patients presented significant differences in BMI according to hypertension and older-sibling factors. Moreover, respiratory function was affected in patients with previous cancer (p = 0.031). Conclusions: Occupational exposure and previous cancer to reproductive organs or breast could be linked to ALS patients. In addition, hypertension and previous cancer could affect their BMI and respiratory function. Other factors such as longer smoking periods and exposition to older siblings could also characterize ALS patients.}, }
@article {pmid39407580, year = {2024}, author = {Forleo, T and Giannossa, LC and De Juan Capdevila, A and Lagioia, G and Mangone, A}, title = {Hats Off to Modeling! Profiling Early Synthetic Dyes on Historic Woolen Samples with ATR-FTIR Spectroscopy and Multivariate Curve Resolution-Alternating Least Square Algorithm.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {19}, pages = {}, pmid = {39407580}, issn = {1420-3049}, abstract = {This research focuses on analyzing wool samples dyed with synthetic dyes from the early 20th century. A methodology to identify and distinguish wool fibers dyed with azo, triphenylmethane, and xanthene dyes, which are no longer in use, using the ATR-FTIR spectra, is presented. Firstly, the dataset was subjected to PCA, which revealed the similarities and differences among the samples, illustrating a distribution pattern based on dye classes. MCR-ALS was employed to extract the spectral profiles of the dyed fibers, thereby enhancing the efficacy of the analytical techniques and extracting the comprehensive information from a single instrument. The combination of ATR-FTIR spectroscopy with chemometric methods, such as PCA and MCR-ALS, has proven to be an effective strategy for identifying and differentiating wool fibers dyed with early azo, triphenylmethane, and xanthene dyes. This approach has demonstrated particular effectiveness in enabling rapid analysis without requiring sampling or pretreatment. Moreover, the analysis is supported by thorough bibliographic research on these no longer used colorants. In order to maximize the potential of non-destructive spectroscopic techniques, such as ATR-FTIR, the approach used has proven to be crucial. This study underscores how chemometric techniques expand the capabilities of spectroscopy, extracting extensive information from a single instrument and aligning with the goals of cultural heritage analysis.}, }
@article {pmid39406675, year = {2025}, author = {Schilfarth, P and Réginault, T and Mathis, S and Le Masson, G and Pillet, O and Grassion, L}, title = {Changes in Non-invasive Ventilation Compliance in Patients With Amyotrophic Lateral Sclerosis: A Post-hoc Analysis.}, journal = {Archivos de bronconeumologia}, volume = {61}, number = {1}, pages = {47-49}, doi = {10.1016/j.arbres.2024.09.003}, pmid = {39406675}, issn = {1579-2129}, }
@article {pmid39406341, year = {2024}, author = {López-Royo, T and Moreno-Martínez, L and Zaragoza, P and García-Redondo, A and Manzano, R and Osta, R}, title = {Differentially expressed lncRNAs in SOD1[G93A] mice skeletal muscle: H19, Myhas and Neat1 as potential biomarkers in amyotrophic lateral sclerosis.}, journal = {Open biology}, volume = {14}, number = {10}, pages = {240015}, pmid = {39406341}, issn = {2046-2441}, support = {//Gobierno de Arag&#xf3;n/ ; //Instituto de Salud Carlos III/ ; //European Union/ ; //Gobierno de Espa&#xf1;a/ ; //Center for Biomedical Research/ ; }, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Mice ; *Muscle, Skeletal/metabolism/pathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Biomarkers/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Humans ; Gene Expression Regulation ; Gene Expression Profiling ; Male ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor function and muscle mass loss. Despite extensive research in the field, the underlying causes of ALS remain incompletely understood, contributing to the absence of specific diagnostic and prognostic biomarkers and effective therapies. This study investigates the expression of long-non-coding RNAs (lncRNAs) in skeletal muscle as a potential source of biomarkers and therapeutic targets for the disease. The expression profiles of 12 lncRNAs, selected from the literature, were evaluated across different disease stages in tissue and muscle biopsies from the SOD1[G93A] transgenic mouse model of ALS. Nine out of the 12 lncRNAs were differentially expressed, with Pvt1, H19 and Neat1 showing notable increases in the symptomatic stages of the disease, and suggesting their potential as candidate biomarkers to support diagnosis and key players in muscle pathophysiology in ALS. Furthermore, the progression of Myhas and H19 RNA levels across disease stages correlated with longevity in the SOD1[G93A] animal model, effectively discriminating between long- and short-term survival individuals, thereby highlighting their potential as prognostic indicators. These findings underscore the involvement of lncRNAs, especially H19 and Myhas, in ALS pathophysiology, offering novel insights for diagnostic, prognostic and therapeutic targets.}, }
@article {pmid39406000, year = {2024}, author = {Zhang, L and Du, Y and Deng, Y and Bai, T and Wang, J and Wang, W and Ji, M}, title = {Mutations in target gene confers resistance to acetolactate synthase inhibitors in Echinochloa phyllopogon.}, journal = {Plant physiology and biochemistry : PPB}, volume = {216}, number = {}, pages = {109194}, doi = {10.1016/j.plaphy.2024.109194}, pmid = {39406000}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/antagonists &amp; inhibitors/metabolism ; *Echinochloa/genetics/drug effects/enzymology ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Mutation ; *Plant Proteins/genetics/metabolism ; Plants, Genetically Modified ; Enzyme Inhibitors/pharmacology ; Arabidopsis/genetics/enzymology/drug effects ; Molecular Docking Simulation ; Sulfonamides ; Uridine/analogs &amp; derivatives ; }, abstract = {Echinochloa phyllopogon is a noxious weed that can harm rice over prolonged periods. Recently, a penoxsulam-resistant variant of E. phyllopogon with a mutation in the acetolactate synthase (ALS) gene was collected in Northeastern China. In the present study, the molecular mechanism underlying herbicide resistance in mutant populations was evaluated. The GR50 and IC50 values of the herbicide-resistant mutant 1-11 were 27.0- and 21.4-fold higher than those of the susceptible population 2-31, respectively. In addition, pre-application of malathion reduced the GR50 value of the resistant population. Additionally, mutant populations developed cross-resistance to other ALS inhibitors. E. phyllopogon ALS sequencing showed a Trp-574-Leu mutation in ALS2 variant 1-11. Molecular docking showed that the Trp-574-Leu substitution reduced the number of hydrogen bonds and altered the interaction between penoxsulam and ALS2. Transgenic Arabidopsis plants harboring the ALS2 mutant gene also showed resistance to penoxsulam and other ALS inhibitors. Overall, our study demonstrated that the Trp-574-Leu mutation and P450-mediated metabolic resistance lead to the cross-resistance of E. phyllopogon to ALS inhibitors.}, }
@article {pmid39405005, year = {2024}, author = {Cheng, JL and Cook, AL and Talbot, J and Perry, S}, title = {How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?.}, journal = {Neurotoxicity research}, volume = {42}, number = {5}, pages = {43}, pmid = {39405005}, issn = {1476-3524}, mesh = {*Induced Pluripotent Stem Cells/drug effects/physiology ; Humans ; *Neurons/drug effects/metabolism ; Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Cell Differentiation/drug effects/physiology ; }, abstract = {Excitotoxicity linked either to environmental causes (pesticide and cyanotoxin exposure), excitatory neurotransmitter imbalance, or to intrinsic neuronal hyperexcitability, is a pathological mechanism central to neurodegeneration in amyotrophic lateral sclerosis (ALS). Investigation of excitotoxic mechanisms using in vitro and in vivo animal models has been central to understanding ALS mechanisms of disease. In particular, advances in induced pluripotent stem cell (iPSC) technologies now provide human cell-based models that are readily amenable to environmental and network-based excitotoxic manipulations. The cell-type specific differentiation of iPSC, combined with approaches to modelling excitotoxicity that include editing of disease-associated gene variants, chemogenetics, and environmental risk-associated exposures make iPSC primed to examine gene-environment interactions and disease-associated excitotoxic mechanisms. Critical to this is knowledge of which neurotransmitter receptor subunits are expressed by iPSC-derived neuronal cultures being studied, how their activity responds to antagonists and agonists of these receptors, and how to interpret data derived from multi-parameter electrophysiological recordings. This review explores how iPSC-based studies have contributed to our understanding of ALS-linked excitotoxicity and highlights novel approaches to inducing excitotoxicity in iPSC-derived neurons to further our understanding of its pathological pathways.}, }
@article {pmid39404920, year = {2025}, author = {Aiello, EN and Curti, B and Torre, S and De Luca, G and Maranzano, A and Colombo, E and Gendarini, C and Cocuzza, A and Messina, S and Doretti, A and Verde, F and Morelli, C and Silani, V and Ticozzi, N and Poletti, B}, title = {Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {2}, pages = {775-782}, pmid = {39404920}, issn = {1590-3478}, support = {NA//Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology/complications/psychology ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests/standards ; Verbal Behavior/physiology ; Executive Function/physiology ; Italy ; Speech Disorders/etiology/diagnosis/physiopathology ; }, abstract = {BACKGROUND: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: N&#x2009;=&#x2009;343 non-demented ALS patients and N&#x2009;=&#x2009;226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW&#x2009;+&#x2009;VFI-; NoW&#x2009;+&#x2009;VFI+), with these groups being compared on ECAS-Executive scores.<br><br>RESULTS: The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p&#x2009;<&#x2009;.001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW&#x2009;+&#x2009;VFI&#x2009;+&#x2009;ones.<br><br>CONCLUSIONS: The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.}, }
@article {pmid39404532, year = {2024}, author = {Tanioka, S and Wu, B and Ballmer, SW}, title = {Experimental demonstration of frequency- downconverted arm-length stabilization for a future upgraded gravitational wave detector.}, journal = {Optics letters}, volume = {49}, number = {20}, pages = {5763-5766}, doi = {10.1364/OL.534141}, pmid = {39404532}, issn = {1539-4794}, abstract = {Ground-based laser interferometric gravitational wave detectors (GWDs) consist of multiple optical cavity systems whose lengths need to be interferometrically controlled. An arm-length stabilization (ALS) system has played an important role in bringing these interferometers into an operational state and enhancing their duty cycle. The sensitivity of these detectors can be improved if the thermal noise of their test mass mirror coatings is reduced. Crystalline AlGaAs coatings are a promising candidate for this. However, the current ALS system with a frequency-doubled 532 nm light is no longer an option with AlGaAs coatings because the 532 nm light is absorbed by AlGaAs coatings due to the narrow bandgap of GaAs. Therefore, alternative locking schemes must be developed. In this Letter, we describe an experimental demonstration of a novel ALS scheme, to the best of our knowledge, which is compatible with AlGaAs coatings. This ALS scheme will enable the use of AlGaAs coatings in current and future terrestrial gravitational wave detectors.}, }
@article {pmid39403566, year = {2024}, author = {Biswas, DD and Sethi, R and Woldeyohannes, Y and Scarrow, ER and El Haddad, L and Lee, J and ElMallah, MK}, title = {Respiratory pathology in the TDP-43 transgenic mouse model of amyotrophic lateral sclerosis.}, journal = {Frontiers in physiology}, volume = {15}, number = {}, pages = {1430875}, pmid = {39403566}, issn = {1664-042X}, support = {R21 NS098131/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in death within 2-5 years of diagnosis. Respiratory failure is the most common cause of death in ALS. Mutations in the transactive response DNA binding protein 43 (TDP-43) encoded by the TARDBP gene are associated with abnormal cellular aggregates in neurons of patients with both familial and sporadic ALS. The role of these abnormal aggregates on breathing is unclear. Since respiratory failure is a major cause of death in ALS, we sought to determine the role of TDP-43 mutations on the respiratory motor unit in the Prp-hTDP-43[A315T] mouse model - a model that expresses human TDP-43 containing the A315T mutation. We assessed breathing using whole-body plethysmography, and investigated neuropathology in hypoglossal and phrenic respiratory motor units. Postmortem studies included quantification of hypoglossal and putative phrenic motor neurons, activated microglia and astrocytes in respiratory control centers, and assessment of hypoglossal and phrenic nerves of TDP43[A315T] mice. The male TDP43[A315T] mice display an early onset of rapid progression of disease, and premature death (less than 15 weeks) compared to control mice and compared to female TDP43[A315T] mice who die between 20 and 35 weeks of age. The TDP43[A315T] mice have progressive and profound breathing deficits at baseline and during a respiratory challenge. Histologically, hypoglossal and putative phrenic motor neurons of TDP43[A315T] mice are decreased and have increased microglial and astrocyte activation, indicating pronounced neurodegeneration and neuroinflammation. Further, there is axonopathy and demyelination in the hypoglossal and phrenic nerve of TDP43[A315T] mice. Thus, the TDP-43[A315T] mice have significant respiratory pathology and neuropathology, which makes them a useful translatable model for the study of novel therapies on breathing in ALS.}, }
@article {pmid39403300, year = {2024}, author = {Aminianfar, A and Fatemi, MH and Azimi, F}, title = {Comprehensive characterization of volatile compounds in Iranian black teas using chemometric analysis of GC-MS fingerprints.}, journal = {Food chemistry: X}, volume = {24}, number = {}, pages = {101859}, pmid = {39403300}, issn = {2590-1575}, abstract = {Black tea, a widely popular non-alcoholic beverage, is renowned for its unique aroma and has attracted significant attention due to its complex composition. However, the chemical profile of Iranian tea remains largely unexplored. In this research, black tea samples from key tea cultivation regions in four geographical areas in northern Iran were firstly analyzed using headspace solid-phase microextraction followed by gas chromatography-mass spectrometry (HS-SPME-GC-MS) to separate, identify, and quantify their volatile organic compounds. Subsequently, employing a robust investigative strategy, we utilized for the first time the well-known multivariate curve resolution-alternating least square (MCR-ALS) method as a deconvolution technique to analyze the complex GC-MS peak clusters of tea samples. This approach effectively addressed challenges such as severe baseline drifts, overlapping peaks, and background noise, enabling the identification of minor components responsible for the distinct flavors and tastes across various samples. The MCR-ALS technique significantly improved the resolution of spectral and elution profiles, enabling both qualitative and semi-quantitative analysis of tea constituents. Qualitative analysis involved comparing resolved peak profiles to theoretical spectra, along with retention indices, while semi-quantification was conducted using the overall volume integration (OVI) approach for volatile compounds, providing a more accurate correlation between peak areas and concentrations. The application of chemometric tools in GC-MS analysis increased the number of recognized components in four tea samples, expanding from 54 to 256 components, all with concentrations exceeding 0.1 %. Among them, 32 volatile compounds were present in every tea sample. Hydrocarbons (including alkenes, alkanes, cycloalkanes, monoterpenes and sesquiterpenes), esters and alcohols were the three major chemical classes, comprising 78 % of the total relative content of volatile compounds. Analyzing black teas from four distinct regions revealed variations not only in their volatile components but also in their relative proportions. This integrated approach provides a comprehensive understanding of the volatile chemical profiles in Iranian black teas, enhances knowledge about their unique characteristics across diverse geographical origin, and lays the groundwork for quality improvement.}, }
@article {pmid39402245, year = {2024}, author = {Wood, H}, title = {Altered muscle cholesterol transport in ALS.}, journal = {Nature reviews. Neurology}, volume = {20}, number = {11}, pages = {643}, doi = {10.1038/s41582-024-01029-8}, pmid = {39402245}, issn = {1759-4766}, }
@article {pmid39402174, year = {2025}, author = {Jellinger, KA}, title = {The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {2}, pages = {217-236}, pmid = {39402174}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/complications ; Humans ; *Mental Disorders/physiopathology/etiology ; Brain/physiopathology ; }, abstract = {Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.}, }
@article {pmid39401554, year = {2025}, author = {Duarte, RRR and Nixon, DF and Powell, TR}, title = {Ancient viral DNA in the human genome linked to neurodegenerative diseases.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {765-770}, pmid = {39401554}, issn = {1090-2139}, mesh = {Humans ; *Neurodegenerative Diseases/genetics/virology ; *Endogenous Retroviruses/genetics ; *Genome, Human ; Genome-Wide Association Study ; DNA, Viral/genetics ; Amyotrophic Lateral Sclerosis/genetics/virology ; Multiple Sclerosis/genetics/virology ; Genetic Predisposition to Disease/genetics ; Brain/metabolism/virology ; Parkinson Disease/genetics/virology ; Male ; Female ; }, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision.<br><br>METHODS: We analysed genetic association statistics pertaining to Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses.<br><br>RESULTS: The primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61_12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE_1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules.<br><br>CONCLUSIONS: We found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention.}, }
@article {pmid39401249, year = {2024}, author = {Pérez de la Lastra Aranda, C and Tosat-Bitrián, C and Porras, G and Dafinca, R and Muñoz-Torrero, D and Talbot, K and Martín-Requero, &#xc1; and Martínez, A and Palomo, V}, title = {Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.}, journal = {ACS chemical neuroscience}, volume = {15}, number = {21}, pages = {3945-3953}, doi = {10.1021/acschemneuro.4c00328}, pmid = {39401249}, issn = {1948-7193}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/drug therapy/pathology ; *Proteome/metabolism ; Precision Medicine/methods ; Motor Neurons/metabolism/drug effects ; Lymphocytes/metabolism/drug effects ; Protein Aggregates/drug effects/physiology ; Induced Pluripotent Stem Cells/metabolism/drug effects ; Protein Aggregation, Pathological/metabolism ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical/methods ; Mutation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.}, }
@article {pmid39400557, year = {2024}, author = {Gelpi, E and Reinecke, R and Gaig, C and Iranzo, A and Sabater, L and Molina-Porcel, L and Aldecoa, I and Endmayr, V and Högl, B and Schmutzhard, E and Poewe, W and Pfausler, B and Popovic, M and Pretnar-Oblak, J and Leypoldt, F and Matschke, J and Glatzel, M and Erro, EM and Jerico, I and Caballero, MC and Zelaya, MV and Mariotto, S and Heidbreder, A and Kalev, O and Weis, S and Macher, S and Berger-Sieczkowski, E and Ferrari, J and Reisinger, C and Klupp, N and Tienari, P and Rautila, O and Niemelä, M and Yilmazer-Hanke, D and Guasp, M and Bloem, B and Van Gaalen, J and Kusters, B and Titulaer, M and Fransen, NL and Santamaria, J and Dawson, T and Holton, JL and Ling, H and Revesz, T and Myllykangas, L and Budka, H and Kovacs, GG and Lewerenz, J and Dalmau, J and Graus, F and Koneczny, I and Höftberger, R}, title = {Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {53}, pmid = {39400557}, issn = {1432-0533}, support = {SYNABS//Austrian Science Fund/ ; I6565-B//Austrian Science Fund/ ; T996-B30//Austrian Science Fund/ ; 01GM2208B//Bundesministerium f&#xfc;r Bildung und Forschung/ ; 01GM2208A//Bundesministerium f&#xfc;r Bildung und Forschung/ ; PI21/00165//Instituto de Salud Carlos III/ ; PI21/00165//Instituto de Salud Carlos III/ ; N&#xb0; 825575//Horizon 2020 Framework Programme/ ; 341007//Tekniikan Akatemia/ ; TYH2022316//Helsingin Yliopisto/ ; }, mesh = {Humans ; *Tauopathies/pathology/immunology ; Middle Aged ; *Brain Stem/pathology/metabolism/immunology ; Male ; Female ; Aged ; Aged, 80 and over ; *tau Proteins/metabolism/immunology ; *Cell Adhesion Molecules, Neuronal/metabolism/immunology ; Adult ; Autoantibodies/immunology ; DNA-Binding Proteins/metabolism ; }, abstract = {Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.}, }
@article {pmid39400020, year = {2024}, author = {Ali, A and A Emad, N and Sultana, N and Waheed, A and Aqil, M and Sultana, Y and Mujeeb, M}, title = {Navigating into the Paradigm of Nose-to-brain Delivery of Nanotherapeutics and their Repurposing as Nanotheranostics for Neurodegenerative Diseases.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273319597240927044906}, pmid = {39400020}, issn = {1996-3181}, abstract = {Repurposing drugs for neurodegenerative diseases using the nose-to-brain route of administration is an intriguing concept with potential benefits. The nose-to-brain route involves delivering drugs directly to the brain via the olfactory or trigeminal pathways, bypassing the blood-brain barrier, which can improve drug efficacy and reduce systemic side effects. Treatment of numerous neurodegenerative diseases such as Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases has been attempted using this route of administration. These drugs may include neuroprotective agents, anti-inflammatory drugs, antioxidants, or diseasemodifying therapies. Nanotheranostics, which integrates therapeutic and diagnostic functions in a nanosystem, improves treatment precision and efficacy. Repurposing nanotherapeutics as nanotheranostics for neurodegenerative diseases through the nose-to-brain route of administration holds great potential for both diagnosis and treatment. This review highlights the various mechanisms engaged in transporting nanocarriers from nose-to-brain and the proposed fate of these nanocarriers using different live imaging techniques. Additionally, the discussion covers the recent combinatorial therapeutic approaches and theranostic applications of various nanocarriers used for neurodegenerative diseases through the nose-to-brain. Toxicity to the CNS and nasal mucosa and regulatory considerations about these delivery systems are also deliberated. Overall, repurposed nanoparticles designed as nanotheranostic agents offer a versatile platform for precise diagnosis, targeted therapy, and personalized management of neurodegenerative diseases, holding great promise for improving patient care and advancing our understanding of these complex disorders.}, }
@article {pmid39399380, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Automated pipeline for denoising, missing data processing, and feature extraction for signals acquired via wearable devices in multiple sclerosis and amyotrophic lateral sclerosis applications.}, journal = {Frontiers in digital health}, volume = {6}, number = {}, pages = {1402943}, pmid = {39399380}, issn = {2673-253X}, abstract = {INTRODUCTION: The incorporation of health-related sensors in wearable devices has increased their use as essential monitoring tools for a wide range of clinical applications. However, the signals obtained from these devices often present challenges such as artifacts, spikes, high-frequency noise, and data gaps, which impede their direct exploitation. Additionally, clinically relevant features are not always readily available. This problem is particularly critical within the H2020 BRAINTEASER project, funded by the European Community, which aims at developing models for the progression of Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) using data from wearable devices.<br><br>METHODS: The objective of this study is to present the automated pipeline developed to process signals and extract features from the Garmin Vivoactive 4 smartwatch, which has been chosen as the primary wearable device in the BRAINTEASER project. The proposed pipeline includes a signal processing step, which applies retiming, gap-filling, and denoising algorithms to enhance the quality of the data. The feature extraction step, on the other hand, utilizes clinical partners' knowledge and feedback to select the most relevant variables for analysis.<br><br>RESULTS: The performance and effectiveness of the proposed automated pipeline have been evaluated through pivotal beta testing sessions, which demonstrated the ability of the pipeline to improve the data quality and extract features from the data. Further clinical validation of the extracted features will be performed in the upcoming steps of the BRAINTEASER project.<br><br>DISCUSSION: Developed in Python, this pipeline can be used by researchers for automated signal processing and feature extraction from wearable devices. It can also be easily adapted or modified to suit the specific requirements of different scenarios.}, }
@article {pmid39397192, year = {2024}, author = {Hamdi, N and Mueller, K and Hamza, A and Soliman, R and Onbool, E and Omran, K and Ocab, O and Freischmidt, A and Siebert, R and Ludolph, A and Fahmy, N}, title = {First insights into genotype and phenotype of familial amyotrophic lateral sclerosis in Egypt: early onset and high consanguinity.}, journal = {Frontiers of medicine}, volume = {18}, number = {6}, pages = {1115-1118}, pmid = {39397192}, issn = {2095-0225}, }
@article {pmid39396990, year = {2024}, author = {Hazell, G and McCallion, E and Ahlskog, N and Sutton, ER and Okoh, M and Shaqoura, EIH and Hoolachan, JM and Scaife, T and Iqbal, S and Bhomra, A and Kordala, AJ and Scamps, F and Raoul, C and Wood, MJA and Bowerman, M}, title = {Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1[G93A] amyotrophic lateral sclerosis (ALS) mouse model.}, journal = {Skeletal muscle}, volume = {14}, number = {1}, pages = {23}, pmid = {39396990}, issn = {2044-5040}, support = {SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; SBF006/1162/AMS_/Academy of Medical Sciences/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; MR/Y003640/1/MRC_/Medical Research Council/United Kingdom ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; 18GRO-PS48-0114//Muscular Dystrophy UK/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *TWEAK Receptor/metabolism/genetics ; *Muscle, Skeletal/metabolism/pathology ; Male ; Female ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Physical Conditioning, Animal ; Mice, Knockout ; Cytokine TWEAK/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1[G93A] ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1[G93A] ALS mice could lead to differential and potentially improved benefits.<br><br>METHODS: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1[G93A] ALS mice. To do so, Fn14 knockout mice (Fn14[-/-]) were crossed onto the SOD1[G93A] background to generate SOD1[G93A];Fn14[-/-] mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14[-/-], SOD1[G93A] and SOD1[G93A];Fn14[-/-]).<br><br>RESULTS: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1[G93A] mice. We then show that Fn14-depleted SOD1[G93A] mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function.&#xa0;Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.<br><br>CONCLUSIONS: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.}, }
@article {pmid39396709, year = {2024}, author = {Wu, J and Wu, J and Chen, T and Cai, J and Ren, R}, title = {Protein aggregation and its affecting mechanisms in neurodegenerative diseases.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105880}, doi = {10.1016/j.neuint.2024.105880}, pmid = {39396709}, issn = {1872-9754}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Protein Aggregation, Pathological/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; Protein Aggregates/physiology ; tau Proteins/metabolism ; }, abstract = {Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.}, }
@article {pmid39396264, year = {2024}, author = {Bermudo Fuenmayor, S and Serrano Castro, PJ and Quiroga Subirana, P and López Palmero, S and Requena Mullor, MM and Parrón Carreño, T}, title = {Design and validation of a questionnaire for monitoring neurological dysphagia and respiratory deterioration in patients with amyotrophic lateral sclerosis (DEREDELA).}, journal = {Neurologia}, volume = {39}, number = {8}, pages = {666-674}, doi = {10.1016/j.nrleng.2024.09.003}, pmid = {39396264}, issn = {2173-5808}, mesh = {*Amyotrophic Lateral Sclerosis/complications ; Humans ; *Deglutition Disorders/diagnosis/etiology ; Surveys and Questionnaires ; Male ; Female ; Reproducibility of Results ; Middle Aged ; Aged ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of unknown origin that affects the motor neurons. It has a rapid, fatal course.<br><br>METHOD: For this study, an initial questionnaire of eleven items was developed by experts in the field, who evaluated the suitability and relevance of the items.<br><br>RESULTS: The questionnaire was then applied to a pilot group of 22 patients diagnosed with ALS. Confirmatory factor analysis, based on estimating maximum likelihood, confirmed the three domains detected in the exploratory factor analysis. The reliability of the scale was tested using Cronbach's &#x3b1; (0.801) and the Kaiser-Meyer-Olkin test (0.770) confirmed the construct validity.<br><br>CONCLUSIONS: The DEREDELA questionnaire is valid, in terms of its content, for monitoring the neurological dysphagia and respiratory deterioration suffered by patients diagnosed with ALS.}, }
@article {pmid39395841, year = {2024}, author = {Tran, M and Rhee, J and Hu, W and Magin, P and Shulruf, B}, title = {General practice trainee, supervisor and educator perspectives on the transitions in postgraduate training: a scoping review.}, journal = {Family medicine and community health}, volume = {12}, number = {4}, pages = {}, pmid = {39395841}, issn = {2009-8774}, mesh = {Humans ; *General Practice/education ; Education, Medical, Graduate ; General Practitioners/education ; Students, Medical/psychology ; }, abstract = {UNLABELLED: Transitions are a period and a process, through which there is a longitudinal adaptation in response to changing circumstances in clinical practice and responsibilities. While the experience of the transition in medical student learning and in hospital-based specialty training programmes are well described and researched, the experience of the transition in community-based postgraduate general practitioner (GP) training has not been described comprehensively.<br><br>OBJECTIVE: We aimed to identify, and categorise, the formative experiences of transitions in GP training and their impacts on personal and professional development.<br><br>DESIGN: We adopted Levac et al's scoping review methodology. Of 1543 retrieved records, 76 were selected for data extraction. Based on a combined model of the socioecological and multiple and multi-dimensional theories of transitions, data relating to the experiences of transitions were organised into contextual themes: being physical, psychosocial, organisational culture and chronological.<br><br>ELIGIBILITY CRITERIA: Empirical studies focused on general practice trainees or training, that discussed the transitions experienced in general practice training and that were published in English were included.<br><br>INFORMATION SOURCES: PubMed, MEDLINE and Web of Science databases were searched in January 2024 with no date limits for empirical studies on the transition experiences of GP into, and through, training.<br><br>RESULTS: Our findings describe context-dependent formative experiences which advance, or impede, learning and development. Time is a significant modulator of the factors contributing to more negative experiences, with some initially adverse experiences becoming more positive. Identification of the inflection point that represents a shift from initially adverse to more positive experiences of transitions may help moderate expectations for learning and performance at different stages of training.<br><br>CONCLUSION: Challenges in training can either advance development and contribute positively to professional identity formation and clinical competency, or detract from learning and potentially contribute to burnout and attrition from training programmes. These findings will assist future research in identifying predictive factors of positive and adverse experiences of transitions and may strengthen existing and nascent GP training programmes. The findings are transferable to other community-based specialty training programmes.}, }
@article {pmid39395630, year = {2024}, author = {Yeewa, R and Sangphukieo, A and Jantaree, P and Wongkummool, W and Yamsri, T and Poompouang, S and Chaiyawat, P and Lo Piccolo, L and Jantrapirom, S}, title = {ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2[ALS] phenotypes in Drosophila melanogaster.}, journal = {Progress in neurobiology}, volume = {242}, number = {}, pages = {102674}, doi = {10.1016/j.pneurobio.2024.102674}, pmid = {39395630}, issn = {1873-5118}, mesh = {Animals ; *Drosophila melanogaster ; *Endoplasmic Reticulum Stress/drug effects/physiology ; *Drosophila Proteins/metabolism/genetics ; *Neurons/metabolism/drug effects ; Phenotype ; Autophagy-Related Proteins/metabolism/genetics ; Disease Models, Animal ; Animals, Genetically Modified ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2[ALS] pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2[ALS] model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2[ALS] and other ER stress-related conditions.}, }
@article {pmid39395475, year = {2024}, author = {Kim, SY and Kim, M and Park, K and Hong, S}, title = {A systematic review on analytical methods of the neurotoxin β-N-methylamino-L-alanine (BMAA), and its causative microalgae and distribution in the environment.}, journal = {Chemosphere}, volume = {366}, number = {}, pages = {143487}, doi = {10.1016/j.chemosphere.2024.143487}, pmid = {39395475}, issn = {1879-1298}, mesh = {*Amino Acids, Diamino/analysis ; *Microalgae/metabolism ; *Cyanobacteria Toxins ; *Neurotoxins/analysis ; *Cyanobacteria/metabolism ; *Tandem Mass Spectrometry ; *Environmental Monitoring/methods ; Ecosystem ; Chromatography, Liquid ; Diatoms/metabolism ; Water Pollutants, Chemical/analysis/metabolism ; }, abstract = {β-N-Methylamino-L-alanine (BMAA), a neurotoxin produced by various microalgal groups, is associated with neurodegenerative diseases and is considered a major environmental factor potentially linked to sporadic amyotrophic lateral sclerosis. This study systematically reviews the analytical methods used to study BMAA in publications from 2019 to the present. It also investigates the causative microalgae of BMAA and its geographical distributions in aquatic ecosystems based on studies conducted since 2003. A comprehensive search using the Web of Science database revealed that hydrolysis for extraction (67%), followed by quantification using LC-MS/MS (LC: 84%; MS/MS: 88%), is the most commonly employed method in BMAA analysis. Among analytical methods, RPLC-MS/MS had the highest percentage (88%) of BMAA-positive results and included a high number of quality control (QC) assessments. Various genera of cyanobacteria and diatoms have been reported to produce BMAA. The widespread geographical distribution of BMAA across diverse ecosystems highlights significant environmental and public health concerns. Notably, BMAA accumulation and biomagnification are likely more potent in marine or brackish water ecosystems than in freshwater ecosystems, potentially amplifying its ecological impacts. Future research should prioritize advanced, sensitive methods, particularly LC-MS/MS with as many QC assessments as possible, and should expand investigations to identify novel microalgal producers and previously uncharted geographical areas, with a special focus on marine or brackish water ecosystems. This effort will enhance our understanding of the environmental distribution and impacts of BMAA.}, }
@article {pmid39394860, year = {2024}, author = {Zhao, J and Kong, D and Zhang, G and Zhang, S and Wu, Y and Dai, C and Chen, Y and Yang, Y and Liu, Y and Wei, D}, title = {An Efficient CRISPR/Cas Cooperative Shearing Platform for Clinical Diagnostics Applications.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {63}, number = {52}, pages = {e202411705}, doi = {10.1002/anie.202411705}, pmid = {39394860}, issn = {1521-3773}, support = {22304031, 61890940//National Natural Science Foundation of China/ ; 2021YFC2301100//the National Key R&amp;D Program of China/ ; XDB30000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; 23XD1420200//the Program of Shanghai Academic Research Leaders/ ; DP2020036//the Chong-qing Bayu Scholar Program/ ; 2023M730635//the China Postdoctoral Science Foundation/ ; T2425006//National Science Fund for Distinguished Young Scholars/ ; }, mesh = {*CRISPR-Cas Systems/genetics ; Humans ; Electrochemical Techniques ; Amyotrophic Lateral Sclerosis/diagnosis/genetics ; }, abstract = {The CRISPR/Cas system is a powerful genome editing tool and possesses widespread applications in molecular diagnostics, therapeutics and genetic engineering. But easy folding of the target sequences causes remarkable deterioration of the recognition and shear efficiency in the case of single Cas-CRISPR RNA (crRNA) duplex. Here, we develop a CRISPR/Cas cooperative shearing (CRISPR-CS) system. Compared with traditional CRISPR/Cas system, two CRISPR/Cas-crRNA duplexes simultaneously recognize different sites in the target sequence, increasing recognition possibility and shearing efficiency. Cooperative shearing cuts more methylene blue-ssDNA reporters on the electrode, enabling unamplified nucleic acid electrochemical assay in less than 5 minutes with a detection limit of 9.5×10[-20] M, 2 to 9 orders of magnitude lower than those of other electrochemical assays. The CRISPR-CS platform detects monkeypox, human papilloma virus and amyotrophic lateral sclerosis with an accuracy up to 98.1 %, demonstrating the potential application of the efficient cooperative shearing.}, }
@article {pmid39393594, year = {2024}, author = {Coppieters, R and Bouzigues, A and Jiskoot, L and Montembeault, M and Tee, BL and ,  and Rohrer, JD and Bruffaerts, R}, title = {A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105909}, doi = {10.1016/j.neubiorev.2024.105909}, pmid = {39393594}, issn = {1873-7528}, mesh = {Humans ; *Frontotemporal Dementia/physiopathology/diagnosis ; *Speech/physiology ; Linguistics ; Language ; Biomarkers ; }, abstract = {Frontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features.}, }
@article {pmid39393030, year = {2024}, author = {Aamodt, WW and Sun, C and Dahodwala, N and Elser, H and Schneider, ALC and Farrar, JT and Coe, NB and Willis, AW}, title = {End-of-Life Health Care Service Use and Cost Among Medicare Decedents With Neurodegenerative Diseases.}, journal = {Neurology}, volume = {103}, number = {9}, pages = {e209925}, pmid = {39393030}, issn = {1526-632X}, mesh = {Humans ; United States ; Male ; Female ; *Medicare/economics/statistics &amp; numerical data ; Aged ; Retrospective Studies ; *Terminal Care/economics/statistics &amp; numerical data ; Aged, 80 and over ; *Neurodegenerative Diseases/economics/therapy/epidemiology ; Patient Acceptance of Health Care/statistics &amp; numerical data ; Health Care Costs/statistics &amp; numerical data ; Emergency Service, Hospital/statistics &amp; numerical data/economics ; Parkinson Disease/economics/therapy/epidemiology ; Hospice Care/economics/statistics &amp; numerical data ; Alzheimer Disease/economics/therapy/epidemiology ; Amyotrophic Lateral Sclerosis/economics/therapy/epidemiology ; }, abstract = {BACKGROUND AND OBJECTIVES: Although neurodegenerative diseases are a leading cause of death, little is known about health care utilization and cost during the end-of-life (EoL) period or how it compares with that of other life-limiting conditions. We aimed to describe and compare resource utilization among US Medicare decedents with neurodegenerative diseases with decedents with cancer.<br><br>METHODS: We conducted a retrospective study of Medicare Part A and B beneficiaries with Alzheimer disease (AD), Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS) who died in 2018. Decedents diagnosed with malignant brain tumors or pancreatic cancer served as non-neurodegenerative comparators. Descriptive analyses examined demographic and clinical characteristics in the last year of life. The probabilities and associated costs of emergency department (ED), inpatient, skilled nursing facility (SNF), and hospice utilization during the last 12 and 6 months of life were also compared between persons with neurodegenerative diseases and cancer, adjusting for sociodemographic factors and comorbidity burden.<br><br>RESULTS: A total of 1,126,799 Medicare beneficiaries died in 2018, of which 357,926 had a qualifying diagnosis. Persons with neurodegenerative diseases were older and more frequently received Medicaid assistance than persons with brain or pancreatic cancer. In all groups, health care service utilization increased over the last year of life, and total costs were predominantly attributable to inpatient care. In the last 6 months of life, neurologist care was infrequent among patients with neurodegenerative disease (AD: 1.5%; PD: 8.6%; ALS: 32.0%). Persons with neurodegenerative diseases as compared to persons with malignant brain tumors also had greater odds of ED use (AD: adjusted odds ratio [aOR] 1.17, 95% CI 1.11-1.23; PD: aOR 1.18, 95% CI 1.11-1.25; ALS: aOR 1.11, 95% CI 1.01-1.23), lower odds of hospitalization (AD: aOR 0.64, 95% CI 0.60-0.68; PD: aOR 0.65, 95% CI 0.61-0.69; ALS: aOR 0.33, 95% CI 0.30-0.37), and lower odds of hospice enrollment (AD: aOR 0.33, 95% CI 0.31-0.36; PD: aOR 0.33, 95% CI 0.31-0.36; ALS: aOR 0.41, 95% CI 0.36-0.46). The findings were similar in pancreatic cancer.<br><br>DISCUSSION: Persons with neurodegenerative diseases in the United States are more likely to visit the ED and less likely to use inpatient and hospice services at EoL than persons with brain or pancreatic cancer. These group differences may stem from prognostic uncertainty and reflect inadequate EoL care practices, requiring further investigation to ensure more timely palliative care and hospice referrals.}, }
@article {pmid39392186, year = {2025}, author = {Corcia, P and Piras, R and Lunetta, C}, title = {Why is the treatment and management of amyotrophic lateral sclerosis so difficult?.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {1}, pages = {1-3}, doi = {10.1080/14737175.2024.2415002}, pmid = {39392186}, issn = {1744-8360}, }
@article {pmid39392096, year = {2024}, author = {}, title = {Correction to "Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis".}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6125-6126}, doi = {10.1111/ejn.16562}, pmid = {39392096}, issn = {1460-9568}, }
@article {pmid39391721, year = {2024}, author = {Hodgson, RE and Rayment, JA and Huang, WP and Sanchez Avila, A and Ellis, BCS and Lin, YH and Soni, N and Hautbergue, GM and Shelkovnikova, TA}, title = {C9orf72 poly-PR forms anisotropic condensates causative of nuclear TDP-43 pathology.}, journal = {iScience}, volume = {27}, number = {10}, pages = {110937}, pmid = {39391721}, issn = {2589-0042}, support = {MR/W028522/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Proteinaceous inclusions formed by C9orf72-derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ∼50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However, DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells including human motor neurons, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-center appearance, resembling TDP-43 anisosomes, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without stress response activation. Cytoplasmic poly-PR aggregates forming under prolonged opto-stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Thus, poly-PR condensation accompanied by nuclear TDP-43 dysfunction may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates of disease-linked proteins may represent a common molecular species in neurodegenerative disease.}, }
@article {pmid39391382, year = {2024}, author = {Osaro, E and Fajardo-Rojas, F and Cooper, GM and Gómez-Gualdrón, D and Colón, YJ}, title = {Active learning of alchemical adsorption simulations; towards a universal adsorption model.}, journal = {Chemical science}, volume = {15}, number = {42}, pages = {17671-17684}, pmid = {39391382}, issn = {2041-6520}, abstract = {Adsorption is a fundamental process studied in materials science and engineering because it plays a critical role in various applications, including gas storage and separation. Understanding and predicting gas adsorption within porous materials demands comprehensive computational simulations that are often resource intensive, limiting the identification of promising materials. Active learning (AL) methods offer an effective strategy to reduce the computational burden by selectively acquiring critical data for model training. Metal-organic frameworks (MOFs) exhibit immense potential across various adsorption applications due to their porous structure and their modular nature, leading to diverse pore sizes and chemistry that serve as an ideal platform to develop adsorption models. Here, we demonstrate the efficacy of AL in predicting gas adsorption within MOFs using "alchemical" molecules and their interactions as surrogates for real molecules. We first applied AL separately to each MOF, reducing the training dataset size by 57.5% while retaining predictive accuracy. Subsequently, we amalgamated the refined datasets across 1800 MOFs to train a multilayer perceptron (MLP) model, successfully predicting adsorption of real molecules. Furthermore, by integrating MOF features into the AL framework using principal component analysis (PCA), we navigated MOF space effectively, achieving high predictive accuracy with only a subset of MOFs. Our results highlight AL's efficiency in reducing dataset size, enhancing model performance, and offering insights into adsorption phenomenon in large datasets of MOFs. This study underscores AL's crucial role in advancing computational material science and developing more accurate and less data intensive models for gas adsorption in porous materials.}, }
@article {pmid39390888, year = {2024}, author = {Boran, HE and Kılınç, H and Kurtkaya Koçak, &#xd6; and Yanık, E and Kuruoğlu, HR and Cengiz, B}, title = {Somatosensory temporal discrimination analysis reveals impaired processing in amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {6}, pages = {1257-1262}, doi = {10.1002/mus.28278}, pmid = {39390888}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Female ; Middle Aged ; *Evoked Potentials, Somatosensory/physiology ; Aged ; *Somatosensory Cortex/physiopathology ; Adult ; Hand/physiopathology ; Sensory Thresholds/physiology ; }, abstract = {INTRODUCTION/AIMS: While amyotrophic lateral sclerosis (ALS) is primarily characterized as a motor system disorder, there is a growing body of evidence indicating sensory involvement. This study aimed to examine the hypothesis that somatosensory processing is impaired in ALS.<br><br>METHODS: Study participants were ALS patients followed at the Neuromuscular Outpatient Unit, as well as healthy volunteers, from March 2021 to July 2023. The Medical Research Council (MRC) sum score was calculated for nine muscle groups bilaterally. The clinical status of patients was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Penn Upper Motor Neuron core. Somatosensory temporal discrimination thresholds (STDTs) were recorded on the medial and lateral parts of both hands. Somatosensory cortex excitability was investigated with the paired somatosensory evoked potentials (SEP) paradigm in a subgroup.<br><br>RESULTS: Increased STD values were detected in ALS patients compared to controls in both medial (107.66&#x2009;&#xb1;&#x2009;35&#x2009;ms vs. 82.7&#x2009;&#xb1;&#x2009;32.5&#x2009;ms, p&#x2009;=&#x2009;.001) and lateral (106.5&#x2009;&#xb1;&#x2009;34.5&#x2009;ms vs. 82.9&#x2009;&#xb1;&#x2009;31.3&#x2009;ms, p&#x2009;=&#x2009;.002) hands. There were no significant differences in STDTs among ALS patients across four regions (medial and lateral parts of the right and left hands). Amplitude ratios obtained from the paired-pulse SEP paradigm were approximately 1 for all interstimulus intervals (ISIs). STDTs did not show any correlations with motor findings or scales.<br><br>DISCUSSION: Somatosensory processing appears to be compromised among ALS patients. The lack of correlation between impaired STDT and motor findings implies that it is a purely sensory deficit in ALS.}, }
@article {pmid39390661, year = {2024}, author = {Howard, IM and Babu, S and Carter, C and Sakowski, SA and Kurent, JE and Cudkowicz, ME and Feldman, EL}, title = {Priorities and Recommendations to Make ALS a Livable Disease Emanating from the 2024 National Academies of Sciences, Engineering, and Medicine Report Living with ALS.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1035-1039}, pmid = {39390661}, issn = {1531-8249}, support = {R01 TS000327/TS/ATSDR CDC HHS/United States ; OT2 NS136938/NS/NINDS NIH HHS/United States ; U01 NS077179/NS/NINDS NIH HHS/United States ; U01 NS136020/NS/NINDS NIH HHS/United States ; //Charles H. Abdalian, Jr. ALS Research Fund/ ; OT2 NS136939/NS/NINDS NIH HHS/United States ; //NeuroNetwork for Emerging Therapies/ ; R01 ES030049/ES/NIEHS NIH HHS/United States ; R01TS000344//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; //American Academy of Neurology/ ; //ALS One/ ; //ALS Association/ ; UF1 NS131791/NS/NINDS NIH HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; 1U01NS136021-01/NH/NIH HHS/United States ; 1U01NS136020-01/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; //Scott L. Pranger/ ; //The Sean M. Healey &amp; AMG Center for ALS/ ; 1U01NS077179-01/NH/NIH HHS/United States ; //Muscular Dystrophy Association/ ; U01 NS136021/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; //The Neurological Clinical Research Institute/ ; UF1NS131791-01/NH/NIH HHS/United States ; 1OT2NS136938-1/NH/NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; //ALS Finding a Cure/ ; OT2NS136939/NH/NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis ; Humans ; United States ; Quality of Life ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a relentless, fatal neurodegenerative disease. The progressive loss of voluntary muscle function, diagnostic delays, lack of effective treatments, and challenges accessing multidisciplinary care and resources have tremendous impact on quality of life. The congressionally directed ALS committee of the National Academies of Science, Engineering, and Medicine, in their 2024 report "Living with ALS," recommends critical actions for specific United States stakeholders to make ALS a livable disease over the next decade. This review summarizes the context and recommendations of the report. Advocacy efforts are critical to make these recommendations a reality for the ALS community. ANN NEUROL 2024;96:1035-1039.}, }
@article {pmid39390590, year = {2024}, author = {Vanderhaeghe, S and Prerad, J and Tharkeshwar, AK and Goethals, E and Vints, K and Beckers, J and Scheveneels, W and Debroux, E and Princen, K and Van Damme, P and Fivaz, M and Griffioen, G and Van Den Bosch, L}, title = {A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {161}, pmid = {39390590}, issn = {2051-5960}, support = {HBC.2019.2575//VLAIO Baekeland mandate/ ; 030383//Flanders Innovation &amp; Entrepreneurship (VLAIO)/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Valosin Containing Protein/genetics/metabolism ; Humans ; *Frontotemporal Dementia/genetics/metabolism/pathology ; *Mitochondria/metabolism/pathology ; *Mitochondrial Permeability Transition Pore/metabolism ; *Mutation ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/genetics ; Mitochondrial Membrane Transport Proteins/genetics/metabolism ; Calcium/metabolism ; }, abstract = {Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA[+] ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP[R191Q/wt] mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.}, }
@article {pmid39390534, year = {2024}, author = {Xu, M and Li, B and Li, C and Chai, P and Qiu, Q and Zheng, Z and Chen, Q and Luo, D and Xu, X and Zhou, C}, title = {Is longer axial length protective of vision-threatening diabetic retinopathy across different ages? A multicenter cohort of 736 patients.}, journal = {International journal of retina and vitreous}, volume = {10}, number = {1}, pages = {74}, pmid = {39390534}, issn = {2056-9920}, support = {22QA1407500//Shanghai Science and Technology Development Foundation/ ; SHWSRS [2022-65]//Shanghai Rising Stars of Medical Talent Youth Development Program/ ; CTCCR-2021C01//Clinical Research Innovation Plan of Shanghai General Hospital/ ; 82471104//National Natural Science Foundation of China/ ; }, abstract = {PURPOSE: Vision-threatening diabetic retinopathy (VTDR) included severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR) and clinically significant diabetic macular edema (DME). To compare the axial length (AL) and assess its influence on VTDR across different ages.<br><br>METHODS: A retrospective cohort study. Medical chart review was performed in 736 consecutive patients with VTDR. The patients were divided into young (&#x2264;&#x2009;45&#xa0;years) and elderly group (>&#x2009;45&#xa0;years) based on their age at the diagnosis of VTDR. After at least one year of standardized treatments, all eligible patients were followed up. The main outcome measures included the presence of tractional retinal detachment (TRD) involving foveal, final best-corrected visual acuity (BCVA), the development of neovascular glaucoma (NVG), and recurrent vitreous hemorrhage (VH) post-vitrectomy. ALs were compared between two age groups. The impact of AL on clinical outcomes was determined by logistic analyses after controlling for systemic parameters.<br><br>RESULTS: The study included 144 patients&#x2009;&#x2264;&#x2009;45&#xa0;years and 592 patients&#x2009;>&#x2009;45&#xa0;years. Young patients had significantly longer AL than elderly participants (23.9&#xa0;mm vs 23.0&#xa0;mm, p&#x2009;<&#x2009;0.001). Over a median follow-up of 25.9&#xa0;months, a larger proportion of young patients developed TRD (34.7% vs 16.2%, p&#x2009;<&#x2009;0.001) and recurrent VH (18.6% vs 10.3%, p&#x2009;=&#x2009;0.040) than elderly patients. In elderly group, longer AL is an independent protective factor in preventing TRD (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.7; P&#x2009;<&#x2009;0.001). However, this beneficial effect was not observed in young patients.<br><br>CONCLUSIONS: Young patients with VTDR exhibited significantly longer AL but more aggressive clinical signs with compromised prognosis. In elderly group, a longer AL independently reduced the risk of TRD, while this protective effect did not exist for young patients.}, }
@article {pmid39389966, year = {2024}, author = {Kamemura, K and Kozono, R and Tando, M and Okumura, M and Koga, D and Kusumi, S and Tamai, K and Okumura, A and Sekine, S and Kamiyama, D and Chihara, T}, title = {Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8777}, pmid = {39389966}, issn = {2041-1723}, support = {P40 OD010949/OD/NIH HHS/United States ; R01 NS107558/NS/NINDS NIH HHS/United States ; 21K18236//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 21H02479//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; }, mesh = {*Endoplasmic Reticulum/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/genetics ; *Vesicular Transport Proteins/metabolism/genetics ; Cell Membrane/metabolism ; Mutation ; Protein Domains ; Membrane Proteins/metabolism/genetics ; HEK293 Cells ; Matrix Metalloproteinase 1/metabolism/genetics ; Protein Transport ; }, abstract = {VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.}, }
@article {pmid39389563, year = {2025}, author = {Feindt, B and Roth, A and Heyde, CE and Behrens, J and Feist, B and Kasprick, L and Sultzer, R and Baerwald, C}, title = {GeriNOT in the Surgical Inpatient Setting.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {137-145}, doi = {10.1055/a-2343-4014}, pmid = {39389563}, issn = {1864-6743}, mesh = {Humans ; Aged ; Female ; Male ; Aged, 80 and over ; Germany ; Retrospective Studies ; *Geriatric Assessment ; Risk Assessment ; Hospitalization/statistics &amp; numerical data ; Femoral Fractures/surgery ; Hip Fractures/surgery ; }, abstract = {Die Richtlinie des Gemeinsamen Bundesausschusses (G-BA) über Maßnahmen zur Qualitätssicherung zur Versorgung von Patient*innen mit hüftgelenknaher Femurfraktur verpflichtet Krankenhäuser zum Einsatz eines validierten geriatrischen Screeninginstruments. Die systematische Anwendung des GeriNOT mit prozessproduzierter Datenerhebung im Akutaufnahmeprozess durch Integration in das Krankenhausinformationssystem (KIS) ermöglicht die Identifikation von Risikopotenzialen auch in anderen geriatrischen Diagnosegruppen.Mit Einbindung des GeriNOT in den Akutaufnahmeprozess wurde geprüft, ob auch andere vulnerable geriatrische Diagnosegruppen von einer frühzeitig eingeleiteten Risikoidentifikation profitieren können.Datengrundlage dieser Untersuchung bildete eine retrospektive bizentrische Erhebung elektronischer Fallakten (Mai 2014 bis April 2015, n = 3443). Aus diesem Primärdatensatz wurde die Subgruppe stationärer Akutaufnahmen (n = 821) der Orthopädie/Unfallchirurgie eines Zentrums in Bezug auf die Endpunkte "Inanspruchnahme bedarfsgerechter poststationärer Pflegeleistungen" und "Neueinzug in stationäre Dauer-/Kurzzeitpflege" analysiert. Es wurden Prädiktionskraft und Klassifikationsgenauigkeit von GeriNOT dieser ab 70-jährigen Personen in Diagnosegruppen für die definierten Endpunkte beurteilt: Akutaufnahmen insgesamt, Frakturen insgesamt, hüftgelenknahe Femurfraktur und Wirbelsäulenerkrankungen inklusive Wirbelsäulenfrakturen.Im Untersuchungszeitraum wurden 821 Personen akutstationär aufgenommen. Das mittlere Alter betrug 81,4 ± 6,8 Jahre (n = 821; 68,1% Frauen, 31,9% Männer). Folgende Diagnosegruppen wurden gebildet und analysiert: Frakturen insgesamt (n = 490), Wirbelsäulenerkrankungen (n = 265), davon Wirbelsäulenfrakturen (n = 174), hüftgelenknahe Femurfraktur (n = 108). In der Gesamtgruppe (n = 821; MW = 4,279; SD = 2,180) und in den Diagnosegruppen lag der Mittelwert des GeriNOT-Scores über dem Schwellenwert ≥ 4. In der Gruppe der hüftgelenknahen Femurfraktur wurde der höchste Wert ermittelt (MW = 4,852; SD = 2,022), der niedrigste in der Gruppe der Wirbelsäulenfrakturen (MW = 4,177; SD = 2,171). In der Aufnahmesituation bez. behandlungsbedürftiger Diagnosen, Polypharmazie und bereits in Anspruch genommener Pflegeleistungen unterschieden sich die Diagnosegruppen nur geringfügig. Einweisungen aus stationärer Kurz- und Dauerpflege erfolgten in der Gesamtgruppe (n = 821) in 16,44% der Fälle, am häufigsten mit 31,48% in der Gruppe der hüftgelenknahen Femurfraktur, hingegen am seltensten in der Diagnosegruppe der Wirbelsäulenerkrankungen mit 6,79%. GeriNOT detektierte für diese Gruppe ein erhöhtes Risiko in Bezug auf die definierten Endpunkte. Nur 4,26% aller Patient*innen mit identifiziertem geriatrischen Risikopotenzial wurden akutgeriatrisch weiterversorgt.Die Ergebnisse zeigten ein erhöhtes geriatrisches Risiko in allen analysierten Diagnosegruppen, am stärksten innerhalb der Gruppe der Wirbelsäulenerkrankungen. Der KIS-gestützte Einsatz des GeriNOT initiiert die systematische Risikoidentifikation im akutstationären Aufnahmemanagement. Die fallbegleitende Ergebnisvisualisierung in den KIS-Arbeitsplätzen könnte als Ausgangspunkt für die nachfolgende Anwendung von Assessmentinstrumenten und risikoadjustierter Behandlungspfade genutzt werden. Mit diesen Erkenntnissen könnte das Patientenoutcome potenziell positiv beeinflusst werden.}, }
@article {pmid39386562, year = {2024}, author = {Dargan, R and Mikheenko, A and Johnson, NL and Packer, B and Li, Z and Craig, EJ and Sarbanes, SL and Bereda, C and Mehta, PR and Keuss, M and Nalls, MA and Qi, YA and Weller, CA and Fratta, P and Ryan, VH}, title = {Altered mRNA transport and local translation in iNeurons with RNA binding protein knockdown.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386562}, issn = {2692-8205}, support = {ZIA AG000547/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Neurons rely on mRNA transport and local translation to facilitate rapid protein synthesis in processes far from the cell body. These processes allow precise spatial and temporal control of translation and are mediated by RNA binding proteins (RBPs), including those known to be associated with neurodegenerative diseases. Here, we use proteomics, transcriptomics, and microscopy to investigate the impact of RBP knockdown on mRNA transport and local translation in iPSC-derived neurons. We find thousands of transcripts enriched in neurites and that many of these transcripts are locally translated, possibly due to the shorter length of transcripts in neurites. Loss of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS)-associated RBPs TDP-43 and hnRNPA1 lead to distinct alterations in the neuritic proteome and transcriptome. TDP-43 knockdown (KD) leads to increased neuritic mRNA and translation. In contrast, hnRNPA1 leads to increased neuritic mRNA, but not translation, and more moderate effects on local mRNA profiles, possibly due to compensation by hnRNPA3. These results highlight the crucial role of FTD/ALS-associated RBPs in mRNA transport and local translation in neurons and the importance of these processes in neuron health and disease.}, }
@article {pmid39386496, year = {2024}, author = {El-Khatib, SM and Vagadia, AR and Le, ACD and Ng, DQ and Baulch, JE and Du, M and Tan, Z and Xu, X and Chan, A and Acharya, MM}, title = {BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.23.614590}, pmid = {39386496}, issn = {2692-8205}, abstract = {Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo . In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT+Veh with the RT+RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.}, }
@article {pmid39386447, year = {2024}, author = {Rodemer, W and Ra, I and Jia, E and Gujral, J and Zhang, B and Hoxha, K and Xing, B and Mehta, S and Farag, M and Porta, S and Jensen, FE and Talos, DM and Lee, VM}, title = {Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.09.24.612703}, pmid = {39386447}, issn = {2692-8205}, abstract = {UNLABELLED: 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 in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43ΔNLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies.<br><br>SIGNIFICANCE STATEMENT: Cytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.}, }
@article {pmid39386324, year = {2024}, author = {Ross, CW and Loudermilk, EL and O'Brien, JJ and Snitker, G}, title = {Lidar-derived structural-complexity data across four experimental forests.}, journal = {Data in brief}, volume = {57}, number = {}, pages = {110955}, pmid = {39386324}, issn = {2352-3409}, abstract = {Structural complexity refers to the three-dimensional arrangement and variability of both biotic and abiotic components of an ecosystem. Metrics that characterize structural complexity are often used to manage various aspects of ecosystem function, such as light transmittance, wildlife habitat, and biological diversity. Additionally, these metrics aid in evaluating resilience to disturbance events, including hurricanes, bark-beetle outbreaks, and wildfire. Recent advances in wildland fire modelling have facilitated the integration of forest structural complexity metrics into the QUIC-Fire model, enabling real-time prediction of fire spread and behaviour by simulating interactions between fire, weather, topography, and forest structure. While QUIC-Fire is designed to be highly adaptable, model performance depends on the availability and accuracy of local data inputs. Expanding the model's usability across different regions can be facilitated by the availability of more comprehensive and high-quality data. Thus, the primary goal behind the data products we developed was to establish a basis for collaborative research across various disciplines, particularly within the focal areas of the Southern Research Station, such as forestry, wildland fire, hydrology, soil science, and cultural resources at Bent Creek, Coweeta, Escambia, and Hitchiti Experimental Forests (EFs). Airborne laser scanning (ALS) was used to collect point-cloud data for each EF during the leaf-off season to minimize interference from foliage. Subsequent processing of the raw lidar data involved outlier detection and filtering, ground and non-ground classification, and the computation of a variety of metrics representing various aspects of topography and forest structure at both the pixel-level and the tree-level. Pixel-level topographic data products include: digital elevation model (DEM), slope, aspect, topographic position index (TPI), topographic roughness index (TRI), roughness, and flow direction. Forest structural-complexity metrics include canopy height, foliar height diversity (FHD), vertical distribution ratio (VDR), canopy rugosity, crown relief ratio (CRR), understory complexity index (UCI), vertical complexity index (VCI), canopy cover, mean vegetation height, and the standard deviation of vegetation height. Tree-level data products were computed from the point cloud using multiple algorithms to perform individual tree detection (ITD) and individual tree segmentation (ITS). The datasets have been harmonized and are openly accessible through the USDA Forest Service Research Data Archive.}, }
@article {pmid39385824, year = {2024}, author = {Chen, L and Chen, J and Weng, W and Wu, M and Zhou, X and Yan, P}, title = {Bibliometric analysis of microRNAs and Parkinson's disease from 2014 to 2023.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1466186}, pmid = {39385824}, issn = {1664-2295}, abstract = {BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Recent research has emphasized a significant correlation between microRNAs (miRNAs) and PD. To identify key research areas, provide a comprehensive overview of current research in various fields, and propose potential directions for future studies, a bibliometric analysis was conducted on the involvement of miRNAs in Parkinson's disease from 2014 to 2023.<br><br>METHODS: Relevant literature records were collected from the Web of Science Core Collection on February 29, 2024. Subsequently, the data underwent analysis using the Bibliometrix R package and VOSviewer (version 1.6.19).<br><br>RESULTS: The annual scientific publications on miRNAs and Parkinson's disease demonstrated an increasing trend, with an annual growth rate of 12.67%. China, the United States, and India emerged as the top three most productive countries/regions. The University of Barcelona had the highest annual publications, followed by Central South University and the Helmholtz Association. The INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES held the top position in terms of H-index and total citations, reflecting its extensive influence and prolific publication output. Kim, J., Junn, E., H&#xe9;bert, S.S., and Doxakis, E. were the most frequently co-cited authors in the field. Based on the analysis of keywords, the most frequently occurring terms included "alpha-synuclein," "neurodegenerative disease," "exosome," "neuroinflammation," "oxidative stress," "autophagy," and "amyotrophic lateral sclerosis," which have emerged as prominent research topics. Concurrently, there has been notable interest in topics such as "ceRNA," "lncRNAs," "mitochondrial dysfunction," and "circular RNA."<br><br>CONCLUSION: This study focused on identifying emerging trends and critical research topics in the bibliometric analysis of microRNAs related to Parkinson's disease. These findings highlight the diverse research landscape and evolving trend of miRNA-related research in PD. The field of miRNA research in Parkinson's disease is actively exploring the underlying mechanisms of miRNA function, identifying potential diagnostic markers, and developing innovative therapeutic strategies. The results of our study offer significant contributions to researchers' ability to track contemporary developments and guide the trajectory of future research in this domain.}, }
@article {pmid39385724, year = {2025}, author = {van den Bos, MAJ and Menon, P and Pavey, N and Higashihara, M and Kiernan, MC and Vucic, S}, title = {Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {4}, pages = {1169-1179}, doi = {10.1093/brain/awae317}, pmid = {39385724}, issn = {1460-2156}, support = {//MND Research Australia/ ; #2021/GNT2010812//NHMRC/ ; //Millhouse Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Male ; *Interneurons/physiology ; Transcranial Magnetic Stimulation/methods ; Middle Aged ; Female ; Aged ; Electroencephalography/methods ; *Motor Cortex/physiopathology ; Evoked Potentials, Motor/physiology ; Adult ; }, abstract = {Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = -0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = -0.698, P < 0.001). In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.}, }
@article {pmid39385461, year = {2025}, author = {Li, X and Wicks, P and Brown, A and Shivaprasad, A and Greene, M and Crayle, J and Barnes, B and Jhooty, S and Ratner, D and Olby, N and Glass, JD and Jackson, C and Cole, N and Armon, C and Mascias Cadavid, J and Pattee, G and Mcdermott, CJ and Chang, V and Maragakis, N and Bertorini, T and Bowser, R and Bedlack, R}, title = {ALSUntangled #76: Wahls protocol.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {181-185}, doi = {10.1080/21678421.2024.2407407}, pmid = {39385461}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/diet therapy ; Humans ; Disease Progression ; Animals ; Diet ; Fatty Acids, Omega-3/therapeutic use ; }, abstract = {The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.}, }
@article {pmid39385408, year = {2024}, author = {Shekhar, AC and Alexander, A and Simms, M and Jahan, M and Haugen, A and Lu, M and Ball, R and Clement, J}, title = {Ambulance Transports from NCAA Division 1 Football Games.}, journal = {Prehospital and disaster medicine}, volume = {39}, number = {3}, pages = {266-269}, pmid = {39385408}, issn = {1945-1938}, mesh = {Humans ; *Ambulances ; Male ; Cross-Sectional Studies ; *Football ; Female ; Young Adult ; Minnesota ; Adult ; Emergency Medical Services ; Universities ; Adolescent ; Crowding ; }, abstract = {INTRODUCTION: There is significant public health interest towards providing medical care at mass-gathering events. Furthermore, mass gatherings have the potential to have a detrimental impact on the availability of already-limited municipal Emergency Medical Services (EMS) resources. This study presents a cross-sectional descriptive analysis to report broad trends regarding patients who were transported from National Collegiate Athletic Association (NCAA) Division 1 collegiate football games at a major public university in order to better inform emergency preparedness and resource planning for mass gatherings.<br><br>METHODS: Patient care reports (PCRs) from ambulance transports originating from varsity collegiate football games at the University of Minnesota across six years were examined. Pertinent information was abstracted from each PCR.<br><br>RESULTS: Across the six years of data, there were a total of 73 patient transports originating from NCAA collegiate football games: 45.2% (n = 33) were male, and the median age was 22 years. Alcohol-related chief complaints were involved in 50.7% (n = 37) of transports. In total, 31.5% of patients had an initial Glasgow Coma Scale (GCS) of less than 15. The majority (65.8%; n = 48; 0.11 per 10,000 attendees) were transported by Basic Life Support (BLS) ambulances. The remaining patients (34.2%; n = 25; 0.06 per 10,000 attendees) were transported by Advanced Life Support (ALS) ambulances and were more likely to be older, have abnormal vital signs, and have a lower GCS.<br><br>CONCLUSIONS: This analysis of ambulance transports from NCAA Division 1 collegiate football games emphasizes the prevalence of alcohol-related chief complaints, but also underscores the likelihood of more life-threatening conditions at mass gatherings. These results and additional research will help inform emergency preparedness at mass-gathering events.}, }
@article {pmid39382075, year = {2025}, author = {Liang, B and Khan, M and Storts, H and Zhang, EH and Zheng, X and Xing, X and Claybon, H and Wilson, J and Li, C and Jin, N and Fishel, R and Miles, WO and Wang, JJ}, title = {Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {1}, pages = {131-140}, pmid = {39382075}, issn = {1538-8514}, support = {R01 CA251753/CA/NCI NIH HHS/United States ; R01 CA208063/CA/NCI NIH HHS/United States ; R01CA215389//National Cancer Institute (NCI)/ ; P30 CA016058/CA/NCI NIH HHS/United States ; R01 CA215389/CA/NCI NIH HHS/United States ; R01 CA067007/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Nucleotidyltransferases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; Mice ; *Membrane Proteins/metabolism ; Humans ; *Signal Transduction/drug effects ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors/metabolism ; *Riluzole/pharmacology/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Cell Line, Tumor ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.}, }
@article {pmid39381976, year = {2024}, author = {Grassano, M and Moglia, C and Palumbo, F and Koumantakis, E and Cugnasco, P and Callegaro, S and Canosa, A and Manera, U and Vasta, R and De Mattei, F and Matteoni, E and Fuda, G and Salamone, P and Marchese, G and Casale, F and De Marchi, F and Mazzini, L and Mora, G and Calvo, A and Chiò, A}, title = {Reply to "Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression".}, journal = {Annals of neurology}, volume = {96}, number = {5}, pages = {1029}, doi = {10.1002/ana.27095}, pmid = {39381976}, issn = {1531-8249}, support = {//ALS Association/ ; //American Brain Foundation/ ; //American Academy of Neurology/ ; }, }
@article {pmid39381934, year = {2024}, author = {Calati, R and Tambuzzi, S and Gravagnuolo, R and Muscatiello, L and Magrin, ME and Crippa, F and Madeddu, F and Zoja, R and Gentile, G}, title = {Suicide in prison in the North of Italy (1993-2022): a case-control study examining differences between suicides inside and outside prison.}, journal = {International clinical psychopharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1097/YIC.0000000000000569}, pmid = {39381934}, issn = {1473-5857}, abstract = {Prisoners constitute a group at suicide risk, showing higher relative rates of suicides than the general population. However, there is limited knowledge about the characteristics of those who die by suicide in Italian prisons. Based on the total sample of suicides of the Institute of Forensic Medicine of Milan (1993-2022), suicides in prison (N = 120) were matched by age and gender with cases that occurred outside prison (N = 300) and compared with them. The considered variables were sociodemographic, clinical, and suicide-related. Univariate analyses and logistic regression model were performed. In univariate analyses, suicides in prison showed higher rates of ethnicity different from white Caucasian, lower rates of depression, higher rates of alcoholism, addiction, respiratory system diseases, hepatitis, and amyotrophic lateral sclerosis, lower use of any medication, and in particular psychotropic medications, and a higher percentage of violent suicide method versus nonviolent compared to suicides outside prison. In the logistic regression model, ethnicity, depression, and addiction were the only features differentiating suicides in prison from ones outside prison. Particular attention should be paid to inmates with non-white ethnicity and those with addiction. Ensuring adequate access to psychiatric care and implementing comprehensive suicide prevention strategies within Italian prisons is crucial.}, }
@article {pmid39380150, year = {2024}, author = {Meshram, VD and Balaji, R and Saravanan, P and Subbamanda, Y and Deeksha, W and Bajpai, A and Joshi, H and Bhargava, A and Patel, BK}, title = {Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.}, journal = {Chemical biology &amp; drug design}, volume = {104}, number = {4}, pages = {e14640}, doi = {10.1111/cbdd.14640}, pmid = {39380150}, issn = {1747-0285}, support = {//Science and Engineering Research Board ; Department of Science and Technology/ ; SRG/2022/002109;SERB/CRG/2021/006856//Science Engineering Research Board, Govt. of India/ ; IFA20-PH-256//Deprartment of Science and Technology, Ministry of Science and Technology, Govt. of India, Inspire faculty fellowship/ ; }, mesh = {*Catechin/analogs &amp; derivatives/chemistry/pharmacology/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/antagonists &amp; inhibitors ; Humans ; *Molecular Dynamics Simulation ; *Molecular Docking Simulation ; *Protein Binding ; Binding Sites ; Thermodynamics ; Protein Aggregates/drug effects ; Protein Domains ; }, abstract = {Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.}, }
@article {pmid39379597, year = {2024}, author = {Fontdevila, L and Povedano, M and Domínguez, R and Boada, J and Serrano, JC and Pamplona, R and Ayala, V and Portero-Otín, M}, title = {Examining the complex Interplay between gut microbiota abundance and short-chain fatty acid production in amyotrophic lateral sclerosis patients shortly after onset of disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23497}, pmid = {39379597}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; *Gastrointestinal Microbiome ; Male ; *Fatty Acids, Volatile/metabolism ; Female ; Middle Aged ; Aged ; Adult ; Case-Control Studies ; }, abstract = {This study aimed to assess differences in the enteral microbiome of relatively recent-onset amyotrophic lateral sclerosis (ALS) patients (< 6-15 months since symptom onset) compared to healthy individuals, focusing on short-chain fatty acids (SCFAs) as potential mediators of host metabolism. We included 28 volunteers (16 ALS, 12 controls) with informed consent. No significant effect of ALS on alpha diversity (measuring the variety and abundance of species within a single sample, and indicating the health and complexity of the microbiome) was observed, but ALS patients had higher abundances of Fusobacteria and Acidobacteria. ALS subtypes influenced specific species, with increased Fusobacteria and Tenericutes in spinal ALS compared to bulbar ALS. ALS patients showed increased Enterobacter, Clostridium, Veillonella, Dialister, Turicibacter, and Acidaminococcus species and decreased Prevotella, Lactobacillus, and Butyricimonas. Correlations between species varied between ALS patients and healthy individuals and among ALS subtypes. No significant differences in SCFA concentrations were found, but spinal ALS samples showed a trend towards decreased propionate content. Relationships between SCFAs and phyla colonization differed by disease status. This study suggests distinct enteral microbiome characteristics in ALS patients, though the implications are unclear. Further research is needed to determine if these differences are causative or consequential and to explore their potential as diagnostic or therapeutic targets. The study also underscores the heterogeneity of microbiome constraints in ALS and the need for more research into ALS and SCFA metabolism.}, }
@article {pmid39378795, year = {2024}, author = {Lehto, A and Schumacher, J and Kasper, E and Teipel, S and Hermann, A and Prudlo, J}, title = {Loss of the ipsilateral silent period in amyotrophic lateral sclerosis is associated with reduced white matter integrity in the motor section of the corpus callosum.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123267}, doi = {10.1016/j.jns.2024.123267}, pmid = {39378795}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology/psychology ; *Corpus Callosum/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; *White Matter/diagnostic imaging/pathology ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Motor Cortex/diagnostic imaging/pathology/physiopathology ; Diffusion Tensor Imaging ; Functional Laterality/physiology ; Diffusion Magnetic Resonance Imaging/methods ; Adult ; Neural Inhibition/physiology ; Evoked Potentials, Motor/physiology ; }, abstract = {OBJECTIVE: Interhemispheric neurons in the motor section of the corpus callosum have an inhibitory effect on neurons of the contralateral motor cortex. Three quarters of patients with amyotrophic laterals sclerosis (ALS) show impaired transcallosal inhibition. We aimed to investigate whether structural changes co-occur with this functional impairment and to explore its phenotypic correlates.<br><br>METHODS: The demographic, clinical, and neuropsychological data of 127 ALS patients were analysed. Transcallosal inhibition was assessed with an ipsilateral silent period (iSP) protocol using transcranial magnetic stimulation. Patients were categorised based on an iSP response or its loss, and the groups were characterised by demographic, clinical, and neuropsychological variables. Diffusion-weighted images from a subset of 63 patients were analysed using tractography, and white matter (WM) structural integrity metrics were compared across groups.<br><br>RESULTS: 54&#xa0;% of patients displayed iSP loss. The average free-water-corrected fractional anisotropy values within the callosal tract between the primary motor cortices were lower for patients with iSP loss compared to patients with an iSP response. There were no group differences based on other diffusivity metrics. The groups did not differ regarding any of the demographic, clinical, or neuropsychological variables.<br><br>INTERPRETATION: We found reduced WM integrity in the motor section of the corpus callosum that differentiated ALS patients with iSP loss from patients with an iSP response, but with a small effect size. Nevertheless, the underlying pathological substrate and potential genetic drivers for these structural and functional changes in a subset of ALS patients remain to be satisfactorily investigated.}, }
@article {pmid39378530, year = {2025}, author = {Meng, T and Wu, W and Wang, B and Li, C and Li, J and Liu, J and Wang, J and Qie, R}, title = {Treating chronic pulmonary heart disease with traditional Chinese medicine: Systematic evaluation and mechanistic insights into the resolving phlegm and activating blood approach.}, journal = {Heart &amp; lung : the journal of critical care}, volume = {69}, number = {}, pages = {111-126}, doi = {10.1016/j.hrtlng.2024.09.017}, pmid = {39378530}, issn = {1527-3288}, mesh = {Humans ; Chronic Disease ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Medicine, Chinese Traditional/methods ; *Pulmonary Heart Disease/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Chronic Pulmonary Heart Disease (CPHD) significantly impacts global health, especially among middle-aged and older adults. In China, the Traditional Chinese Medicine (TCM) technique of Resolving Phlegm and Activating Blood (RPAB) is widely used to treat CPHD, although high-quality evidence supporting its efficacy remains limited.<br><br>OBJECTIVES: The purpose of this study was to rigorously assess the clinical efficacy of RPAB for CPHD and elucidate the mechanisms underlying its primary herbal components.<br><br>METHODS: Through a detailed search of literature in both Chinese and English and strict inclusion and exclusion criteria, 18 randomized controlled trials (RCTs) were selected for meta-analysis. We identified RPAB's core herbal combinations using association rule analysis. This method statistically analyzes the frequency and correlation of herbal medicine usage. We then analyzed the chemical components of these combinations and investigated their potential intervention mechanisms on CPHD through network pharmacology.<br><br>RESULTS: The combination of RPAB with Western medicine was superior to Western medicine alone in improving blood gas analysis and pulmonary function and reducing plasma viscosity in CPHD patients. The core herbal combination identified was Astragalus membranaceus (Fisch.) Bunge, Ligusticum chuanxiong Hort. ex S. H. Qiu &amp; al., and Stellaria alsine Grimm (ALS). This combination targeted 588 therapeutic and 27 core targets. It influenced ten core compounds across 34 pathways, primarily through the chemokine signaling pathway and the JAK-STAT signaling pathway.<br><br>CONCLUSION: RPAB with Western medicine significantly improves CPHD treatment outcomes. The study highlights the therapeutic potential of the ALS combination, which operates through multiple pathways to remodel pulmonary arteries, decrease inflammation, and lessen oxidative stress. These insights support the clinical application of RPAB in CPHD treatment and open new avenues for research and therapeutic development.}, }
@article {pmid39378421, year = {2024}, author = {Knox, L and Coates, E and Griffiths, A and Ali, Y and Hobson, E and McDermott, C}, title = {Development and Evaluation of the Telehealth in Motor Neuron Disease System: The TIME Study Protocol.}, journal = {JMIR research protocols}, volume = {13}, number = {}, pages = {e57685}, pmid = {39378421}, issn = {1929-0748}, mesh = {*Motor Neuron Disease/therapy ; Humans ; *Telemedicine ; Surveys and Questionnaires ; Caregivers/psychology ; }, abstract = {BACKGROUND: For more responsive care provision for motor neuron disease and caregivers, a digital system called Telehealth in MND-Care (TiM-C) was created. TiM-C sends regular symptom questionnaires to users; their responses are sent to health care professionals (HCPs). To enable people with motor neuron disease to participate in research studies more easily, a parallel platform was developed from TiM-C, called Telehealth in MND-Research (TiM-R). TiM-R can advertise studies, collect data, and make them available to MND researchers.<br><br>OBJECTIVE: This study has 4 work packages (WPs) to facilitate service approval, codevelop the TiM systems, and evaluate the service. Each WP aims to understand (1) what helps and hinders the approval of the TiM-C system as a National Health Service; (2) what aspects of MND care and research are currently unmet and can be addressed through the TiM-C and TiM-R systems; (3) how TiM-C influences MND care, from the perspective of people with motor neuron disease, their caregivers, and HCPs; and (4) the costs and benefits associated with TiM-C.<br><br>METHODS: WP1 will use semistructured interviews with 10-15 people involved in the approval of TiM-C to understand the barriers and facilitators to governance processes. WP2 will use individual and group interviews with 25-35 users (people with motor neuron disease, caregivers, HCPs, MND researchers, and industry) of TiM-C and TiM-R to understand the current unmet needs of these user groups and how TiM services can be developed to meet these needs. WP3 will use a process evaluation involving 5 elements; local context, engagement, user experiences, service impact, and mechanisms of action. A range of methods, including audits, analysis of routine data, questionnaires, interviews, and observations will be used with people with motor neuron disease, caregivers, and HCPs, both those using the system and those who declined the service when invited. WP4 will use data collected through the process evaluation and known costs to conduct a cost-consequence and budget impact analysis to explore the cost-benefit of the TiM-C service. Most data collected will be qualitative, with thematic and framework analysis used to develop themes from transcripts and observations. Descriptive statistics or t tests and chi-square tests will be used to describe and analyze quantitative data.<br><br>RESULTS: This study has received ethical approval and has begun recruitment in 1 site. Further, 13 specialist MND centers will adopt TiM-C and the TIME study, beginning in July 2024. The study will conclude in November 2026 and a final report will be produced 3 months after the completion date.<br><br>CONCLUSIONS: This study will facilitate the implementation and development of TiM-C and TiM-R and fully evaluate the TiM-C service, enabling informed decision-making among health care providers regarding continued involvement and contribute to the wider literature relating to how technology-enabled care services can affect clinical care.<br><br>DERR1-10.2196/57685.}, }
@article {pmid39377567, year = {2024}, author = {Rani, P and Rajak, BK and Mahato, GK and Rathore, RS and Chandra, G and Singh, DV}, title = {Strategic lead compound design and development utilizing computer-aided drug discovery (CADD) to address herbicide-resistant Phalaris minor in wheat fields.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8455}, pmid = {39377567}, issn = {1526-4998}, support = {//Science and Engineering Research Board, India/ ; //Department of Biotechnology, Ministry of Science and Technology, India/ ; //Department of Science and Technology, Ministry of Science and Technology, India/ ; }, abstract = {Wheat (Triticum aestivum) is a vital cereal crop and a staple food source worldwide. However, wheat grain productivity has significantly declined as a consequence of infestations by Phalaris minor. Traditional weed control methods have proven inadequate owing to the physiological similarities between P. minor and wheat during early growth stages. Consequently, farmers have turned to herbicides, targeting acetyl-CoA carboxylase (ACCase), acetolactate synthase (ALS) and photosystem II (PSII). Isoproturon targeting PSII was introduced in mid-1970s, to manage P. minor infestations. Despite their effectiveness, the repetitive use of these herbicides has led to the development of herbicide-resistant P. minor biotypes, posing a significant challenge to wheat productivity. To address this issue, there is a pressing need for innovative weed management strategies and the discovery of novel herbicide molecules. The integration of computer-aided drug discovery (CADD) techniques has emerged as a promising approach in herbicide research, that facilitates the identification of herbicide targets and enables the screening of large chemical libraries for potential herbicide-like molecules. By employing techniques such as homology modelling, molecular docking, molecular dynamics simulation and pharmacophore modelling, CADD has become a rapid and cost-effective medium to accelerate the herbicide discovery process significantly. This approach not only reduces the dependency on traditional experimental methods, but also enhances the precision and efficacy of herbicide development. This article underscores the critical role of bioinformatics and CADD in developing next-generation herbicides, offering new hope for sustainable weed management and improved wheat cultivation practices. © 2024 Society of Chemical Industry.}, }
@article {pmid39376539, year = {2024}, author = {Kouchmeshky, A and Whiting, A and McCaffery, P}, title = {Neuroprotective effects of ellorarxine in neuronal models of degeneration.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1422294}, pmid = {39376539}, issn = {1662-4548}, abstract = {INTRODUCTION: Retinoic acid (RA) was first recognised to be important for the central nervous system (CNS) in its developmental regulatory role and, given this action, it has been proposed in the adult CNS to regulate plasticity and promote regeneration. These types of roles have included support of neurogenesis, induction of neurite outgrowth, and protection from neuronal death. These functions are predominantly mediated by the retinoic acid receptor (RAR) transcription factor, and hence agonists for the RARs have been tested in a variety of models of neurodegeneration. This present study employs several in vitro models less explored for the action of RAR agonists to reverse neurodegeneration.<br><br>METHODS: A series of assays are used in which neuronal cells are placed under the types of stress that have been linked to neurodegeneration, in particular amyotrophic lateral sclerosis (ALS), and the neuroprotective influence of a new potent agonist for RAR, ellorarxine, is tested out. In these assays, neuronal cells were subjected to excitotoxic stress induced by glutamate, proteostasis disruption caused by epoxomicin, and oxidative stress leading to stress granule formation triggered by sodium arsenite.<br><br>RESULTS: Ellorarxine effectively reversed neuronal death in excitotoxic and proteostasis disruption assays and mitigated stress granule formation induced by sodium arsenite. This study also highlights for the first time the novel observation of RAR modulation of stress granules, although it is unknown whether this change in stress granules will be neuroprotective or potentially regenerative. Furthermore, the distribution of RAR agonists following intraperitoneal injection was assessed in mice, revealing preferential accumulation in the central nervous system, particularly in the spinal cord, compared to the liver. Gene expression studies in the spinal cord demonstrated that ellorarxine induces transcriptional changes at a low dose (0.01 mg/kg).<br><br>DISCUSSION: These findings underscore the therapeutic potential of RAR agonists, such as ellorarxine, for ALS and potentially other neurodegenerative diseases.}, }
@article {pmid39376212, year = {2024}, author = {Tomiyama, ALMR and Cartarozzi, LP and de Oliveira Coser, L and Chiarotto, GB and Oliveira, ALR}, title = {Corrigendum: Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1[G93A] mice.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1493884}, doi = {10.3389/fncel.2024.1493884}, pmid = {39376212}, issn = {1662-5102}, abstract = {[This corrects the article DOI: 10.3389/fncel.2023.1211486.].}, }
@article {pmid39375835, year = {2024}, author = {Altomare, D and Bracca, V and Premi, E and Micheli, A and Cotelli, MS and Gasparotti, R and Alberici, A and Borroni, B}, title = {Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.}, journal = {Psychiatry and clinical neurosciences}, volume = {78}, number = {12}, pages = {818-825}, pmid = {39375835}, issn = {1440-1819}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Frontotemporal Lobar Degeneration/diagnostic imaging/pathology/physiopathology ; Retrospective Studies ; *Frontotemporal Dementia/diagnostic imaging/physiopathology/pathology ; Longitudinal Studies ; Magnetic Resonance Imaging ; Amyotrophic Lateral Sclerosis/diagnostic imaging/complications ; }, abstract = {AIM: Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes.<br><br>METHODS: This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory.<br><br>RESULTS: A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P&#x2009;<&#x2009;0.05); was associated with younger age (odds ratio [OR]&#x2009;=&#x2009;0.96 [95% CI: 0.94-0.99]), (P&#x2009;=&#x2009;0.003) and positive family history for dementia (OR&#x2009;=&#x2009;2.03 [95% CI: 1.18-3.49], P&#x2009;=&#x2009;0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR&#x2009;=&#x2009;1.08 [95% CI: 1.06-1.10], P&#x2009;<&#x2009;0.001) and with the presence of several behavioral symptoms (P&#x2009;<&#x2009;0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (&#x3b2;&#x2009;=&#x2009;+0.15, P&#x2009;=&#x2009;0.011) or semantic variant of primary progressive aphasia (&#x3b2;&#x2009;=&#x2009;+0.34, P&#x2009;=&#x2009;0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.}, }
@article {pmid39375041, year = {2024}, author = {Shah, NM and Rossel, A and Abdulaziz, B and Sheridan, S and Madden-Scott, S and Radcliffe, G and D'Cruz, R and Suh, ES and Steier, J and Hart, N and Murphy, PB and Ramsay, M and Kaltsakas, G}, title = {Effect of nostril occlusion and mouth sealing in the measurement of sniff nasal inspiratory pressure.}, journal = {Thorax}, volume = {80}, number = {1}, pages = {42-44}, doi = {10.1136/thorax-2024-221910}, pmid = {39375041}, issn = {1468-3296}, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Respiratory Muscles/physiology/physiopathology ; *Amyotrophic Lateral Sclerosis/physiopathology ; *Inhalation/physiology ; *Mouth ; Adult ; Nose ; Muscle Strength/physiology ; Respiratory Function Tests/methods ; }, abstract = {Sniff nasal inspiratory pressure (SNIP) is used to assess respiratory muscle strength in neuromuscular diseases like amyotrophic lateral sclerosis (ALS). The effect of contralateral nostril occlusion and mouth sealing on SNIP measurement are unclear. 81 participants were included (16 healthy, 39 patients with limb-onset ALS and 26 patients with bulbar-onset ALS). SNIP was obtained with combinations of mouth open/sealed and contralateral nostril open/occluded. Occluding the contralateral nostril (with mouth closed) increased SNIP by 12 cmH2O (95% CI 4, 20; p=0.003) in the healthy participants, by 9 cmH2O (95% CI 5, 12; p<0.001) in the limb-onset cohort and by 10 cmH2O (95% CI 5, 14; p<0.001) in the bulbar-onset cohort. Opening the mouth decreased SNIP by 19 cmH2O (95% CI 5, 34; p<0.009) in healthy participants, by 8 cmH2O (95% CI 4, 13; p<0.001) in the limb-onset cohort and by 13 cmH2O (95% CI 7, 19; p<0.001) in the bulbar-onset cohort. With contralateral nostril occlusion, 11% fewer individuals would have qualified for non-invasive ventilation. In conclusion, contralateral nostril occlusion increased SNIP compared with standard technique, likely reflecting true strength. Opening the mouth reduced SNIP, emphasising the need for good mouth sealing. Documenting SNIP technique is important for longitudinal assessments and clinical decision-making.}, }
@article {pmid39374890, year = {2024}, author = {Zhang, J and Liu, L and Li, M and Liu, H and Gong, X and Tang, Y and Zhang, Y and Zhou, X and Lin, Z and Guo, H and Pan, L}, title = {Molecular Basis of the Recognition of the Active Rab8a by Optineurin.}, journal = {Journal of molecular biology}, volume = {436}, number = {22}, pages = {168811}, doi = {10.1016/j.jmb.2024.168811}, pmid = {39374890}, issn = {1089-8638}, mesh = {*rab GTP-Binding Proteins/metabolism/chemistry/genetics ; *Cell Cycle Proteins/metabolism/chemistry/genetics ; *Membrane Transport Proteins/metabolism/chemistry/genetics ; Humans ; *Protein Binding ; *Transcription Factor TFIIIA/metabolism/genetics/chemistry ; Models, Molecular ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; Crystallography, X-Ray ; GTPase-Activating Proteins/metabolism/chemistry/genetics ; Mutation ; Protein Conformation ; }, abstract = {Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism. Here, using biochemical and structural approaches, we systematically characterize the interaction between OPTN and Rab8a, revealing that OPTN selectively recognizes the GTP-bound active Rab8a through its leucine-zipper domain (LZD). The determined crystal structure of OPTN LZD in complex with the active Rab8a not only elucidates the detailed binding mechanism of OPTN with Rab8a but also uncovers a unique binding mode of Rab8a with its effectors. Furthermore, we demonstrate that the central coiled-coil domain of OPTN and the active Rab8a can simultaneously interact with the TBC domain of TBC1D17 to form a ternary complex. Finally, based on the OPTN LZD/Rab8a complex structure and relevant biochemical analyses, we also evaluate several known ALS-associated mutations found in the LZD of OPTN. Collectively, our findings provide mechanistic insights into the interaction of OPTN with Rab8a, expanding our understanding of the binding modes of Rab8a with its effectors and the potential etiology of diseases caused by OPTN mutations.}, }
@article {pmid39374680, year = {2024}, author = {Tirassa, P and Rosso, P and Fico, E and Marenco, M and Mallone, F and Gharbiya, M and Lambiase, A and Severini, C}, title = {Perspective role of Substance P in Amyotrophic Lateral Sclerosis: From neuronal vulnerability to neuroprotection.}, journal = {Neuroscience and biobehavioral reviews}, volume = {167}, number = {}, pages = {105914}, doi = {10.1016/j.neubiorev.2024.105914}, pmid = {39374680}, issn = {1873-7528}, mesh = {*Substance P/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/physiopathology ; Humans ; Animals ; Receptors, Neurokinin-1/metabolism ; Neuroprotection/physiology ; Motor Neurons/metabolism/physiology ; }, abstract = {The neuropeptide Substance P (SP) and its preferred Neurokinin1 Receptor (NK1R) are known to participate in the physiopathology of neurodegenerative diseases and mainly exert a neuroprotective role. In the present work, we have described the involvement of SP and NK1R in Amyotrophic Lateral Sclerosis (ALS). This was demonstrated by the detection of altered levels of SP in the brain, spinal cord and cerebrospinal fluid (CSF) of patients and preclinical models of ALS, and by its ability to inhibit excitotoxicity-induced neurodegeneration in ALS animal models. These data are supported by results indicating an excitatory effect of SP at the motor neuron (MN) level, which promotes locomotor activity. ALS patients are characterized by a differential susceptibility to MNs degeneration, since sphincters and extraocular muscles are classically spared. It is hypothesized that SP may play a role in the maintenance of the ocular system and the innervation of the pelvic floor by contributing directly or indirectly to the selective resistance of this subset of MNs.}, }
@article {pmid39373990, year = {2024}, author = {Appel, SH and Thonhoff, JR}, title = {Barriers to Tofersen Therapy for Variant SOD1-Mediated ALS.}, journal = {JAMA neurology}, volume = {81}, number = {12}, pages = {1239-1240}, doi = {10.1001/jamaneurol.2024.3331}, pmid = {39373990}, issn = {2168-6157}, }
@article {pmid39373307, year = {2025}, author = {Rajagopalan, V and Pioro, EP}, title = {Graph theory network analysis reveals widespread white matter damage in brains of patients with classic ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {85-92}, doi = {10.1080/21678421.2024.2410281}, pmid = {39373307}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnostic imaging ; Male ; Female ; *White Matter/diagnostic imaging/pathology ; Middle Aged ; Aged ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Gray Matter/diagnostic imaging/pathology ; Adult ; Image Processing, Computer-Assisted ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients.<br><br>METHODS: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients.<br><br>RESULTS AND CONCLUSIONS: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p&#x2009;<&#x2009;0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.}, }
@article {pmid39372031, year = {2024}, author = {Pillai, M and Jha, SK}, title = {Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.}, journal = {ACS omega}, volume = {9}, number = {39}, pages = {40286-40297}, pmid = {39372031}, issn = {2470-1343}, abstract = {Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). TDP-43 protein assumes several different conformations and oligomeric states under the diseased condition. In this review, we explore the intrinsic relationship between the conformational variability of TDP-43 protein, with a particular focus on the RRM domains, and its propensity to undergo aggregation. We further emphasize the probable mechanism behind the formation of these conformations and suggest a potential diagnostic and therapeutic strategy in the context of these conformational states of the protein.}, }
@article {pmid39371851, year = {2024}, author = {Po, K and Olaivar, M}, title = {Juvenile Amyotrophic Lateral Sclerosis: A Case Report of a Rare and Aggressive Presentation in a 22-Year-Old Filipino Male.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68579}, pmid = {39371851}, issn = {2168-8184}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder primarily affecting adults, but juvenile-onset ALS is exceptionally rare. We report a rare case of a 22-year-old Filipino male patient who exhibited early-onset weakness, muscle atrophy, and tongue fasciculations, followed by rapidly progressive dysphagia and respiratory distress. Electromyography - Nerve Conduction Velocity (EMG-NCV) findings showed evidence for a chronic, active predominantly motor neuronal-axonal loss type of neuropathy involving the tongue and limb muscles bilaterally consistent with a motor neuron disease. The patient was treated with riluzole with no significant improvement in symptoms. Despite multidisciplinary interventions, the disease rapidly progressed, highlighting the challenges in managing juvenile ALS cases. This case report emphasizes the importance of considering ALS in the differential diagnosis of progressive motor dysfunction in younger patients and the complexities involved in their care.}, }
@article {pmid39371161, year = {2024}, author = {Angrick, M and Luo, S and Rabbani, Q and Joshi, S and Candrea, DN and Milsap, GW and Gordon, CR and Rosenblatt, K and Clawson, L and Maragakis, N and Tenore, FV and Fifer, MS and Ramsey, NF and Crone, NE}, title = {Real-time detection of spoken speech from unlabeled ECoG signals: A pilot study with an ALS participant.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371161}, support = {UH3 NS114439/NS/NINDS NIH HHS/United States ; }, abstract = {OBJECTIVE: Brain-Computer Interfaces (BCIs) hold significant promise for restoring communication in individuals with partial or complete loss of the ability to speak due to paralysis from amyotrophic lateral sclerosis (ALS), brainstem stroke, and other neurological disorders. Many of the approaches to speech decoding reported in the BCI literature have required time-aligned target representations to allow successful training - a major challenge when translating such approaches to people who have already lost their voice.<br><br>APPROACH: In this pilot study, we made a first step toward scenarios in which no ground truth is available. We utilized a graph-based clustering approach to identify temporal segments of speech production from electrocorticographic (ECoG) signals alone. We then used the estimated speech segments to train a voice activity detection (VAD) model using only ECoG signals. We evaluated our approach using held-out open-loop recordings of a single dysarthric clinical trial participant living with ALS, and we compared the resulting performance to previous solutions trained with ground truth acoustic voice recordings.<br><br>MAIN RESULTS: Our approach achieves a median error rate of around 0.5 seconds with respect to the actual spoken speech. Embedded into a real-time BCI, our approach is capable of providing VAD results with a latency of only 10 ms.<br><br>SIGNIFICANCE: To the best of our knowledge, our results show for the first time that speech activity can be predicted purely from unlabeled ECoG signals, a crucial step toward individuals who cannot provide this information anymore due to their neurological condition, such as patients with locked-in syndrome.<br><br>CLINICAL TRIAL INFORMATION: ClinicalTrials.gov, registration number NCT03567213.}, }
@article {pmid39370211, year = {2024}, author = {Kajitani, GS and Xavier, G and Villena-Rueda, BE and Karia, BTR and Santoro, ML}, title = {Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.}, journal = {Current topics in membranes}, volume = {94}, number = {}, pages = {299-336}, doi = {10.1016/bs.ctm.2024.06.002}, pmid = {39370211}, issn = {1063-5823}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Neurodegenerative Diseases/metabolism/pathology/therapy ; *Biomarkers/metabolism ; Mental Disorders/metabolism/drug therapy/therapy ; Animals ; Nervous System Diseases/metabolism/pathology ; }, abstract = {Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.}, }
@article {pmid39369804, year = {2024}, author = {Daniels, N and Bindoff, AD and Vickers, JC and King, AE and Collins, JM}, title = {Vulnerability of neurofilament-expressing neurons in frontotemporal dementia.}, journal = {Molecular and cellular neurosciences}, volume = {131}, number = {}, pages = {103974}, doi = {10.1016/j.mcn.2024.103974}, pmid = {39369804}, issn = {1095-9327}, mesh = {Humans ; *Frontotemporal Dementia/metabolism/genetics/pathology ; Aged ; *Neurons/metabolism/pathology ; *Neurofilament Proteins/metabolism ; Female ; Male ; Middle Aged ; *tau Proteins/metabolism/genetics ; Aged, 80 and over ; DNA-Binding Proteins/metabolism/genetics ; }, abstract = {Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.}, }
@article {pmid39369616, year = {2024}, author = {Zhao, Y and Li, X and Wang, K and Iyer, G and Sakowski, SA and Zhao, L and Teener, S and Bakulski, KM and Dou, JF and Traynor, BJ and Karnovsky, A and Batterman, SA and Feldman, EL and Sartor, MA and Goutman, SA}, title = {Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.}, journal = {EBioMedicine}, volume = {109}, number = {}, pages = {105383}, pmid = {39369616}, issn = {2352-3964}, support = {R01 TS000289/TS/ATSDR CDC HHS/United States ; R01 TS000327/TS/ATSDR CDC HHS/United States ; K23 ES027221/ES/NIEHS NIH HHS/United States ; R01 ES030049/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; R01 NS120926/NS/NINDS NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/etiology/mortality ; Male ; Female ; *Epigenesis, Genetic ; *Occupational Exposure/adverse effects ; Middle Aged ; *DNA Methylation ; Aged ; Sex Factors ; Aging/genetics ; Case-Control Studies ; Adult ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival.<br><br>METHODS: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes.<br><br>FINDINGS: Participants with ALS had higher average EAA by 1.80&#xa0;&#xb1;&#xa0;0.30 years (p&#xa0;<&#xa0;0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p&#xa0;=&#xa0;0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p&#xa0;=&#xa0;0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p&#xa0;<&#xa0;0.0001) and metals (adj.p&#xa0;=&#xa0;0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons.<br><br>INTERPRETATION: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS.<br><br>FUNDING: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.}, }
@article {pmid39368746, year = {2024}, author = {Sharma, R and Mehan, S and Khan, Z and Das Gupta, G and Narula, AS}, title = {Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration.}, journal = {Neurochemistry international}, volume = {180}, number = {}, pages = {105876}, doi = {10.1016/j.neuint.2024.105876}, pmid = {39368746}, issn = {1872-9754}, mesh = {Animals ; *Oleanolic Acid/pharmacology/therapeutic use ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Male ; *Methylmercury Compounds/toxicity ; *Glycogen Synthase Kinase 3 beta/metabolism ; *TOR Serine-Threonine Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Rats, Wistar ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Neuroprotection/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.}, }
@article {pmid39368179, year = {2025}, author = {Brito, ALB and Cardoso, IF and Viegas, LP and Fausto, R}, title = {Semi-quantitative chemometric models for characterization of mixtures of sugars using infrared spectral data.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125225}, doi = {10.1016/j.saa.2024.125225}, pmid = {39368179}, issn = {1873-3557}, mesh = {*Chemometrics/methods ; *Models, Chemical ; *Sugars/analysis ; Spectrophotometry, Infrared ; Principal Component Analysis ; Multivariate Analysis ; Least-Squares Analysis ; }, abstract = {Sugars (saccharides) are sweet-tasting carbohydrates that are abundant in foods and play very important roles in living organisms, particularly as sources and stores of energy, and as structural elements in cellular membranes. They are desirable therapeutic targets, as they participate in multiple metabolic processes as fundamental elements. However, the physicochemical characterization of sugars is a challenging task, mostly due to the structural similarity shared by the large diversity of compounds of this family. The need for fast, accurate enough, and cost-effective analytical methods for these substances is of extreme relevance, in particular because of the recently increasing importance of carbohydrates in Medicine and food industry. With this in view, this work focused on the development of chemometric models for semi-quantitative analysis of samples of different types of sugars (glucose, galactose, mannitol, sorbose and fructose) using infrared spectra as data, as an example of application of a novel approach, where the Principal Component Analysis (PCA) score plots are used to estimate the composition (weight-%) of the mixtures of the sugars. In these plots, polygonal geometric shapes emerge in the vectorial space of the most significant principal components, that allow grouping different types of samples on the vertices, edges, faces and interior of the polygons according to the composition of the samples. This approach was applied successfully to mixtures of up to 5 sugars and shown to appropriately extract the compositional information from the hyper-redundant complex spectral data. Thought the method has been applied here to a specific problem, it shall be considered as a general procedure for the semi-quantitative analysis of other types of mixtures and applicable to other types of data reflecting their composition. In fact, the methodology appears as an efficient tool to solve three main general problems: (i) use hyper-redundant (in variables) data, as spectral information, directly and with minimum pre-treatment, to evaluate semi-quantitatively the composition of mixtures; (ii) do this for systems which produce data that can be considered rather similar; and (iii) do it for a number of substances present in the mixtures that might be greater than that usually considered in chemistry, which in general is limited to 3 components. In addition, this work also demonstrates that, similarly to the developed analysis based on the PCA score plots, the Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS) chemometric method can also be used successfully for the qualitative (when used without any previous knowledge of the components present in the samples) or semi-quantitative (when the pure components spectral profiles are provided as references) analyses of mixtures of (at least) up to 5 distinct sugars.}, }
@article {pmid39367779, year = {2025}, author = {Duran, S and Aydogdu, A}, title = {The effect of structured psychoeducation for caregivers of ALS patients on perceived stress, psychological resilience and self-compassion.}, journal = {Health education research}, volume = {40}, number = {1}, pages = {}, doi = {10.1093/her/cyae031}, pmid = {39367779}, issn = {1465-3648}, mesh = {Humans ; *Caregivers/psychology/education ; *Resilience, Psychological ; Female ; Male ; Middle Aged ; *Stress, Psychological ; *Adaptation, Psychological ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Empathy ; Adult ; Surveys and Questionnaires ; Aged ; }, abstract = {Patients diagnosed with amyotrophic lateral sclerosis (ALS) become dependent on caregivers to meet their daily needs and perform personal care activities. For this reason, ALS is a disease that can challenge both the patient and the caregiver physically, mentally and socially. Supporting the caregiver indirectly affects the patient's quality of care and mental well-being. Therefore, this study aimed to determine the effect of a structured psychoeducation program on coping with stress, psychological resilience and self-compassion in caregivers of ALS patients. This quasi-experimental study with a pre-test-post-test control group was conducted with caregivers of 62 ALS patients in Türkiye. The study was conducted between July 2023 and February 2024. A psychoeducation program was applied to five different groups via zoom application for 6 weeks each. The survey form, Perceived Stress Scale, Brief Resilience Scale and Short Form of Self-Compassion Questionnaire were used as measurement tools. The chi-squared test and paired samples t-test were used to analyze the data. While there was no significant difference between the intervention group and the control group in the pre-test in terms of their mean scores on the coping with stress inventory, short psychological resilience scale and self-compassion scale, at the post-test, psychological resilience and self-compassion scores were significantly higher in the intervention group. This study revealed that psychoeducational programs that support caregivers are effective in increasing psychological resilience and self-compassion.}, }
@article {pmid39367309, year = {2024}, author = {Makled, AF and Ali, SAM and Labeeb, AZ and Salman, SS and Shebl, DZM and Hegazy, SG and Sabal, MS}, title = {Characterization of Candida species isolated from clinical specimens: insights into virulence traits, antifungal resistance and molecular profiles.}, journal = {BMC microbiology}, volume = {24}, number = {1}, pages = {388}, pmid = {39367309}, issn = {1471-2180}, mesh = {Humans ; *Candida/genetics/pathogenicity/drug effects/isolation &amp; purification/classification ; *Drug Resistance, Fungal/genetics ; *Antifungal Agents/pharmacology ; *Virulence Factors/genetics ; *Candidiasis/microbiology ; *Biofilms/growth &amp; development ; *Microbial Sensitivity Tests ; Virulence/genetics ; Multiplex Polymerase Chain Reaction ; Male ; Female ; Adult ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Candida species have emerged as a significant cause of opportunistic infections. Alongside the expression of various virulence factors, the rise of antifungal resistance among Candida species presents a considerable clinical challenge.<br><br>AIM: This study aimed to identify different Candida species isolated from clinical specimens, evaluate their antifungal sensitivity patterns, identify key genes regulating virulence mechanisms using multiplex PCR and to assess any correlation between their virulence profiles and antifungal resistance patterns.<br><br>METHOD: A total of 100 Candida spp. was isolated from 630 different clinical specimens and identified to the species level. Their antifungal susceptibility was phenotypically evaluated in accordance with CLSI guidelines using the Vitek-2 Compact System. Virulence markers, including biofilm formation capacity, protease production, melanin production, coagulase production and hemolysin production, were also phenotypically detected. The genetic determinants for biofilm formation and extracellular hydrolytic enzymes were assessed using a multiplex PCR assay.<br><br>RESULTS: The prevalence of Candida spp. was 15.9%, with C. albicans (48%) and C. glabrata (16%) being the most common. C. albicans showed the highest virulence, with strong biofilm formation, and high proteinase and melanin production. Multiplex PCR revealed Hlp in 22.0%, Hwp in 80.0%, Als in 56.0%, and Sap genes in 56.0% of isolates. Virulence genes were more common in C. albicans than in non-albicans Candida (NAC). Resistance patterns significantly correlated with virulence profiles, with notable associations between flucytosine resistance and the presence of Hlp and Hwp genes.<br><br>CONCLUSION: The significant correlation between virulent markers such as germination, coagulase, hemolysin production and resistance patterns among different Candida isolates is crucial for predicting the severity and outcomes of Candida infections. This understanding aids in guiding tailored treatment strategies.}, }
@article {pmid39367212, year = {2024}, author = {Cogan, G and Zaki, MS and Issa, M and Keren, B and Guillaud-Bataille, M and Renaldo, F and Isapof, A and Lallemant, P and Stevanin, G and Guillot-Noel, L and Courtin, T and Buratti, J and Freihuber, C and Gleeson, JG and Howarth, R and Durr, A and de Sainte Agathe, JM and Mignot, C}, title = {Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.}, journal = {Human genetics}, volume = {143}, number = {11}, pages = {1353-1362}, pmid = {39367212}, issn = {1432-1203}, mesh = {Humans ; Female ; Male ; *Paraparesis, Spastic/genetics ; *Pedigree ; Child ; Adolescent ; Adult ; Membrane Proteins/genetics ; Alleles ; Phenotype ; Mutation ; Child, Preschool ; Young Adult ; Intellectual Disability/genetics ; }, abstract = {Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.}, }
@article {pmid39367160, year = {2024}, author = {Metzger, M and Dukic, S and McMackin, R and Giglia, E and Mitchell, M and Bista, S and Costello, E and Peelo, C and Tadjine, Y and Sirenko, V and McManus, L and Buxo, T and Fasano, A and Chipika, R and Pinto-Grau, M and Schuster, C and Heverin, M and Coffey, A and Broderick, M and Iyer, PM and Mohr, K and Gavin, B and Pender, N and Bede, P and Muthuraman, M and Hardiman, O and Nasseroleslami, B}, title = {Distinct Longitudinal Changes in EEG Measures Reflecting Functional Network Disruption in ALS Cognitive Phenotypes.}, journal = {Brain topography}, volume = {38}, number = {1}, pages = {3}, pmid = {39367160}, issn = {1573-6792}, support = {HRA-POR-2013-246; MRCG-2018-02 and HRB ILP-POR-2022-046//Health Research Board of Ireland/ ; IceBucket Award; MRCG2018-02 to B.N., McManus/Apr22/888-791 to L.M. and McMackin/Oct20/972-799 to R.M//Irish/UK Motor Neurone Disease Research Foundation/ ; Project-ID 424778381-TRR 295//Deutsche Forschungsgemeinschaft/ ; Emerging Investigator Award HRB-EIA-2017-019//Health Research Board of Ireland/ ; GOIPD/2015/213 to B.N. and GOIPG/2017/1014 to R.M.//Irish Research Council/ ; /WT_/Wellcome Trust/United Kingdom ; 16/ ERCD/3854 and Royal Society/SFI URF\R1\221917 to L.M./SFI_/Science Foundation Ireland/Ireland ; multi-year grant 20-IIA-546//ALS Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; *Electroencephalography/methods ; Middle Aged ; Longitudinal Studies ; Aged ; Phenotype ; Brain/physiopathology ; Cognition/physiology ; Disease Progression ; Cognitive Dysfunction/physiopathology ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in [Formula: see text]-band spectral power over time in the temporal region along with increased [Formula: see text]-band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS.}, }
@article {pmid39366938, year = {2024}, author = {Hutchings, AJ and Hambrecht, B and Veh, A and Giridhar, NJ and Zare, A and Angerer, C and Ohnesorge, T and Schenke, M and Selvaraj, BT and Chandran, S and Sterneckert, J and Petri, S and Seeger, B and Briese, M and Stigloher, C and Bischler, T and Hermann, A and Damme, M and Sendtner, M and Lüningschrör, P}, title = {Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8622}, pmid = {39366938}, issn = {2041-1723}, support = {LU 2347/3-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; VORAN-2 16LW066//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/ ; }, mesh = {Animals ; Humans ; Male ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Autophagy ; Disease Models, Animal ; Exocytosis ; *Guanine Nucleotide Exchange Factors/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism ; Lysosomes/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; *Motor Neurons/metabolism ; Presynaptic Terminals/metabolism ; rab GTP-Binding Proteins/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; }, abstract = {Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1[G93A] following deletion of Plekhg5 in SOD1[G93A] mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.}, }
@article {pmid39365785, year = {2024}, author = {Putri, KD and Guntoro, D and Ardie, SW and Hariyadi, }, title = {A new amino acid substitution in the MvALS1 gene of metsulfuron-methyl resistant biotypes Monochoria vaginalis (Burm. f.) C. Presl from West Java, Indonesia.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0308465}, pmid = {39365785}, issn = {1932-6203}, mesh = {Indonesia ; *Arylsulfonates/pharmacology ; *Amino Acid Substitution ; *Herbicide Resistance/genetics ; Herbicides/pharmacology ; Plant Proteins/genetics ; Mutation ; }, abstract = {The most bothersome weed in rice fields in the Indonesian province of West Java is Monochoria vaginalis (Burm. F.) C. Presl, an aquatic herbaceous plant. Metsulfuron-methyl has long been used in wetland rice in West Java with a high enough intensity. However, the case of Monochoria vaginalis resistance to metsulfuron-methyl herbicides in Indonesia has not been widely reported and investigated. The study aims to (1) classify the resistance level of M. vaginalis toward metsulfuron-methyl, (2) identify Target Site Resistance (TSR) mechanism mutations in the MvALS1 gene of the resistant biotype of M. vaginalis. The Whole Plant Pot Test method was utilized to assess the resistance level of Monochoria vaginalis. Following that, all samples were subjected to DNA sequencing using the PCR method to identify mutations in the MvALS1 gene from the resistant biotype. After then, this study used DUET, a server with an integrated computational methodology, to anticipate the effect of mutations on protein stability. The result showed that Monochoria vaginalis from Rawamerta, Karawang showed a moderate level of resistance to metsulfuron-methyl with a resistance ratio of 6.00, Patokbeusi, Subang showed a low level of resistance to metsulfuron-methyl with a resistance ratio of 3.89, compared to susceptible Monochoria vaginalis. Nucleotide base alignment in the MvALS1 gene revealed that base substitutions occurred in the Monochoria vaginalis biotype from Rawamerta and Patokbeusi, resulting in 5 amino acid substitutions: Ser-64-Ala, Asp-66-Glu, Asn-240-Asp, Glu-426-Asn, and Ser-469-Asn and Sukra: Ser-64-Ala, Asp-66-Glu, and Asn-240-Asp. The analysis showed that S64A, D66E, and N240D stabilize the protein, whereas E426N and S469N destabilize it. This study confirms for the first time that Ser-64-Ala, Asn-240-Asp, and Glu-426-Asn amino acid mutations were found in cases of M. vaginalis resistance to metsulfuron-methyl (ALS inhibitor).}, }
@article {pmid39364420, year = {2024}, author = {Aiello, EN and Contarino, VE and Conte, G and Solca, F and Curti, B and Maranzano, A and Torre, S and Casale, S and Doretti, A and Colombo, E and Verde, F and Silani, V and Liu, C and Cinnante, C and Triulzi, FM and Morelli, C and Poletti, B and Ticozzi, N}, title = {QSM-detected iron accumulation in the cerebellar gray matter is selectively associated with executive dysfunction in non-demented ALS patients.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1426841}, pmid = {39364420}, issn = {1664-2295}, abstract = {BACKGROUND: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECAS-Carer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume.<br><br>RESULTS: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted (ps&#x2009;&#x2264;&#x2009;0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF (ps&#x2009;&#x2264;&#x2009;0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks.<br><br>DISCUSSION: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in non-demented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients.}, }
@article {pmid39364217, year = {2024}, author = {Samuel Olajide, T and Oyerinde, TO and Omotosho, OI and Okeowo, OM and Olajide, OJ and Ijomone, OM}, title = {Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.}, journal = {Neuroprotection}, volume = {2}, number = {3}, pages = {182-195}, pmid = {39364217}, issn = {2770-730X}, support = {K43 TW011920/TW/FIC NIH HHS/United States ; }, abstract = {The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.}, }
@article {pmid39363643, year = {2025}, author = {Capelle, DP and Sabirin, W and Zulhairy-Liong, NA and Edgar, S and Goh, KJ and Ahmad-Annuar, A and Shahrizaila, N}, title = {Multistep modeling applied to a Malaysian ALS registry.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {157-161}, doi = {10.1080/21678421.2024.2410280}, pmid = {39363643}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis ; Malaysia/epidemiology ; Male ; *Registries ; Female ; Middle Aged ; Aged ; Adult ; *Disease Progression ; Incidence ; Age of Onset ; }, abstract = {OBJECTIVE: To apply the multistep model of pathogenesis in amyotrophic lateral sclerosis (ALS) to data from a multiethnic Malaysian registry.<br><br>METHODS: Clinical data, including age at symptom onset, was collected from 289 patients who presented to our multidisciplinary clinic from 2016 until 2024. A least squares linear regression model was constructed from the logarithm of approximated incidence and the logarithm of age. Population incidence was approximated by adjusting the absolute numbers of patients in 5 year groups by the size of the general population in the respective age group.<br><br>RESULTS: A linear relationship between log of incidence versus log of age was observed, with a slope of 4.57 (95% CI, 3.3-5.8) and an r[2] value of 0.93, suggesting a 6-step process.<br><br>CONCLUSION: Progression toward symptom onset in Malaysian ALS patients appears consistent with a multistep model of disease as observed in other cohorts.}, }
@article {pmid39363348, year = {2024}, author = {Chevalier, E and Audrain, M and Ratnam, M and Ollier, R and Fuchs, A and Piorkowska, K and Pfeifer, A and Kosco-Vilbois, M and Seredenina, T and Afroz, T}, title = {Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {156}, pmid = {39363348}, issn = {2051-5960}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; Mice ; *Disease Models, Animal ; *Frontotemporal Dementia/pathology/metabolism ; *Antibodies, Monoclonal/pharmacology ; Humans ; Mice, Transgenic ; }, abstract = {Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.}, }
@article {pmid39362869, year = {2024}, author = {Ma, YY and Li, X and Yu, ZY and Luo, T and Tan, CR and Bai, YD and Xu, G and Sun, BD and Bu, XL and Liu, YH and Jin, WS and Gao, YQ and Zhou, XF and Liu, J and Wang, YJ}, title = {Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {415}, pmid = {39362869}, issn = {2158-3188}, support = {92249305//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Edaravone/pharmacology/administration &amp; dosage ; *Cognitive Dysfunction/etiology/drug therapy/prevention &amp; control ; Mice ; *Oxidative Stress/drug effects ; Male ; *Hypoxia/complications/drug therapy/metabolism ; *Altitude ; Antioxidants/pharmacology/administration &amp; dosage ; Mice, Inbred C57BL ; Administration, Oral ; Hippocampus/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Brain/drug effects/metabolism ; }, abstract = {Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.}, }
@article {pmid39362568, year = {2024}, author = {Velasquez, E and Savchenko, E and Marmolejo-Martínez-Artesero, S and Challuau, D and Aebi, A and Pomeshchik, Y and Lamas, NJ and Vihinen, M and Rezeli, M and Schneider, B and Raoul, C and Roybon, L}, title = {TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106687}, doi = {10.1016/j.nbd.2024.106687}, pmid = {39362568}, issn = {1095-953X}, mesh = {*Astrocytes/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; Mice ; *Tumor Necrosis Factor-alpha/metabolism ; *Fibroblast Growth Factor 4/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; Superoxide Dismutase-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Spinal Cord/metabolism/pathology ; }, abstract = {Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1[G93A] mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.}, }
@article {pmid39361871, year = {2025}, author = {Fernandes, JPM and Garcia, LP and Gouhie, FA and Pereira, RC and Santos, DFD}, title = {Association between motor neuron disease and HIV infection: A systematic review of case reports.}, journal = {International journal of STD &amp; AIDS}, volume = {36}, number = {1}, pages = {24-35}, doi = {10.1177/09564624241288283}, pmid = {39361871}, issn = {1758-1052}, mesh = {Humans ; *HIV Infections/drug therapy/complications ; *Motor Neuron Disease/complications ; Adult ; Male ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; Female ; Middle Aged ; Riluzole/therapeutic use ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a well-known group of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most common form. Since 1985, a possible association between MND/ALS and HIV infection has been described.<br><br>METHODS: We performed a systematic review of case reports and case series involving people living with HIV with MND/ALS through PubMed, Bireme, Embase, and Lilacs databases. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Case Reports.<br><br>RESULTS: We analyzed 36 articles presenting 88 cases. The mean age was 41.6&#xa0;years. Antiretroviral therapy (ART) was used by 89.8% and riluzole by 16.9%. First signs and symptoms were similarly present on cervical/upper (25%) and lumbosacral/lower limbs (23.9%), mostly with fasciculations (69.8%) and hyperreflexia (58.8%). MND had a progressive course in 32.9% patients and a clinical improve in 54.6% following ART. The mean survival of the 32 patients who died was 12.3&#xa0;months and the mean survival of the living patients was 62&#xa0;months. Respiratory failure was the main cause of death (35.7%).<br><br>CONCLUSIONS: MND/ALS may present differently in the people living with HIV as a rapidly progressive disease in younger people but with the potential to improve weakness and survival through antiretroviral therapy.}, }
@article {pmid39361759, year = {2024}, author = {Wilkins, OG and Chien, MZYJ and Wlaschin, JJ and Barattucci, S and Harley, P and Mattedi, F and Mehta, PR and Pisliakova, M and Ryadnov, E and Keuss, MJ and Thompson, D and Digby, H and Knez, L and Simkin, RL and Diaz, JA and Zanovello, M and Brown, AL and Darbey, A and Karda, R and Fisher, EMC and Cunningham, TJ and Le Pichon, CE and Ule, J and Fratta, P}, title = {Creation of de novo cryptic splicing for ALS and FTD precision medicine.}, journal = {Science (New York, N.Y.)}, volume = {386}, number = {6717}, pages = {61-69}, pmid = {39361759}, issn = {1095-9203}, support = {MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; CC0102/ARC_/Arthritis Research UK/United Kingdom ; 215593/WT_/Wellcome Trust/United Kingdom ; CC0102/CRUK_/Cancer Research UK/United Kingdom ; CC0102/MRC_/Medical Research Council/United Kingdom ; ZIA HD008966/ImNIH/Intramural NIH HHS/United States ; CC0102/WT_/Wellcome Trust/United Kingdom ; U54 NS123743/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; Deep Learning ; *DNA-Binding Proteins/genetics/metabolism ; *Frontotemporal Dementia/genetics/therapy ; Gene Editing ; HEK293 Cells ; *Precision Medicine ; RNA Splice Sites ; *RNA Splicing ; RNA-Binding Proteins/metabolism/genetics ; }, abstract = {Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design to generate customizable cryptic splicing events within protein-coding sequences. We demonstrate that expression of TDP-REG reporters is tightly coupled to TDP-LOF in vitro and in vivo. TDP-REG enables genomic prime editing to ablate the UNC13A cryptic donor splice site specifically upon TDP-LOF. Finally, we design TDP-REG vectors encoding a TDP-43/Raver1 fusion protein that rescues key pathological cryptic splicing events, paving the way for the development of precision therapies for TDP43-related disorders.}, }
@article {pmid39360635, year = {2024}, author = {Abbassi, Y and Cappelli, S and Spagnolo, E and Gennari, A and Visani, G and Barattucci, S and Paron, F and Stuani, C and Droppelmann, CA and Strong, MJ and Buratti, E}, title = {Axon guidance genes are regulated by TDP-43 and RGNEF through long-intron removal.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {38}, number = {19}, pages = {e70081}, doi = {10.1096/fj.202400743RR}, pmid = {39360635}, issn = {1530-6860}, support = {//Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA)/ ; //Temetry Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/genetics ; Humans ; Introns ; Guanine Nucleotide Exchange Factors/metabolism/genetics ; Animals ; Axon Guidance/genetics ; Motor Neurons/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Gene Expression Regulation ; }, abstract = {Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons.}, }
@article {pmid39360554, year = {2025}, author = {Quigley, S and McNamara, B and Cronin, S}, title = {Alteration in ornithine metabolism due to mutation in ALDH18A1 masquerading as ALS in pregnancy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {172-174}, doi = {10.1080/21678421.2024.2410982}, pmid = {39360554}, issn = {2167-9223}, mesh = {Humans ; Female ; Pregnancy ; Adult ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Ornithine/blood ; *Mutation/genetics ; Aldehyde Dehydrogenase/genetics ; Pregnancy Complications/genetics/diagnosis ; Spastic Paraplegia, Hereditary/genetics/diagnosis ; Diagnosis, Differential ; }, abstract = {Clinical onset and exacerbation of autosomal dominant SPG9A hereditary spastic paraplegia, including reversible wasting, has been described during pregnancy. SPG9A is due to ALDH18A1 mutations resulting in proline and ornithine deficiency. We present the case of a 29 year old primagravida at 32 weeks who presented with six months of upper limb amyotrophic wasting on a background unrecognized progressive spasticity due to SPG9A. The wasting reversed significantly following delivery. Our report highlights the unusual clinical features including cataract and joint laxity which may suggest SPG9A, echoes the existing descriptions of pregnancy-related provocation of amyotrophy in this condition and documents the outcome of two subsequent pregnancies following dietary intervention.}, }
@article {pmid39360074, year = {2024}, author = {Puri, SN and Raghuveer, R and Jachak, S and Tikhile, P}, title = {Exploring the Impact of Personalized Physical Therapy on a Patient With Motor Neuron Disorder: A Case Study.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68373}, pmid = {39360074}, issn = {2168-8184}, abstract = {This case study examines the effect of a tailor-made physiotherapy regimen on an 85-year-old male patient who was suffering from bulbar motor neuron disease (MND) and had a history of stroke and COVID-19. The physiotherapy plan was designed to strategically address the patient's respiratory issues, generalized weakness affecting limb muscles, and speech and swallowing difficulties. Frequent evaluations made it possible to adjust the treatment plan, emphasizing a holistic strategy to improve the patient's overall quality of life. Improvements in scores on multiple functional scales and manual muscle testing were shown by outcome measures and follow-up evaluations. This case emphasizes how important customized physiotherapy is for maximizing functional outcomes and enhancing the quality of life for patients dealing with the complicated conditions of bulbar MND.}, }
@article {pmid39359088, year = {2025}, author = {Kim, K}, title = {Carboplatin restores neuronal toxicity in FUS-linked amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {8}, pages = {2319-2320}, pmid = {39359088}, issn = {1673-5374}, }
@article {pmid39353548, year = {2025}, author = {Bosco, DB and Kremen, V and Haruwaka, K and Zhao, S and Wang, L and Ebner, BA and Zheng, J and Xie, M and Dheer, A and Perry, JF and Barath, A and Nguyen, AT and Worrell, GA and Wu, LJ}, title = {Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus.}, journal = {Brain, behavior, and immunity}, volume = {123}, number = {}, pages = {540-555}, pmid = {39353548}, issn = {1090-2139}, support = {R01 NS088627/NS/NINDS NIH HHS/United States ; R01 NS112144/NS/NINDS NIH HHS/United States ; R35 NS132326/NS/NINDS NIH HHS/United States ; }, mesh = {*Receptors, Immunologic/metabolism/genetics ; Animals ; *Status Epilepticus/metabolism/genetics ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Mice, Knockout ; Male ; *Phagocytosis/physiology/genetics ; Mice ; *Neurons/metabolism ; Humans ; Disease Models, Animal ; Kainic Acid ; Mice, Inbred C57BL ; Epilepsy, Temporal Lobe/metabolism/genetics ; Seizures/metabolism/genetics ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; }, abstract = {In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.}, }
@article {pmid39355693, year = {2024}, author = {Leger, D and Bater, S and Paulin, MV and Linn, K and Taylor, S and Shelton, GD}, title = {Presumptive motor neuron degeneration in an adult cat.}, journal = {The Canadian veterinary journal = La revue veterinaire canadienne}, volume = {65}, number = {10}, pages = {1034-1040}, pmid = {39355693}, issn = {0008-5286}, mesh = {Cats ; Male ; Animals ; *Cat Diseases/pathology/diagnosis/drug therapy ; *Motor Neuron Disease/veterinary/pathology/diagnosis ; Prednisolone/therapeutic use ; Immunosuppressive Agents/therapeutic use ; Motor Neurons/pathology ; Muscular Atrophy/veterinary/pathology ; Muscle, Skeletal/pathology ; }, abstract = {An 8-year-old neutered male Bengal cat was referred because of a 1-year history of progressive and relapsing generalized muscle weakness and muscle atrophy. Before referral, the cat was treated with immunosuppressive doses of oral prednisolone, intermittently for 6 mo, and had responded well when the immunosuppressive dose was maintained. Generalized paresis, diffuse muscle atrophy, and diminished spinal reflexes were present in all limbs, consistent with a generalized lower motor neuron disease. Histopathologic evaluation of muscle biopsies confirmed a pattern of muscle fiber atrophy consistent with chronic and severe denervation. No specific abnormalities were identified in the nerve biopsy or within intramuscular nerve branches. A presumptive antemortem diagnosis of an adult-onset motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS) or spinal muscle atrophy was suspected. However, given the response to immunosuppressive doses of corticosteroids, an autoimmune process or other degenerative process could not be definitively excluded. Key clinical message: In this case, an adult cat had a chronic, progressive history of lower motor neuron weakness and absent spinal reflexes; biopsies revealed a neurogenic pattern of muscle fiber atrophy and histologically normal peripheral nerve and intramuscular nerve branches. Although reports of motor neuron disease are rare in the veterinary literature, this case report highlights the importance of muscle and nerve biopsies that lead to a presumptive diagnosis of motor neuron degeneration.}, }
@article {pmid39355247, year = {2024}, author = {Yang, JL and Wu, JY and Liu, JJ and Zheng, GQ}, title = {Herbal medicines for SOD1[G93A] mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1433929}, pmid = {39355247}, issn = {1664-3224}, mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/immunology/genetics ; Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; Humans ; Superoxide Dismutase-1/genetics ; Herbal Medicine ; }, abstract = {Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.}, }
@article {pmid39352715, year = {2024}, author = {Sung, SF and Hu, YH and Chen, CY}, title = {Disambiguating Clinical Abbreviations by One-to-All Classification: Algorithm Development and Validation Study.}, journal = {JMIR medical informatics}, volume = {12}, number = {}, pages = {e56955}, pmid = {39352715}, issn = {2291-9694}, mesh = {*Natural Language Processing ; *Electronic Health Records ; Humans ; *Algorithms ; *Abbreviations as Topic ; }, abstract = {BACKGROUND: Electronic medical records store extensive patient data and serve as a comprehensive repository, including textual medical records like surgical and imaging reports. Their utility in clinical decision support systems is substantial, but the widespread use of ambiguous and unstandardized abbreviations in clinical documents poses challenges for natural language processing in clinical decision support systems. Efficient abbreviation disambiguation methods are needed for effective information extraction.<br><br>OBJECTIVE: This study aims to enhance the one-to-all (OTA) framework for clinical abbreviation expansion, which uses a single model to predict multiple abbreviation meanings. The objective is to improve OTA by developing context-candidate pairs and optimizing word embeddings in Bidirectional Encoder Representations From Transformers (BERT), evaluating the model's efficacy in expanding clinical abbreviations using real data.<br><br>METHODS: Three datasets were used: Medical Subject Headings Word Sense Disambiguation, University of Minnesota, and Chia-Yi Christian Hospital from Ditmanson Medical Foundation Chia-Yi Christian Hospital. Texts containing polysemous abbreviations were preprocessed and formatted for BERT. The study involved fine-tuning pretrained models, ClinicalBERT and BlueBERT, generating dataset pairs for training and testing based on Huang et al's method.<br><br>RESULTS: BlueBERT achieved macro- and microaccuracies of 95.41% and 95.16%, respectively, on the Medical Subject Headings Word Sense Disambiguation dataset. It improved macroaccuracy by 0.54%-1.53% compared to two baselines, long short-term memory and deepBioWSD with random embedding. On the University of Minnesota dataset, BlueBERT recorded macro- and microaccuracies of 98.40% and 98.22%, respectively. Against the baselines of Word2Vec + support vector machine and BioWordVec + support vector machine, BlueBERT demonstrated a macroaccuracy improvement of 2.61%-4.13%.<br><br>CONCLUSIONS: This research preliminarily validated the effectiveness of the OTA method for abbreviation disambiguation in medical texts, demonstrating the potential to enhance both clinical staff efficiency and research effectiveness.}, }
@article {pmid39352708, year = {2024}, author = {Crose, JJ and Crose, A and Ransom, JT and Lightner, AL}, title = {Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {3-4}, pages = {111-117}, pmid = {39352708}, issn = {1758-2032}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; *Extracellular Vesicles ; Male ; Middle Aged ; Female ; Pilot Projects ; Aged ; Mesenchymal Stem Cells ; Mesenchymal Stem Cell Transplantation/methods ; Infusions, Intravenous ; Adult ; Treatment Outcome ; }, abstract = {Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenous infusions of the IP given 1 month apart and evaluated over 3 months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.}, }
@article {pmid39351695, year = {2024}, author = {Wang, PS and Yang, XX and Wei, Q and Lv, YT and Wu, ZY and Li, HF}, title = {Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2407522}, pmid = {39351695}, issn = {1365-2060}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; *Amyotrophic Lateral Sclerosis/genetics ; China/epidemiology ; East Asian People ; Exome Sequencing ; *Founder Effect ; Genetic Association Studies ; Haplotypes ; Mutation ; Phenotype ; *Superoxide Dismutase-1/genetics ; }, abstract = {OBJECTIVE: In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1. This study aimed to summarize the genotype-phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor.<br><br>METHODS: A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members.<br><br>RESULTS: A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2-5&#xa0;years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1[V48A] fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder.<br><br>CONCLUSIONS: Our study expanded the understanding of the genotype-phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.}, }
@article {pmid39351260, year = {2024}, author = {Gao, FQ and Zhu, JQ and Feng, XD}, title = {Innovative mesenchymal stem cell treatments for fatty liver disease.}, journal = {World journal of stem cells}, volume = {16}, number = {9}, pages = {846-853}, pmid = {39351260}, issn = {1948-0210}, abstract = {The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.}, }
@article {pmid39350404, year = {2025}, author = {Mohan, M and Mannan, A and Kakkar, C and Singh, TG}, title = {Nrf2 and Ferroptosis: Exploring Translational Avenues for Therapeutic Approaches to Neurological Diseases.}, journal = {Current drug targets}, volume = {26}, number = {1}, pages = {33-58}, pmid = {39350404}, issn = {1873-5592}, mesh = {Humans ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Reactive Oxygen Species/metabolism ; Translational Research, Biomedical ; Iron/metabolism ; }, abstract = {Nrf2, a crucial protein involved in defense mechanisms, particularly oxidative stress, plays a significant role in neurological diseases (NDs) by reducing oxidative stress and inflammation. NDs, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, stroke, epilepsy, schizophrenia, depression, and autism, exhibit ferroptosis, iron-dependent regulated cell death resulting from lipid and iron-dependent reactive oxygen species (ROS) accumulation. Nrf2 has been shown to play a critical role in regulating ferroptosis in NDs. Age-related decline in Nrf2 expression and its target genes (HO-1, Nqo-1, and Trx) coincides with increased iron-mediated cell death, leading to ND onset. The modulation of iron-dependent cell death and ferroptosis by Nrf2 through various cellular and molecular mechanisms offers a potential therapeutic pathway for understanding the pathological processes underlying these NDs. This review emphasizes the mechanistic role of Nrf2 and ferroptosis in multiple NDs, providing valuable insights for future research and therapeutic approaches.}, }
@article {pmid39349916, year = {2025}, author = {Soliman, R and Onbool, E and Omran, K and Fahmy, N}, title = {Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {3}, pages = {1225-1236}, pmid = {39349916}, issn = {1590-3478}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/genetics/diagnosis ; Male ; Female ; Egypt/epidemiology ; Adult ; Middle Aged ; Age of Onset ; Prospective Studies ; Disease Progression ; Cohort Studies ; }, abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons. It is a growing and underestimated disease, prompting this epidemiological study to describe the characteristics of ALS in Egyptian patients.<br><br>METHODS: This is a prospective hospital based study. ALS patients were recruited consecutively from Neuromuscular Unit in Ain Shams university Hospital from December 2018 to June 2023. Demographic data and disease related parameters were recorded.<br><br>RESULTS: 203 ALS patients had a mean age of onset equal 39&#xa0;years and an inter quartile range IQR of (28.00-51.00). 76% of the cases were spinal onset ALS. Median disease duration was 2&#xa0;years with IQR of (1-4&#xa0;years); male to female ratio was 2.5:1; 18% of patients were familial ALS (FALS), while 19% were Juvenile ALS (JALS). Median diagnostic delay was 12&#x2009;&#xb1;&#x2009;(6-36) months. Median Amyotrophic Lateral Sclerosis Functional Rating Scale Revised scores (ALSFRS-R) at presentation was 34.5 IQR of (26.00-40.00). Also, the mean rate of disease progression ALSFRS-R decline [points/month] was 0.76&#x2009;&#xb1;&#x2009;0.51.<br><br>CONCLUSION: Our cohort was characterized by a younger age of onset, male predominance, more familial cases, within average Initial ALSFRS-R scores as well as diagnostic delay. Juvenile ALS patients were much more common in our population. These findings suggest an influential presence of genetic and epigenetic factors affecting the clinical phenotype of Egyptian ALS patients.}, }
@article {pmid39349171, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Dupuy, C and Lefevre, A and Emond, P and Beltran, S and Gissot, V and Pisella, PJ and Blasco, H and Corcia, P}, title = {Metabolomics of basal tears in amyotrophic lateral sclerosis: A cross-sectional study.}, journal = {The ocular surface}, volume = {34}, number = {}, pages = {363-369}, doi = {10.1016/j.jtos.2024.09.005}, pmid = {39349171}, issn = {1937-5913}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/diagnosis ; Male ; Female ; Prospective Studies ; Middle Aged ; *Metabolomics/methods ; Cross-Sectional Studies ; Aged ; *Tears/metabolism ; Case-Control Studies ; Biomarkers/metabolism ; Chromatography, High Pressure Liquid ; Adult ; }, abstract = {PURPOSE: Amyotrophic lateral sclerosis (ALS) clinical variability, along with the lack of conclusive diagnostic instruments, result in average diagnosis delays of 9 months. This study aimed to assess whether metabolomic profiling of basal tears in ALS patients could act as a biological marker for diagnosing ALS, predicting prognosis, and discriminating between endophenotypes.<br><br>METHODS: A single-center prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. Two microliters of basal tears were collected using microcapillary glass tubes and analyzed with ultra-high performance liquid chromatography coupled with mass spectrometry. Both univariate and multivariate analyses were performed.<br><br>RESULTS: Twenty-five patients with ALS and 30 controls were included. No significant differences in metabolite levels were found between ALS and control groups (p&#xa0;>&#xa0;0.05). The basal tear metabolome significantly discriminated bulbar and spinal forms of ALS based on 6 metabolites, among which 5 were decreased (aniline, trigonelline, caffeine, theophylline and methyl beta-D-galactoside) in the bulbar form and 1 was decreased in the spinal form (dodecanedioic acid).<br><br>CONCLUSION: This study represents the first prospective analysis of basal tear metabolomics in individuals with ALS. Despite the inability to distinguish between ALS patients and controls based on metabolic signatures, these findings could contribute to understanding the phenotypic diversity of ALS. Notably, distinct metabolic profiles were identified that differentiate between the bulbar and spinal forms of the disease.}, }
@article {pmid39349054, year = {2025}, author = {Simpson, JT and Nordham, KD and Tatum, D and Haut, ER and Ali, A and Maher, Z and Goldberg, AJ and Tatebe, LC and Chang, G and Taghavi, S and Raza, S and Toraih, E and Mendiola Plá, M and Ninokawa, S and Anderson, C and Maluso, P and Keating, J and Burruss, S and Reeves, M and Craugh, LE and Shatz, DV and Bhupathi, A and Spalding, MC and LaRiccia, A and Bird, E and Noorbakhsh, MR and Babowice, J and Nelson, MC and Jacobson, LE and Williams, J and Vella, M and Dellonte, K and Hayward, TZ and Holler, E and Lieser, MJ and Berne, JD and Mederos, DR and Askari, R and Okafor, B and Etchill, E and Fang, R and Roche, SL and Whittenburg, L and Bernard, AC and Haan, JM and Lightwine, KL and Norwood, SH and Murry, J and Gamber, MA and Carrick, MM and Bugaev, N and Tatar, A}, title = {Stop the Bleed-Wait for the Ambulance or Get in the Car and Drive? A Post Hoc Analysis of an EAST Multicenter Trial.}, journal = {The American surgeon}, volume = {91}, number = {2}, pages = {233-241}, doi = {10.1177/00031348241265135}, pmid = {39349054}, issn = {1555-9823}, mesh = {Humans ; Male ; Female ; Adult ; *Ambulances ; Emergency Medical Services ; Wounds, Penetrating/mortality/therapy ; Middle Aged ; Hemorrhage/therapy/mortality ; Trauma Centers ; Propensity Score ; Transportation of Patients ; }, abstract = {Background: The Stop the Bleed campaign gives bystanders an active role in prehospital hemorrhage control. Whether extending bystanders' role to private vehicle transport (PVT) for urban penetrating trauma improves survival is unknown, but past research has found benefit to police and PVT. We hypothesized that for penetrating trauma in an urban environment, where prehospital procedures have been proven harmful, PVT improves outcomes compared to any EMS or advanced life support (ALS) transport.Methods: Post-hoc analysis of an EAST multicenter trial was performed on adult patients with penetrating torso/proximal extremity trauma at 25 urban trauma centers from 5/2019-5/2020. Patients were allocated to PVT and any EMS or ALS transport using nearest neighbor propensity score matching. Univariate analyses included Wilcoxon signed rank or McNemar's Test and logistic regression.Results: Of 1999 penetrating trauma patients in urban settings, 397 (19.9%) had PVT, 1433 (71.7%) ALS transport, and 169 (8.5%) basic life support (BLS) transport. Propensity matching yielded 778 patients, distributed equally into balanced groups. PVT patients were primarily male (90.5%), Black (71.2%), and sustained gunshot wounds (68.9%). ALS transport had significantly higher ED mortality (3.9% vs 1.9%, P = 0.03). There was no difference in in-hospital mortality rate, hospital LOS, or complications for all EMS or ALS only transport patients.Conclusion: Compared to PVT, ALS, which provides more prehospital procedures than BLS, provided no survival benefit for penetrating trauma patients in urban settings. Bystander education incorporating PVT for early arrival of penetrating trauma patients in urban settings to definitive care merits further investigation.}, }
@article {pmid39347895, year = {2025}, author = {Yin, KF and Chen, T and Gu, XJ and Jiang, Z and Su, WM and Duan, QQ and Wen, XJ and Cao, B and Li, JR and Chi, LY and Chen, YP}, title = {Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.}, journal = {Molecular neurobiology}, volume = {62}, number = {3}, pages = {3892-3902}, pmid = {39347895}, issn = {1559-1182}, support = {2022NSFSC0749//National Natural Science Fund of Sichuan/ ; 2023HXFH032//1&#xb7;3&#xb7;5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University/ ; 2022YFC2703101//National Key Research and Development Program of China/ ; 2023YFS0269//Science and Technology Bureau Fund of Sichuan Province/ ; 81971188//National Natural Science Fund of China/ ; C2023124417//National Innovation and Entrepreneurship Training Program for College Students/ ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; *Mitochondria/genetics/metabolism ; *Neurodegenerative Diseases/genetics ; *Quantitative Trait Loci/genetics ; *Bayes Theorem ; Genetic Predisposition to Disease ; DNA, Mitochondrial/genetics ; }, abstract = {Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.}, }
@article {pmid39347334, year = {2024}, author = {Aljehani, NS and Al-Gunaid, ST and Hobani, AH and Alhinti, MF and Khubrani, YA and Abu-Hamoud, LM and Alrayes, AA and Alharbi, LB and Sultan, AA and Turkistani, DA and Naiser, SS and Albraik, L and Alakel, AM and Alotaibi, M and Asiri, AY}, title = {Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e68008}, pmid = {39347334}, issn = {2168-8184}, abstract = {The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.}, }
@article {pmid39346793, year = {2024}, author = {Ghaderi, S and Mohammadi, S and Fatehi, F}, title = {Calcium accumulation or iron deposition: Delving into the temporal sequence of amyotrophic lateral sclerosis pathophysiology in the primary motor cortex.}, journal = {Ibrain}, volume = {10}, number = {3}, pages = {375-377}, pmid = {39346793}, issn = {2769-2795}, abstract = {Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, but an in vivo understanding of its early pathology remains limited. A recent study used topographic layer imaging to investigate iron and calcium accumulation in the primary motor cortex (M1) of patients with ALS compared with controls. Despite the preserved cortical thickness, ALS patients showed increased iron in layer 6 and calcium accumulation in layer 5a and the superficial layer. Calcium accumulation was particularly prominent in the low-myelin borders, potentially preceding the demyelination. This study reveals a novel in vivo pathology in ALS, suggesting that calcium dysregulation may precede iron accumulation and contribute to early M1 cell degeneration. Further investigation using quantitative susceptibility mapping and complementary techniques, such as diffusion kurtosis imaging, along with ultrahigh-field magnetic resonance imaging, into the role of calcium and early intervention strategies is warranted.}, }
@article {pmid39346681, year = {2024}, author = {Fisher, RMA and Torrente, MP}, title = {Histone post-translational modification and heterochromatin alterations in neurodegeneration: revealing novel disease pathways and potential therapeutics.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1456052}, pmid = {39346681}, issn = {1662-5099}, support = {R15 NS125394/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD), and Amyotrophic lateral sclerosis (ALS) are complex and fatal neurodegenerative diseases. While current treatments for these diseases do alleviate some symptoms, there is an imperative need for novel treatments able to stop their progression. For all of these ailments, most cases occur sporadically and have no known genetic cause. Only a small percentage of patients bear known mutations which occur in a multitude of genes. Hence, it is clear that genetic factors alone do not explain disease occurrence. Chromatin, a DNA-histone complex whose basic unit is the nucleosome, is divided into euchromatin, an open form accessible to the transcriptional machinery, and heterochromatin, which is closed and transcriptionally inactive. Protruding out of the nucleosome, histone tails undergo post-translational modifications (PTMs) including methylation, acetylation, and phosphorylation which occur at specific residues and are connected to different chromatin structural states and regulate access to transcriptional machinery. Epigenetic mechanisms, including histone PTMs and changes in chromatin structure, could help explain neurodegenerative disease processes and illuminate novel treatment targets. Recent research has revealed that changes in histone PTMs and heterochromatin loss or gain are connected to neurodegeneration. Here, we review evidence for epigenetic changes occurring in AD, PD, and FTD/ALS. We focus specifically on alterations in the histone PTMs landscape, changes in the expression of histone modifying enzymes and chromatin remodelers as well as the consequences of these changes in heterochromatin structure. We also highlight the potential for epigenetic therapies in neurodegenerative disease treatment. Given their reversibility and pharmacological accessibility, epigenetic mechanisms provide a promising avenue for novel treatments. Altogether, these findings underscore the need for thorough characterization of epigenetic mechanisms and chromatin structure in neurodegeneration.}, }
@article {pmid39345637, year = {2024}, author = {Morgan, KJ and Carley, E and Coyne, AN and Rothstein, JD and Lusk, CP and King, MC}, title = {Visualizing nuclear pore complex plasticity with Pan-Expansion Microscopy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345637}, issn = {2692-8205}, support = {F31 HL158119/HL/NHLBI NIH HHS/United States ; R01 GM129308/GM/NIGMS NIH HHS/United States ; R01 NS122236/NS/NINDS NIH HHS/United States ; R21 AR081661/AR/NIAMS NIH HHS/United States ; }, abstract = {Cell-type specific and environmentally-responsive plasticity in nuclear pore complex (NPC) composition and structure is an emerging area of investigation, but its molecular underpinnings remain ill defined. To understand the cause and consequence of NPC plasticity requires technologies to visualize differences within individual NPCs across the thousands in a given nucleus. We evaluate the utility of Pan Expansion Microscopy (Pan-ExM), which enables 16-20 fold isotropic cell enlargement while preserving the proteome, to reveal NPC plasticity. NPCs are robustly identified by deep learning-facilitated segmentation as tripartite structures corresponding to the nucleoplasmic ring, inner ring with central transport channel, and cytoplasmic ring, as confirmed by immunostaining. We demonstrate a range of NPC diameters with a bias for dilated NPCs at the basal nuclear surface, often in local clusters. These diameter biases are eliminated by disrupting linker of nucleoskeleton and cytoskeleton (LINC) complex-dependent connections between the nuclear envelope (NE) and the cytoskeleton, supporting that they reflect local variations in NE tension. Pan-ExM further reveals that the transmembrane nucleoporin/nup POM121 resides specifically at the nuclear ring in multiple model cell lines, surprising given the expectation that it would be a component of the inner ring like other transmembrane nups. Remarkably, however, POM121 shifts from the nuclear ring to the inner ring specifically in aged induced pluripotent stem cell derived neurons (iPSNs) from a patient with C9orf72 amyotrophic lateral sclerosis (ALS). Thus, Pan-ExM allows the visualization of changes in NPC architecture that may underlie early steps in an ALS pathomechanism. Taken together, Pan-ExM is a powerful and accessible tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.}, }
@article {pmid39345438, year = {2024}, author = {Elsayyid, M and Tanis, JE and Yu, Y}, title = {In-cell processing enables rapid and in-depth proteome analysis of low-input Caenorhabditis elegans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345438}, issn = {2692-8205}, support = {P20 GM104316/GM/NIGMS NIH HHS/United States ; R01 GM135433/GM/NIGMS NIH HHS/United States ; T32 GM133395/GM/NIGMS NIH HHS/United States ; }, abstract = {Caenorhabditis elegans is a widely used genetic model organism, however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming, but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach, which can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LCMS analysis, we identified over 9,400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it with conventional lysis-based methods. Our data suggest equivalent and unbiased performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower input samples, then used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD-1, a gene associated with amyotrophic lateral sclerosis (ALS). Analysis of 8,800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics analysis.}, }
@article {pmid39344431, year = {2025}, author = {Quail, NPA and Leighton, DJ and Newton, J and Davidson, S and Kelly, L and McKeown, A and Chandran, S and Pal, S and Gorrie, GH}, title = {Influences of Specialist Palliative Care Team Input, Advance Care Planning, Non-Invasive Ventilation and Gastrostomy Status on Unscheduled Hospital Admissions and Place of Death for People with Motor Neuron Disease: A Retrospective Cohort Analysis.}, journal = {Journal of palliative care}, volume = {40}, number = {1}, pages = {89-97}, doi = {10.1177/08258597241283179}, pmid = {39344431}, issn = {2369-5293}, mesh = {Humans ; Male ; *Motor Neuron Disease/therapy/mortality ; Female ; *Advance Care Planning/statistics &amp; numerical data ; Retrospective Studies ; Aged ; *Gastrostomy/statistics &amp; numerical data ; Middle Aged ; *Palliative Care/statistics &amp; numerical data ; *Noninvasive Ventilation/statistics &amp; numerical data ; Aged, 80 and over ; Scotland ; Cohort Studies ; Hospitalization/statistics &amp; numerical data ; Terminal Care/statistics &amp; numerical data ; Adult ; }, abstract = {Objective: Motor neuron disease is a rapidly progressing neurological condition. People with life-limiting conditions generally prefer to die at home and avoid hospital admissions, with Specialist Palliative Care Team involvement often pivotal. Our aim was to investigate the role of advance care planning, Specialist Palliative Care Team input and other relevant variables on place of death and unscheduled hospital admissions in a Scottish population of people with motor neuron disease. Methods: National CARE-MND audit data, primary and secondary care data, and local Palliative Care records were interrogated. Chi-square, point-biserial correlation and binary logistic regression analysed associations (p < 0.05 statistically significant). Participants (188) were deceased, having a verified motor neuron disease diagnosis between 2015-2017, diagnosis occurring ≥28 days before death. Results: Advance care planning and Specialist Palliative Care Team input of ≥28 days were associated with increased odds of dying outside hospital (BLR:OR 3.937, CI 1.558-9.948, p = 0.004 and OR 2.657, CI 1.135-6.222, p = 0.024 respectively). Non-invasive ventilation decreased the odds of dying outside hospital (BLR:OR 0.311, CI 0.124-0.781, p = 0.013). Having a gastrostomy increased odds of ≥1 admissions in the last year of life (BLR:OR 5.142, CI 1.715-15.417, p = 0.003). Statistical significance was retained with removal of gastrostomy-related complications. Conclusion: Early Specialist Palliative Care input and advance care planning may increase the likelihood of death outside of hospital for persons with motor neuron disease. Further research is warranted into barriers of facilitating death outside of hospital with home non-invasive ventilation use and the association between gastrostomy status and unscheduled admissions.}, }
@article {pmid39344228, year = {2024}, author = {Li, P and Tao, Z and Zhao, X}, title = {The Role of Osteopontin (OPN) in Regulating Microglia Phagocytosis in Nervous System Diseases.}, journal = {Journal of integrative neuroscience}, volume = {23}, number = {9}, pages = {169}, doi = {10.31083/j.jin2309169}, pmid = {39344228}, issn = {0219-6352}, mesh = {*Osteopontin/metabolism/physiology ; *Microglia/metabolism/physiology ; *Phagocytosis/physiology ; Animals ; Humans ; Nervous System Diseases/metabolism ; }, abstract = {Phagocytosis is the process by which certain cells or organelles internalise foreign substances by engulfing them and then digesting or disposing of them. Microglia are the main resident phagocytic cells in the brain. It is generally believed that microglia/macrophages play a role in guiding the brain's repair and functional recovery processes. However, the resident and invading immune cells of the central nervous system can also exacerbate tissue damage by stimulating inflammation and engulfing viable neurons. The functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon in acute brain injury because it eliminates dead cells and induces an anti-inflammatory response. Osteopontin (OPN) is a phosphorylated glycoprotein induced by injury in various tissues, including brain tissue. In acute brain injuries such as hemorrhagic stroke and ischemic stroke, OPN is generally believed to have anti-inflammatory effects. OPN can promote the reconstruction of the blood-brain barrier and up-regulate the scavenger receptor CD36. But in chronic diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), OPN can cause microglia to engulf neurons and worsen disease progression. We explored the role of OPN in promoting microglial phagocytosis in nervous system disorders.}, }
@article {pmid39344189, year = {2025}, author = {Khorshidi, Z and Adibi, I and Ghasemi, M}, title = {Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.}, journal = {Hormone molecular biology and clinical investigation}, volume = {46}, number = {1}, pages = {13-19}, pmid = {39344189}, issn = {1868-1891}, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Humans ; *Hexosaminidases/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; }, abstract = {INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder.<br><br>CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant).<br><br>SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.}, }
@article {pmid39343990, year = {2024}, author = {Xia, L and Qiu, Y and Li, J and Xu, M and Dong, Z}, title = {The Potential Role of Artemisinins Against Neurodegenerative Diseases.}, journal = {The American journal of Chinese medicine}, volume = {52}, number = {6}, pages = {1641-1660}, doi = {10.1142/S0192415X24500642}, pmid = {39343990}, issn = {1793-6853}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Artemisinins/pharmacology ; *Neuroprotective Agents/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Parkinson Disease/drug therapy/metabolism ; Ferroptosis/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Huntington Disease/drug therapy/metabolism ; Autophagy/drug effects ; }, abstract = {Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A[Formula: see text]-induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases.}, }
@article {pmid39343443, year = {2024}, author = {O'Brien, D and Shaw, PJ}, title = {New developments in the diagnosis and management of motor neuron disease.}, journal = {British medical bulletin}, volume = {152}, number = {1}, pages = {4-15}, doi = {10.1093/bmb/ldae010}, pmid = {39343443}, issn = {1471-8391}, support = {NIHR 203321//NIHR Sheffield Biomedical Research Centre/ ; 972-797//AMBRoSIA Biosampling Programme/ ; 764-780//MNDA (Sheffield Care and Research Centre for Motor Neuron Disorders/ ; }, mesh = {Humans ; *Motor Neuron Disease/therapy/diagnosis ; Neuroprotective Agents/therapeutic use ; Riluzole/therapeutic use ; }, abstract = {INTRODUCTION: Motor neuron disease (MND) is a devastating neurodegenerative disease characterized by progressive muscle weakness.<br><br>SOURCES OF DATA: PubMed, MEDLINE, and Cochrane databases were searched for articles to March 2024. Searches involved the terms 'motor neuron disease' or 'amyotrophic lateral sclerosis' and 'epidemiology', 'diagnosis', 'clinical', 'genetic', 'management', 'treatment', or 'trial'.<br><br>AREAS OF AGREEMENT: Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. Tofersen should be offered to treat SOD1-MND.<br><br>AREAS OF CONTROVERSY: Edaravone and Relyvrio are approved treatments in the USA, but insufficient evidence was found to support approval in the UK and Europe.<br><br>GROWING POINTS: The discovery of neurofilaments as MND biomarkers, growth of platform trials and development of novel therapies provide optimism for more powerful neuroprotective therapies.<br><br>Further work should focus on the elucidation of environmental causes of MND, gene-environment interactions, and advanced cellular models of disease.}, }
@article {pmid39342484, year = {2025}, author = {Deneubourg, C and Salimi Dafsari, H and Lowe, S and Martinez-Cotrina, A and Mazaud, D and Park, SH and Vergani, V and Almacellas Barbanoj, A and Maroofian, R and Averdunk, L and Ghayoor-Karimiani, E and Jayawant, S and Mignot, C and Keren, B and Peters, R and Kamath, A and Mattas, L and Verma, S and Silwal, A and Distelmaier, F and Houlden, H and Lignani, G and Antebi, A and Jepson, J and Jungbluth, H and Fanto, M}, title = {Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients.}, journal = {Autophagy}, volume = {21}, number = {2}, pages = {447-459}, pmid = {39342484}, issn = {1554-8635}, mesh = {Animals ; *Autophagy/physiology/genetics ; Humans ; *Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism/genetics ; *Epilepsy/genetics/metabolism/physiopathology/pathology ; Cataract/metabolism/pathology/genetics/physiopathology ; Male ; Mutation/genetics ; Vesicular Transport Proteins/metabolism/genetics ; Female ; Autophagy-Related Proteins/metabolism/genetics ; Disease Models, Animal ; Proteotoxic Stress ; Agenesis of Corpus Callosum ; }, abstract = {Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions.Abbreviations: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC: TSC complex; VS: Vici syndrome.}, }
@article {pmid39341837, year = {2024}, author = {Hollingworth, D and Thomas, F and Page, DA and Fouda, MA and De Castro, RL and Sula, A and Mykhaylyk, VB and Kelly, G and Ulmschneider, MB and Ruben, PC and Wallace, BA}, title = {Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8426}, pmid = {39341837}, issn = {2041-1723}, support = {BB/105581//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CC1078/ARC_/Arthritis Research UK/United Kingdom ; mutiple grants//Diamond Light Source/ ; /WT_/Wellcome Trust/United Kingdom ; BB/V0183511//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; CF2-100001//Rosetrees Trust/ ; BB/S017844//RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)/ ; studentship//Wellcome Trust (Wellcome)/ ; }, mesh = {*Riluzole/pharmacology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; Humans ; *Neuroprotective Agents/pharmacology ; Voltage-Gated Sodium Channels/metabolism/chemistry ; HEK293 Cells ; Animals ; Sodium/metabolism ; Motor Neurons/drug effects/metabolism ; }, abstract = {Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na[+] conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.}, }
@article {pmid39341656, year = {2024}, author = {Paris, A and Lakatos, A}, title = {Cell and gene therapy for amyotrophic lateral sclerosis.}, journal = {Handbook of clinical neurology}, volume = {205}, number = {}, pages = {217-241}, doi = {10.1016/B978-0-323-90120-8.00017-4}, pmid = {39341656}, issn = {0072-9752}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Animals ; Cell- and Tissue-Based Therapy/methods/trends ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disorder with rapidly progressive skeletal muscle weakness, which can also cause a variable cognitive deficit. Genetic causes are only identified in approximately 10% of all cases, with complex genotype-phenotype associations, making it challenging to identify treatment targets. What further hampers therapeutic development is a broad heterogeneity in mechanisms, possible targets, and disturbances across various cell types, aside from the cortical and spinal motor neurons that lie at the heart of the pathology of ALS. Over the last decade, significant progress in biotechnologic techniques, cell and ribonucleic acid (RNA) engineering, animal models, and patient-specific human stem cell and organoid models have accelerated both mechanistic and therapeutic discoveries. The growing number of clinical trials mirrors this. This chapter reviews the current state of human preclinical models supporting trial strategies as well as recent clinical cell and gene therapy approaches.}, }
@article {pmid39341507, year = {2024}, author = {Sivalingam, AM}, title = {Advances in understanding biomarkers and treating neurological diseases - Role of the cerebellar dysfunction and emerging therapies.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102519}, doi = {10.1016/j.arr.2024.102519}, pmid = {39341507}, issn = {1872-9649}, mesh = {Humans ; *Biomarkers/metabolism ; Animals ; *Cerebellar Diseases/therapy/diagnosis/metabolism/genetics ; Genetic Therapy/methods/trends ; Nervous System Diseases/therapy/diagnosis/metabolism ; Cerebellum/metabolism/pathology ; }, abstract = {Cerebellar dysfunction is increasingly recognized as a critical factor in various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Research has revealed distinct cerebellar atrophy patterns in conditions such as AD and multiple system atrophy, and studies in mice have highlighted its impact on motor control and cognitive functions. Emerging research into autism spectrum disorder (ASD) has identified key targets, such as elevated levels of chemokine receptors and ZIC family genes. Biomarkers, including cerebrospinal fluid (CSF), genetic markers, and advances in AI and bioinformatics, are enhancing early diagnosis and personalized treatment across neurodegenerative disorders. Notable advancements include improved diagnostic tools, gene therapy, and novel clinical trials. Despite progress, challenges such as the bloodbrain barrier and neuroinflammation persist. Current therapies for AD, PD, HD, and ALS, including antisense oligonucleotides and stem cell treatments, show promise but require further investigation. A comprehensive approach that integrates diagnostic methods and innovative therapies is essential for effective management and improved patient outcomes.}, }
@article {pmid39340928, year = {2024}, author = {Dahl, R and Bezprozvanny, I}, title = {SERCA pump as a novel therapeutic target for treating neurodegenerative disorders.}, journal = {Biochemical and biophysical research communications}, volume = {734}, number = {}, pages = {150748}, doi = {10.1016/j.bbrc.2024.150748}, pmid = {39340928}, issn = {1090-2104}, support = {R01 AG071310/AG/NIA NIH HHS/United States ; R56 AG078337/AG/NIA NIH HHS/United States ; R42 AG062001/AG/NIA NIH HHS/United States ; }, mesh = {*Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Humans ; Animals ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Molecular Targeted Therapy/methods ; *Neuroprotective Agents/pharmacology/therapeutic use ; Calcium Signaling/drug effects ; Calcium/metabolism ; }, abstract = {The neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Despite intense research into the causes of these disorders, only marginal progress has been made in the clinic and no cures exist for any of them. Most of the scientific effort has been focused on identification of the major causes of these diseases and on developing ways to target them, such as targeting amyloid accumulation for AD or targeting expression of mutant Huntingtin for HD. Calcium (Ca[2+]) signaling has long been proposed to play an important role in the pathogenesis of neurodegenerative disorders, but blockers of Ca[2+] channels and Ca[2+] signaling proteins have not been translated to clinic primarily due to side effects related to the important roles of target molecules for these compounds at the peripheral tissues. In this review article, we would like to discuss an idea that recently identified positive allosteric modulators (PAMs) of the sarco-endoplasmic reticulum calcium (SERCA) pump may provide a promising approach to develop therapeutic compounds for treatment of these disorders. This hypothesis is supported by the preclinical data obtained with animal models of AD and PD. The first critical test of this idea will be an imminent phase I study that will offer an opportunity to evaluate potential side effects of this class of compounds in humans.}, }
@article {pmid39340874, year = {2024}, author = {Xiong, Z and Zeng, Q and Hu, Y and Lai, C and Wu, H}, title = {Optineurin inhibits IBDV replication via interacting with VP1.}, journal = {Veterinary microbiology}, volume = {298}, number = {}, pages = {110261}, doi = {10.1016/j.vetmic.2024.110261}, pmid = {39340874}, issn = {1873-2542}, mesh = {*Virus Replication ; Animals ; *Infectious bursal disease virus/physiology ; *Chickens ; Membrane Transport Proteins/metabolism/genetics ; Cell Cycle Proteins/metabolism/genetics ; Poultry Diseases/virology ; Humans ; Ubiquitination ; Birnaviridae Infections/veterinary/virology ; Cell Line ; Capsid Proteins/metabolism/genetics ; Transcription Factor TFIIIA/metabolism/genetics ; HEK293 Cells ; }, abstract = {Avibirnavirus, specifically Infectious Bursal Disease Virus (IBDV), is a highly contagious pathogen that causes significant economic losses in the poultry industry. The polymerase protein VP1 of IBDV is critical to the viral life cycle, facilitating the synthesis of viral mRNA and the genome. Previous studies have suggested that various host factors influence the regulation of IBDV polymerase activity. In this study, we identified that IBDV infection induces the expression of optineurin (OPTN), a mitophagy receptor and a protein associated with amyotrophic lateral sclerosis (ALS), as well as a negative regulator of interferon I production. The induced expression of OPTN acts as a suppressor of IBDV replication, a function dependent on its ubiquitin-binding domain (UBAN). Furthermore, we demonstrated that OPTN exerts its antiviral effects through direct interactions with VP1 and VP3, which inhibit the polymerase activity of VP1 by preventing K63-linked ubiquitination of VP1. To our knowledge, this study is the first to report that OPTN, upregulated during IBDV infection, functions as a novel antiviral host factor that limits the virus's replicative capacity, offering a potential target for anti-IBDV therapeutic strategies.}, }
@article {pmid39340590, year = {2024}, author = {Ghiasvand, K and Amirfazli, M and Moghimi, P and Safari, F and Takhshid, MA}, title = {The role of neuron-like cell lines and primary neuron cell models in unraveling the complexity of neurodegenerative diseases: a comprehensive review.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1024}, doi = {10.1007/s11033-024-09964-x}, pmid = {39340590}, issn = {1573-4978}, mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Neurons/metabolism ; Animals ; Coculture Techniques/methods ; Cell Line ; Models, Biological ; Alzheimer Disease/pathology/genetics ; }, abstract = {Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons. As to developing effective therapeutic interventions, it is crucial to understand the underlying mechanisms of NDs. Cellular models have become invaluable tools for studying the complex pathogenesis of NDs, offering insights into disease mechanisms, determining potential therapeutic targets, and aiding in drug discovery. This review provides a comprehensive overview of various cellular models used in ND research, focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Cell lines, such as SH-SY5Y and PC12 cells, have emerged as valuable tools due to their ease of use, reproducibility, and scalability. Additionally, co-culture models, involving the growth of distinct cell types like neurons and astrocytes together, are highlighted for simulating brain interactions and microenvironment. While cell lines cannot fully replicate the complexity of the human brain, they provide a scalable method for examining important aspects of neurodegenerative diseases. Advancements in cell line technologies, including the incorporation of patient-specific genetic variants and improved co-culture models, hold promise for enhancing our understanding and expediting the development of effective treatments. Integrating multiple cellular models and advanced technologies offers the potential for significant progress in unraveling the intricacies of these debilitating diseases and improving patient outcomes.}, }
@article {pmid39340541, year = {2024}, author = {Gagliardi, D and Rizzuti, M and Masrori, P and Saccomanno, D and Del Bo, R and Sali, L and Meneri, M and Scarcella, S and Milone, I and Hersmus, N and Ratti, A and Ticozzi, N and Silani, V and Poesen, K and Van Damme, P and Comi, GP and Corti, S and Verde, F}, title = {Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7557-7571}, pmid = {39340541}, issn = {1432-1459}, support = {RF-2018-12366357//Ministero della Salute/ ; RF-2021-12374238//Ministero della Salute/ ; GR-2016-02364373//Ministero della Salute/ ; Ricerca corrente//Ministero della Salute/ ; C1//VIB, KU Leuven/ ; 'Opening the Future' Fund//VIB, KU Leuven/ ; FWO-Vlaanderen//Fund for Scientific Research Flanders/ ; T003519N//TBM grant from FWO-Vlaanderen/ ; G077121N//FWO-Vlaanderen/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis/genetics ; Female ; Male ; *Neurofilament Proteins/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Aged ; *MicroRNAs/cerebrospinal fluid ; Prognosis ; Adult ; Cohort Studies ; Disease Progression ; Aged, 80 and over ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b.}, }
@article {pmid39340452, year = {2024}, author = {Tchounwou, C and Jobanputra, AJ and Lasher, D and Fletcher, BJ and Jacinto, J and Bhaduri, A and Best, RL and Fisher, WS and Ewert, KK and Li, Y and Feinstein, SC and Safinya, CR}, title = {Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase-Separated Coacervates.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {40}, number = {40}, pages = {21041-21051}, doi = {10.1021/acs.langmuir.4c02471}, pmid = {39340452}, issn = {1520-5827}, mesh = {*tau Proteins/chemistry/metabolism ; *Liposomes/chemistry ; *Anions/chemistry ; Humans ; Phosphatidylcholines/chemistry ; Phosphatidylserines/chemistry ; Phosphatidylglycerols/chemistry ; Intrinsically Disordered Proteins/chemistry ; }, abstract = {Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein that binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full-length human protein tau and other negatively charged binding substrates, as revealed by differential interference contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase-separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes (i.e. tau-lipoplexes) exhibited distinct types of morphologies. This included large ∼20-30 μm tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles and tau-mediated finite-size assemblies of small liposomes. As the salt concentration was increased to near and above 150 mM for 1:1 electrolytes, AL-tau complexes remained stable, while tau self-coacervate droplets were found to dissolve, indicative of the breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen-facing monolayer of the axon's plasma membrane, suggesting the possibility of transient yet robust interactions near relevant ionic strengths found in neurons.}, }
@article {pmid39340290, year = {2025}, author = {Alves, I and Gromicho, M and Oliveira Santos, M and Pinto, S and de Carvalho, M}, title = {Assessing disease progression in ALS: prognostic subgroups and outliers.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {58-63}, doi = {10.1080/21678421.2024.2407412}, pmid = {39340290}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/mortality/physiopathology ; *Disease Progression ; Male ; Female ; Middle Aged ; Prognosis ; Aged ; Adult ; Cohort Studies ; }, abstract = {BACKGROUND: The rate of disease progression, measured by the decline of ALS Functional Rating Scale-Revised (ALSFRS-R) from symptom onset to diagnosis (ΔFS) is a well-established prognostic biomarker for predicting survival. Objectives: This study aims to categorize a large patient cohort based on the initial ΔFS and subsequently investigate survival deviations from the expected prognosis defined by ΔFS.<br><br>METHODS: 1056 ALS patients were stratified into three progression categories based on their &#x394;FS: slow progressors (below 25th percentile), intermediate progressors (between 25th and 75th percentiles), and fast progressors (above 75th percentile). Survival outcomes were classified as short survivors (<2 years), average survivors (2-5 years), and long survivors (>5 years). Clinical and demographic characteristics within each subgroup were then analyzed.<br><br>RESULTS: &#x394;FS stratification yielded cutoff values of <0.29, 0.29-1.03, and >1.03 points/month. Long survivors comprised 26% and 21% were short survivors. Six percent of the fast progressors had a life expectancy of more than 5 years, and none of the clinical and demographic characteristics analyzed could fully explain this discrepancy. Conversely, 13% of intermediate progressors lived less than 2 years, according to a short-diagnostic delay in these patients.<br><br>DISCUSSION: Our study reaffirms &#x394;FS as a prognostic biomarker for ALS. We disclosed outliers defying anticipated patterns. The observed shift in progression categories underscores the non-linear nature of disease progression. Genetic and unknown biological reasons may explain these deviations. Further research is needed to fully understand modulation of ALS survival.}, }
@article {pmid39338620, year = {2024}, author = {Razzaq, Z and Brahimi, N and Rehman, HZU and Khan, ZH}, title = {Intelligent Control System for Brain-Controlled Mobile Robot Using Self-Learning Neuro-Fuzzy Approach.}, journal = {Sensors (Basel, Switzerland)}, volume = {24}, number = {18}, pages = {}, pmid = {39338620}, issn = {1424-8220}, mesh = {*Fuzzy Logic ; *Robotics/methods ; Humans ; *Brain-Computer Interfaces ; *Electroencephalography/methods ; Algorithms ; Brain/physiology ; Neural Networks, Computer ; Machine Learning ; }, abstract = {Brain-computer interface (BCI) provides direct communication and control between the human brain and physical devices. It is achieved by converting EEG signals into control commands. Such interfaces have significantly improved the lives of disabled individuals suffering from neurological disorders-such as stroke, amyotrophic lateral sclerosis (ALS), and spinal cord injury-by extending their movement range and thereby promoting self-independence. Brain-controlled mobile robots, however, often face challenges in safety and control performance due to the inherent limitations of BCIs. This paper proposes a shared control scheme for brain-controlled mobile robots by utilizing fuzzy logic to enhance safety, control performance, and robustness. The proposed scheme is developed by combining a self-learning neuro-fuzzy (SLNF) controller with an obstacle avoidance controller (OAC). The SLNF controller robustly tracks the user's intentions, and the OAC ensures the safety of the mobile robot following the BCI commands. Furthermore, SLNF is a model-free controller that can learn as well as update its parameters online, diminishing the effect of disturbances. The experimental results prove the efficacy and robustness of the proposed SLNF controller including a higher task completion rate of 94.29% (compared to 79.29%, and 92.86% for Direct BCI and Fuzzy-PID, respectively), a shorter average task completion time of 85.31 s (compared to 92.01 s and 86.16 s for Direct BCI and Fuzzy-PID, respectively), and reduced settling time and overshoot.}, }
@article {pmid39338563, year = {2024}, author = {Dow, CT and Pierce, ES and Sechi, LA}, title = {Mycobacterium paratuberculosis: A HERV Turn-On for Autoimmunity, Neurodegeneration, and Cancer?.}, journal = {Microorganisms}, volume = {12}, number = {9}, pages = {}, pmid = {39338563}, issn = {2076-2607}, abstract = {Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn's disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association.}, }
@article {pmid39337908, year = {2024}, author = {Wang, R and Chen, L and Zhang, Y and Sun, B and Liang, M}, title = {Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39337908}, issn = {2075-1729}, support = {YJXJ-JZ-2021-0014//Scientific Research Project of Beijing Yicheng Cooperative Development Foundation in 2021-Public welfare projects of rare disease related topics/ ; KM202310858001//R&amp;D Program of Beijing Municipal Education Commission/ ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.}, }
@article {pmid39337696, year = {2024}, author = {Niazi, SK}, title = {Bioavailability as Proof to Authorize the Clinical Testing of Neurodegenerative Drugs-Protocols and Advice for the FDA to Meet the ALS Act Vision.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337696}, issn = {1422-0067}, mesh = {Humans ; *United States Food and Drug Administration ; United States ; *Drug Approval ; *Biological Availability ; *Amyotrophic Lateral Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Clinical Trials as Topic ; }, abstract = {Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.}, }
@article {pmid39337560, year = {2024}, author = {Malaguarnera, M and Cabrera-Pastor, A}, title = {Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337560}, issn = {1422-0067}, support = {PI23/00204//Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educaci&#xf3;n/Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, subvenciones para la realizaci&#xf3;n de proyectos de I+D+i desarro/ ; CIGE/083//This research was funded by Instituto de Salud Carlos III (ISCIII) through the project "PI23/00204" and co-funded by the European Union; and Conselleria de Educaci&#xf3;n/Innovaci&#xf3;n, Universidades, Ciencia y Sociedad Digital, subvenciones para la realizaci&#xf3;n d/ ; }, mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/therapy/metabolism/diagnosis ; Animals ; Central Nervous System Diseases/metabolism/therapy/diagnosis ; Blood-Brain Barrier/metabolism ; }, abstract = {The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.}, }
@article {pmid39337454, year = {2024}, author = {Rizea, RE and Corlatescu, AD and Costin, HP and Dumitru, A and Ciurea, AV}, title = {Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337454}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/diagnosis/physiopathology/metabolism/genetics ; Humans ; Biomarkers ; Genetic Therapy/methods ; Oxidative Stress ; Animals ; Mitochondria/metabolism ; }, abstract = {This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well as emerging treatments. The purpose is to condense key findings and illustrate the complexity of ALS, which is shaped by both genetic and environmental influences. We reviewed the literature to discuss recent advancements in understanding molecular mechanisms such as protein misfolding, mitochondrial dysfunction, oxidative stress, and axonal transport defects, which are critical for identifying potential therapeutic targets. Significant progress has been made in refining diagnostic criteria and identifying biomarkers, leading to earlier and more precise diagnoses. Although current drug treatments provide some benefits, there is a clear need for more effective therapies. Emerging treatments, such as gene therapy and stem cell therapy, show potential in modifying disease progression and improving the quality of life for ALS patients. The review emphasizes the importance of continued research to address challenges such as disease variability and the limited effectiveness of existing treatments. Future research should concentrate on further exploring the molecular foundations of ALS and developing new therapeutic approaches. The implications for clinical practice include ensuring the accessibility of new treatments and that healthcare systems are equipped to support ongoing research and patient care.}, }
@article {pmid39337436, year = {2024}, author = {Guo, D and Liu, Z and Zhou, J and Ke, C and Li, D}, title = {Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337436}, issn = {1422-0067}, support = {2023Y9415//Joint Funds for the innovation of science and Technology, Fujian province/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Signal Transduction ; Animals ; *Apoptosis ; Ferroptosis ; Neurons/metabolism/pathology ; }, abstract = {Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases.}, }
@article {pmid39337251, year = {2024}, author = {Escudier, O and Zhang, Y and Whiting, A and Chazot, P}, title = {Evaluation of a Synthetic Retinoid, Ellorarxine, in the NSC-34 Cell Model of Motor Neuron Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337251}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; Retinoids/pharmacology ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Cell Line ; Humans ; Receptors, AMPA/metabolism ; Motor Neurons/drug effects/metabolism/pathology ; Benzoates/pharmacology ; Motor Neuron Disease/drug therapy/metabolism/pathology ; Calcium/metabolism ; Neurites/drug effects/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3-30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca[2+] baseline, increased level of excitability, and reduced Ca[2+] spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS.}, }
@article {pmid39336788, year = {2024}, author = {Tourtourikov, I and Todorov, T and Angelov, T and Chamova, T and Tournev, I and Mitev, V and Todorova, A}, title = {Genetic Modifiers of ALS: The Impact of Chromogranin B P413L in a Bulgarian ALS Cohort.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336788}, issn = {2073-4425}, support = {Grant No. D-148/ 03.08.2023//Medical University of Sofia/ ; National Recovery and Resilience Plan of the Republic of Bulgaria, project &#x2116; BG-RRP-2.004-0004-C01//European Union-NextGenerationEU/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; Female ; Bulgaria ; Middle Aged ; Aged ; Adult ; *Genetic Predisposition to Disease ; *Chromogranin B/genetics ; Age of Onset ; Alleles ; Genotype ; Polymorphism, Single Nucleotide ; Cohort Studies ; Gene Frequency ; Kaplan-Meier Estimate ; }, abstract = {This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan-Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ[2] = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan-Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts.}, }
@article {pmid39336748, year = {2024}, author = {Chami, AA and Bedja-Iacona, L and Richard, E and Lanznaster, D and Marouillat, S and Veyrat-Durebex, C and Andres, CR and Corcia, P and Blasco, H and Vourc'h, P}, title = {N-Terminal Fragments of TDP-43-In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.}, journal = {Genes}, volume = {15}, number = {9}, pages = {}, pmid = {39336748}, issn = {2073-4425}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; *DNA-Binding Proteins/genetics/metabolism ; HEK293 Cells ; Protein Domains ; Cell Survival/genetics ; }, abstract = {Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells. The N-terminal domain (NTD) alone was not sufficient to produce aggregates. Fragments containing the NTD and all or part of the RRM1 domain produced nuclear aggregates without affecting cell viability. Only large fragments also containing the RRM2 domain, with or without the glycine-rich domain, produced cytoplasmic aggregates. Of these, only NTFs containing even a very short portion of the glycine-rich domain caused a reduction in cell viability. Our results provide insights into the involvement of different TDP-43 domains in the formation of nuclear or cytoplasmic aggregates and support the idea that work on the development of therapeutic molecules targeting TDP-43 must also take into account NTFs and, in particular, those containing even a small part of the glycine-rich domain.}, }
@article {pmid39336146, year = {2024}, author = {Duranti, E and Villa, C}, title = {From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.}, journal = {Biology}, volume = {13}, number = {9}, pages = {}, pmid = {39336146}, issn = {2079-7737}, abstract = {Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.}, }
@article {pmid39335997, year = {2024}, author = {Dork, J and Mangan, E and Burns, L and Dimenstein, E}, title = {Affective Instability: Impact of Fluctuating Emotions on Regulation and Psychological Well-Being.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {14}, number = {9}, pages = {}, pmid = {39335997}, issn = {2076-328X}, abstract = {Previous research has focused on understanding the occurrence of intense and fluctuating emotions and the ability to manage these emotions and affective states. These phenomena have been, respectively, labeled as affective instability and emotion regulation and have been studied among individuals diagnosed with borderline personality disorder (BPD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and post-traumatic stress disorder (PTSD). Previous findings suggest that affective instability may be associated with poorer psychological well-being. The present study aims to investigate the general tendency of affective instability and capacity for emotional regulation among college students, regardless of a previous psychological diagnosis, and to understand the relationship between these processes and psychological well-being. Three questionnaires were administered to measure levels of affective instability, the ability to manage fluctuating affective states, and overall psychological well-being. The findings suggest that (1) individuals with diagnoses experience affective lability and difficulty regulating emotions at a greater rate than those without, (2) higher affective lability scores are consistent with more significant emotion dysregulation and lower overall psychological well-being, and (3) scores on the Affective lability Scale (ALS) and the Difficulties in Emotional Regulation Scale (DERS) are reliable predictors of one's estimated Global Assessment of Functioning (GAF) scores. Although causation has not been established, the evidence suggests that individuals with diagnoses experience greater difficulty in regulating their emotions, have greater affective lability, and experience diminished psychological well-being and day-to-day functionality. Certain anecdotal evidence suggests that emotional lability can be endogenous and affect multiple aspects of an individual's social, occupational, and personal life. By revising the existing literature and the present findings, the authors provide insights into the significance of endogenous factors in the context of affective lability and offer suggestions for future research.}, }
@article {pmid39335582, year = {2024}, author = {Carata, E and Muci, M and Mariano, S and Panzarini, E}, title = {BV2 Microglial Cell Activation/Polarization Is Influenced by Extracellular Vesicles Released from Mutated SOD1 NSC-34 Motoneuron-like Cells.}, journal = {Biomedicines}, volume = {12}, number = {9}, pages = {}, pmid = {39335582}, issn = {2227-9059}, abstract = {Microglia-mediated neuroinflammation is a key player in the pathogenesis of amyotrophic lateral sclerosis (ALS) as it can contribute to the progressive degeneration of motor neurons (MNs). Here, we investigated the role of mSOD1 NSC-34 MN-like cell-derived extracellular vesicles (EVs) in inducing the activation of BV2 microglial cells. NSC-34-released EVs were isolated by culture medium differential ultracentrifugation to obtain two fractions, one containing small EVs (diameter < 200 nm) and the other containing large EVs (diameter > 200 nm). BV2 cells were incubated with the two EV fractions for 12, 24, and 48 h to evaluate 1) the state of microglial inflammation through RT-PCR of IL-1β, IL-6, IL-4, and IL-10 and 2) the expression of proteins involved in inflammasome activation (IL-β and caspase 1), cell death (caspase 3), and glial cell recruitment (CXCR1), and presence of the TGFβ cytokine receptor (TGFβ-R2). The obtained results suggest a mSOD1 type-dependent polarization of BV2 cells towards an early neurotoxic phenotype and a late neuroprotective status, with an appearance of mixed M1 and M2 microglia subpopulations. A significant role in driving microglial cell activation is played by the TGFβ/CX3CR1 axis. Therefore, targeting the dysregulated microglial response and modulating neuroinflammation could hold promise as a therapeutic strategy for ALS.}, }
@article {pmid39335395, year = {2024}, author = {Ore, A and Angelastro, JM and Giulivi, C}, title = {Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.}, journal = {Brain sciences}, volume = {14}, number = {9}, pages = {}, pmid = {39335395}, issn = {2076-3425}, support = {R21 NS128751/NS/NINDS NIH HHS/United States ; }, abstract = {The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.}, }
@article {pmid39334855, year = {2024}, author = {Hasan, A and Staveley, BE}, title = {Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334855}, issn = {2218-273X}, support = {RGPIN-2016-04828//Natural Sciences and Engineering Research Council/ ; }, mesh = {Animals ; *Aging/genetics/metabolism ; Cytoskeletal Proteins ; *Drosophila melanogaster/genetics/metabolism ; *Drosophila Proteins/metabolism/genetics ; Dynamins/genetics/metabolism ; GTP-Binding Proteins ; Longevity/genetics ; Mitochondrial Proteins/genetics/metabolism ; Phenotype ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Membrane Proteins/metabolism ; }, abstract = {The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.}, }
@article {pmid39334843, year = {2024}, author = {Lucchi, C and Simonini, C and Rustichelli, C and Avallone, R and Zucchi, E and Martinelli, I and Biagini, G and Mandrioli, J}, title = {Reduced Levels of Neurosteroids in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients.}, journal = {Biomolecules}, volume = {14}, number = {9}, pages = {}, pmid = {39334843}, issn = {2218-273X}, support = {Ricerca Finalizzata bando 2021 (RF-2021-12373036)//Ministero della Salute/ ; bando FAR 2021, Progetti di ricerca Interdisciplinari Mission Oriented, NEURALS project//University of Modena and Reggio Emilia/ ; Neurobiobanca di Modena//Fondazione Cassa di Risparmio di Modena/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/cerebrospinal fluid ; Humans ; Middle Aged ; Male ; Female ; *Neurosteroids/cerebrospinal fluid ; Case-Control Studies ; Aged ; Biomarkers/cerebrospinal fluid ; Pregnanolone/cerebrospinal fluid ; Adult ; Pregnenolone/cerebrospinal fluid ; Progesterone/cerebrospinal fluid ; Testosterone/cerebrospinal fluid ; Chromatography, Liquid ; Tandem Mass Spectrometry ; }, abstract = {Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography-electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients' CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients' CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration.}, }
@article {pmid39334720, year = {2024}, author = {Munteanu, C and Galaction, AI and Turnea, M and Blendea, CD and Rotariu, M and Poștaru, M}, title = {Redox Homeostasis, Gut Microbiota, and Epigenetics in Neurodegenerative Diseases: A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {39334720}, issn = {2076-3921}, abstract = {Neurodegenerative diseases encompass a spectrum of disorders marked by the progressive degeneration of the structure and function of the nervous system. These conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS), often lead to severe cognitive and motor deficits. A critical component of neurodegenerative disease pathologies is the imbalance between pro-oxidant and antioxidant mechanisms, culminating in oxidative stress. The brain's high oxygen consumption and lipid-rich environment make it particularly vulnerable to oxidative damage. Pro-oxidants such as reactive nitrogen species (RNS) and reactive oxygen species (ROS) are continuously generated during normal metabolism, counteracted by enzymatic and non-enzymatic antioxidant defenses. In neurodegenerative diseases, this balance is disrupted, leading to neuronal damage. This systematic review explores the roles of oxidative stress, gut microbiota, and epigenetic modifications in neurodegenerative diseases, aiming to elucidate the interplay between these factors and identify potential therapeutic strategies. We conducted a comprehensive search of articles published in 2024 across major databases, focusing on studies examining the relationships between redox homeostasis, gut microbiota, and epigenetic changes in neurodegeneration. A total of 161 studies were included, comprising clinical trials, observational studies, and experimental research. Our findings reveal that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, with gut microbiota composition and epigenetic modifications significantly influencing redox balance. Specific bacterial taxa and epigenetic markers were identified as potential modulators of oxidative stress, suggesting novel avenues for therapeutic intervention. Moreover, recent evidence from human and animal studies supports the emerging concept of targeting redox homeostasis through microbiota and epigenetic therapies. Future research should focus on validating these targets in clinical settings and exploring the potential for personalized medicine strategies based on individual microbiota and epigenetic profiles.}, }
@article {pmid39333504, year = {2024}, author = {Cozzi, M and Magri, S and Tedesco, B and Patelli, G and Ferrari, V and Casarotto, E and Chierichetti, M and Pramaggiore, P and Cornaggia, L and Piccolella, M and Galbiati, M and Rusmini, P and Crippa, V and Mandrioli, J and Pareyson, D and Pisciotta, C and D'Arrigo, S and Ratti, A and Nanetti, L and Mariotti, C and Sarto, E and Pensato, V and Gellera, C and Di Bella, D and Cristofani, RM and Taroni, F and Poletti, A}, title = {Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.}, journal = {Cell death &amp; disease}, volume = {15}, number = {9}, pages = {692}, pmid = {39333504}, issn = {2041-4889}, support = {GGP19128//Fondazione Telethon (Telethon Foundation)/ ; 23236//AFM-T&#xe9;l&#xe9;thon (French Muscular Dystrophy Association)/ ; PRIN n. 2022EFLFL8//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PRIN n. P2022B5J32//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; Scientific Exchange Grant n. 9643//European Molecular Biology Organization (EMBO)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; 2021-1544//Fondazione Cariplo (Cariplo Foundation)/ ; RF-2018-12367768//Ministero della Salute (Ministry of Health, Italy)/ ; RRC 2023//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Charcot-Marie-Tooth Disease/genetics/metabolism/pathology ; *Kinesins/metabolism/genetics ; Mitochondria/metabolism/genetics ; *Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism/pathology ; *Neurodevelopmental Disorders/genetics/metabolism/pathology ; }, abstract = {Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.}, }
@article {pmid39332091, year = {2024}, author = {Sharma, O and Kaur Grewal, A and Khan, H and Gurjeet Singh, T}, title = {Exploring the nexus of cGAS STING pathway in neurodegenerative terrain: A therapeutic odyssey.}, journal = {International immunopharmacology}, volume = {142}, number = {Pt B}, pages = {113205}, doi = {10.1016/j.intimp.2024.113205}, pmid = {39332091}, issn = {1878-1705}, mesh = {Humans ; *Membrane Proteins/metabolism/genetics ; Animals ; *Neurodegenerative Diseases/drug therapy/immunology/metabolism ; *Nucleotidyltransferases/metabolism/genetics ; *Signal Transduction ; Immunity, Innate ; }, abstract = {By detecting and responding to cytosolic DNA, the cGAS STING pathway regulates the innate immune responses bymediatinginflammatory reactions and antiviral defense. Thederegulation and modification of this system have been linked to variousneurodegenerative diseases like AD, PD and ALS. Accumulation of tau protein and Aβ aggregates to activate the pathway and releases neuroinflammatory cytokines which accelerates neuronal dysfunction and cognitive impairment as the symptom of AD. Similarly, in PD Alpha-synuclein aggregates activate the cGAS STING pathway and regulate the neuroinflammation and oxidative stress. In ALS, mutation of the genes causes the activation of the pathway which leads to motor neuron degeneration. Alteration of the cGAS STING pathway also leads to mitochondrial dysfunction and impaired autophagy. Preclinical investigations of AD, PD, and ALS animal models showed that STING pathway inhibitors reduced inflammation and improved neurological outcomes and modulators of the cGAS STING pathway may treat these neurodegenerative disorders. In this review we focus on the fact thatneuroinflammation, neuronal dysfunction, and various disease progressions can be treated byaltering the cGAS STING pathway. Understanding the processes and creating specific interventions for this route may offer new treatments for these terrible illnesses.}, }
@article {pmid39330700, year = {2024}, author = {Everett, WH and Bucelli, RC}, title = {Tofersen for SOD1 ALS.}, journal = {Neurodegenerative disease management}, volume = {14}, number = {5}, pages = {149-160}, pmid = {39330700}, issn = {1758-2032}, mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Oligonucleotides/therapeutic use ; *Superoxide Dismutase-1/antagonists &amp; inhibitors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in SOD1 make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of SOD1 mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.}, }
@article {pmid39329756, year = {2024}, author = {Trainito, A and Muscarà, C and Gugliandolo, A and Chiricosta, L and Salamone, S and Pollastro, F and Mazzon, E and D'Angiolini, S}, title = {Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.}, journal = {Cells}, volume = {13}, number = {18}, pages = {}, pmid = {39329756}, issn = {2073-4409}, support = {Current Research Funds 2024//Ministero della Salute/ ; }, mesh = {*Ion Channels/metabolism/genetics ; Animals ; *Synapses/metabolism/drug effects ; *Transcriptome/drug effects/genetics ; Mice ; Cell Line ; Gene Expression Profiling ; Cannabinoids/pharmacology ; Humans ; Gene Expression Regulation/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.}, }
@article {pmid39329381, year = {2025}, author = {Lee, I and Vestrucci, M and Lee, S and Rosenbaum, M and Mitsumoto, H}, title = {Blood glycated hemoglobin level is not associated with disease progression in amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {175-179}, pmid = {39329381}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; Male ; *Disease Progression ; Female ; *Glycated Hemoglobin/metabolism/analysis ; Middle Aged ; Aged ; Cohort Studies ; Blood Glucose/metabolism ; }, abstract = {OBJECTIVE: A high glycemic index and high glycemic load diet has been associated with slower progression of amyotrophic lateral sclerosis (ALS), suggesting a benefit from high blood glucose levels. We examined the association between average blood glucose level and ALS progression in two independent cohorts.<br><br>METHODS: Sporadic ALS patients enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS) who completed a 3-month follow-up visit and had available blood samples were included. Hemoglobin A1c (HbA1c) was measured from whole blood collected at the 3-month follow-up. From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we included ALS patients with one or more HbA1c measurements at enrollment and available death information. Associations between HbA1c with revised ALS functional rating scale (ALSFRS-R)/ALSFRS total score change, and tracheostomy-free survival/survival were examined in these cohorts using linear regression, linear mixed-effects models, and Cox proportional hazard models, adjusted for covariates.<br><br>RESULTS: In the ALS COSMOS cohort (n&#x2009;=&#x2009;193), HbA1c level was not significantly associated with the change in the ALSFRS-R total score from baseline to the 3-month follow-up (p&#x2009;=&#x2009;0.8) nor baseline to the 6-month follow-up (p&#x2009;=&#x2009;0.4). No significant association was found between HbA1c level and tracheostomy-free survival (p&#x2009;=&#x2009;0.8). In the PRO-ACT cohort (n&#x2009;=&#x2009;928), no significant association was found between HbA1c level and the rate of ALSFRS decline in the first 200 days (p&#x2009;=&#x2009;0.81 for interaction) nor between HbA1c level and survival (p&#x2009;=&#x2009;0.45).<br><br>INTERPRETATION: We did not find convincing evidence that mean blood glucose level is associated with disease progression among ALS patients.}, }
@article {pmid39328853, year = {2024}, author = {Ali, M and Ramadan, A and Surani, S}, title = {Obstructive sleep apnea-hypopnea syndrome immunological relationship.}, journal = {World journal of clinical cases}, volume = {12}, number = {27}, pages = {6011-6014}, pmid = {39328853}, issn = {2307-8960}, abstract = {Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a complex disorder characterized by symptoms resulting from intermittent hypoxia and hypopnea, with research indicating a crucial role of immune system dysregulation and genetic variations in its pathogenesis. A recent Zhao et al study utilizes Mendelian randomization analysis to explore the causal relationship between immune cell characteristics and OSAHS. The study identifies specific lymphocyte subsets associated with OSAHS, providing valuable insights into the disease's pathophysiology and potential targets for therapeutic intervention. The findings underscore the significance of genetic and immunological factors in sleep disorders, offering a fresh perspective on OSAHS's complexities. Compared to existing literature, Zhao et al's study stands out for its focus on genetic markers and specific immune responses associated with OSAHS, expanding upon previous research primarily centered on systemic inflammation. In conclusion, the study represents a significant advancement in the field, shedding light on the causal role of immune cells in OSAHS and paving the way for future research and targeted treatments.}, }
@article {pmid39328135, year = {2024}, author = {Sharma, S and Mehan, S and Khan, Z and Tiwari, A and Kumar, A and Gupta, GD and Narula, AS and Kalfin, R}, title = {Exploring the Neuroprotective Potential of Icariin through Modulation of Neural Pathways in the Treatment of Neurological Diseases.}, journal = {Current molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665240317650240924041923}, pmid = {39328135}, issn = {1875-5666}, abstract = {Neuropathological diseases involve the death of neurons and the aggregation of proteins with altered properties in the brain. Proteins are used at the molecular level to categorize neurodegenerative disorders, emphasizing the importance of protein-processing mechanisms in their development. Natural herbal phytoconstituents, such as icariin, have addressed these neurological complications. Icariin, the principal compound in Epimedium, has been studied for its antineuroinflammatory, anti-oxidative, and antiapoptotic properties. Recent scientific investigations have shown that icariin exhibits promising therapeutic and preventive properties for mental and neurodegenerative disorders. In preclinical, icariin has been shown to inhibit amyloid development and reduce the expression of APP and BACE-1. Previous preclinical studies have demonstrated that icariin can regulate proinflammatory responses in neurological conditions like Parkinson's disease, depression, cerebral ischemia, ALS, and multiple sclerosis. Studies have shown that icariin possesses neuroprotective properties by modulating signaling pathways and crossing the blood-brain barrier, suggesting its potential to address various neurocomplications. This review aims to establish a foundation for future clinical investigations by examining the existing literature on icariin and exploring its potential therapeutic implications in treating neurodegenerative disorders and neuropsychiatric conditions. Future research may address numerous concerns and yield captivating findings with far-reaching implications for various aspects of icariin.}, }
@article {pmid39328012, year = {2024}, author = {Cui, Y and Chen, J and Li, H and Zheng, D and Shi, X}, title = {The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.}, journal = {Brain and behavior}, volume = {14}, number = {10}, pages = {e70018}, pmid = {39328012}, issn = {2162-3279}, support = {2023A03J0438//Science and Technology Program of Guangzhou/ ; 2020A1515010063//Natural Science Foundation of Guangdong Province/ ; 2023A1515011047//Natural Science Foundation of Guangdong Province/ ; //Guangzhou Research-oriented Hospital/ ; //Guangzhou High-level Clinical Key Specialty/ ; 2022A1515220119//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2021-2023//Guangzhou Municipal Key Discipline in Medicine/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis ; *Epilepsy/genetics/epidemiology/etiology ; *Genome-Wide Association Study ; Causality ; }, abstract = {OBJECTIVES: Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method.<br><br>METHODS: We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1&#x2009;&#xd7;&#x2009;10[-5] as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy.<br><br>RESULTS: The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p&#xa0;=&#xa0;.130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P&#xa0;=&#xa0;.300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p&#xa0;=&#xa0;.019). Moreover, the investigation of reverse causalities did not reveal significant results.<br><br>CONCLUSIONS: The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.}, }
@article {pmid39327888, year = {2024}, author = {Fitri, HU and Saputra, R and Suhardita, K and Suarta, IM and Oktasari, M and Aminah, S and Laras, PB}, title = {Digging deeper: A critique of the mediation study of spirituality in ALS patients.}, journal = {Palliative &amp; supportive care}, volume = {22}, number = {5}, pages = {1550-1551}, doi = {10.1017/S1478951524001275}, pmid = {39327888}, issn = {1478-9523}, }
@article {pmid39327159, year = {2024}, author = {Vassallu, F and Igaz, LM}, title = {TDP-43 nuclear condensation and neurodegenerative proteinopathies.}, journal = {Trends in neurosciences}, volume = {47}, number = {11}, pages = {849-850}, doi = {10.1016/j.tins.2024.09.003}, pmid = {39327159}, issn = {1878-108X}, mesh = {Animals ; Humans ; Cell Nucleus/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; Neurodegenerative Diseases/metabolism ; *TDP-43 Proteinopathies/metabolism/genetics/pathology ; }, abstract = {RNA-binding proteins (RBPs) can undergo phase separation and form condensates, processes that, in turn, can be critical for their functionality. In a recent study, Huang, Ellis, and colleagues show that cellular stress can trigger transient alterations in nuclear TAR DNA-binding protein 43 (TDP-43), leading to changes crucial for proper neuronal function. These findings have implications for understanding neurological TDP-43 proteinopathies.}, }
@article {pmid39326369, year = {2024}, author = {Suzuki, Y and Adachi, T and Yoshida, K and Sakuwa, M and Hanajima, R}, title = {Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123249}, doi = {10.1016/j.jns.2024.123249}, pmid = {39326369}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/psychology ; Male ; Female ; Aged ; *DNA-Binding Proteins/metabolism ; Middle Aged ; Mental Disorders/etiology/pathology/metabolism ; Brain/pathology/metabolism ; Aged, 80 and over ; Neurons/pathology/metabolism ; }, abstract = {BACKGROUND: ALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS.<br><br>METHODS: We investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43-positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed.<br><br>RESULTS: Of the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms.<br><br>CONCLUSION: Psychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).}, }
@article {pmid39324867, year = {2024}, author = {Li, J and Gao, C and Wang, Q and Liu, J and Xie, Z and Zhao, Y and Yu, M and Zheng, Y and Lv, H and Zhang, W and Yuan, Y and Meng, L and Deng, J and Wang, Z}, title = {Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16493}, pmid = {39324867}, issn = {1468-1331}, support = {82071409//National Natural Science Foundation of China/ ; 82101469//National Natural Science Foundation of China/ ; 82171846//National Natural Science Foundation of China/ ; U20A20356//National Natural Science Foundation of China/ ; 2022-4-40716//Capitals Funds for Health Improvement and Research/ ; 20220484017//Beijing Nova Program/ ; 20230484403//Beijing Nova Program/ ; 2023CX05//Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital/ ; 2023HQ03//National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics ; Male ; Female ; *DNA, Mitochondrial/blood/genetics ; Middle Aged ; Aged ; *Interleukin-6/blood ; *Cell-Free Nucleic Acids/blood ; *Superoxide Dismutase-1/blood/genetics ; Mutation ; Adult ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.<br><br>METHODS: The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n&#x2009;=&#x2009;62) and age-matched healthy controls (n&#x2009;=&#x2009;46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.<br><br>RESULTS: Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1&#x2009;&#xd7;&#x2009;10[5] mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p&#x2009;<&#x2009;0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (&#x394;FS; rs&#x2009;=&#x2009;-0.26, p&#x2009;=&#x2009;0.044), but not the ALSFRS-R score (rs&#x2009;=&#x2009;0.06, p&#x2009;=&#x2009;0.625). Importantly, the correlation between ccf-mtDNA and &#x394;FS was more pronounced in the SOD1 mutation group (rs&#x2009;=&#x2009;-0.62, p&#x2009;=&#x2009;0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r&#x2009;s=&#x2009;0.41, p&#x2009;=&#x2009;0.038).<br><br>CONCLUSION: Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.}, }
@article {pmid39323877, year = {2024}, author = {Engelberg-Cook, E and Shah, JS and Teixeira da Silva Hucke, A and Vera-Garcia, DV and Dagher, JE and Donahue, MH and Belzil, VV and Oskarsson, B}, title = {Prognostic Factors and Epidemiology of Amyotrophic Lateral Sclerosis in Southeastern United States.}, journal = {Mayo Clinic proceedings. Innovations, quality &amp; outcomes}, volume = {8}, number = {5}, pages = {482-492}, pmid = {39323877}, issn = {2542-4548}, abstract = {OBJECTIVE: To assess the performance of known survival predictors and evaluate their stratification capability in patients with amyotrophic lateral sclerosis (ALS).<br><br>PATIENTS AND METHODS: We analyzed demographic and clinical variables collected at the Mayo Clinic, Florida ALS center during the first clinical visit of 1442 (100%) patients with ALS.<br><br>RESULTS: Our cohort had a median (interquartile range [IQR]) age at diagnosis of 64.8 (57-72) years; 1350 (92%) were non-Hispanic White; and 771 (53.5%) were male. The median (IQR) diagnostic delay was 10.1 (6-18) months, body mass index was 25.4 (23-49), and forced vital capacity was 72% (52%-87%). Approximately 12% of patients tested carried a pathologic C9orf72 hexanucleotide repeat expansion. Median (IQR) ALS functional rating scale-revised score was 35 (29-40) and ALS cognitive behavioral screen score was 15 (12-17). The median (IQR) survival after diagnosis was 17.2 (9-31) months, and survival from symptom onset was 30 (20-48) months. We found that older age decreased forced vital capacity, and fast-progressing ALS functional rating scale-revised scores significantly (P<.0001) influence survival curves and associated hazard risk.<br><br>CONCLUSION: Although results obtained from our cohort are consistent with other reports (eg, men with spinal onset experience a longer survival than women with bulbar onset), they remind us of the complexity of the disease's natural history and the limited prognostic power of the most common clinical predictors.}, }
@article {pmid39323817, year = {2024}, author = {Zeng, A and Huang, Y and Xin, J and Li, J and Qiu, W and Zhang, M}, title = {Progress and recommendations of developing occupational exposure limits for noise-A systematic review.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37878}, pmid = {39323817}, issn = {2405-8440}, abstract = {OBJECTIVE: Noise exposure limit is one of the critical measures to prevent noise-induced hearing loss (NIHL). This review aimed to review the progress and recommendations for developing occupational exposure limits (OELs) for workplace noise.<br><br>METHODS: A systematic review was used. Thirty-eight national or international organizations' noise exposure standards (including OEL) and laws, regulations, and guidelines for noise exposure control were analyzed. Articles on recommendations for revising noise OEL standards between 2000 and 2023 were selected.<br><br>RESULTS: The definition of different noise types (especially for non-steady and impulsive noise) varied worldwide, and the used 8-h OEL varied from 80 to 90&#xa0;dB(A). Maximum sound pressure level (Lmax) and noise dose for industrial noise and peak sound pressure level (Lpeak) for impulsive noise have been incorporated into the OELs. Countries developed noise risk management measures based on OELs, action levels (ALs), and exposure risk ratio or classification. The risk of co-exposure to noise and ototoxic organic substances and the effects of noise on susceptible populations were concerns in EU country standards. Scholars suggested revising the existing noise exposure standards based on noise's temporal structure (expressed by kurtosis), effective noise level, impulsive noise OEL, action level, and key factors of risk assessment.<br><br>CONCLUSIONS: Indicators such as Lmax, noise dose, Lpeak, and action level can be incorporated into noise OELs. Developing noise OEL standards should consider the co-exposure of noise and ototoxic substances, HPD's noise attenuation, susceptible groups, and noise's temporal structure.}, }
@article {pmid39323783, year = {2024}, author = {You, J and Maksimovic, K and Metri, MN and Schoeppe, A and Chen, K and Lee, J and Santos, JR and Youssef, MMM and Salter, MW and Park, J}, title = {Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {18}, pages = {e37926}, pmid = {39323783}, issn = {2405-8440}, abstract = {Microglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by the Clec7a gene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show that Clec7a mRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3 [S85C/S85C]) of ALS. Furthermore, a significant increase in the number of Dectin-1[+] microglia coincides with the onset of motor deficits, and this number increases with disease progression. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses in Matr3 [S85C/S85C] mice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression.}, }
@article {pmid39322357, year = {2024}, author = {Mehta, RI and Ranjan, M and Haut, MW and Carpenter, JS and Rezai, AR}, title = {Focused Ultrasound for Neurodegenerative Diseases.}, journal = {Magnetic resonance imaging clinics of North America}, volume = {32}, number = {4}, pages = {681-698}, doi = {10.1016/j.mric.2024.03.001}, pmid = {39322357}, issn = {1557-9786}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging ; Ultrasonic Therapy/methods ; Brain/diagnostic imaging ; Animals ; }, abstract = {Neurodegenerative diseases are a leading cause of death and disability and pose a looming global public health crisis. Despite progress in understanding biological and molecular factors associated with these disorders and their progression, effective disease modifying treatments are presently limited. Focused ultrasound (FUS) is an emerging therapeutic strategy for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these contexts, applications of FUS include neuroablation, neuromodulation, and/or blood-brain barrier opening with and without facilitated intracerebral drug delivery. Here, the authors review preclinical evidence and current and emerging applications of FUS for neurodegenerative diseases and summarize future directions in the field.}, }
@article {pmid39321879, year = {2024}, author = {Lei, T and Zhang, X and Fu, G and Luo, S and Zhao, Z and Deng, S and Li, C and Cui, Z and Cao, J and Chen, P and Yang, H}, title = {Advances in human cellular mechanistic understanding and drug discovery of brain organoids for neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {102}, number = {}, pages = {102517}, doi = {10.1016/j.arr.2024.102517}, pmid = {39321879}, issn = {1872-9649}, mesh = {Humans ; *Organoids/drug effects/pathology ; *Neurodegenerative Diseases/pathology/drug therapy ; *Drug Discovery/methods ; *Brain/pathology/drug effects ; Animals ; }, abstract = {The prevalence of neurodegenerative diseases (NDs) is increasing rapidly as the aging population accelerates, and there are still no treatments to halt or reverse the progression of these diseases. While traditional 2D cultures and animal models fail to translate into effective therapies benefit patients, 3D cultured human brain organoids (hBOs) facilitate the use of non-invasive methods to capture patient data. The purpose of this study was to review the research and application of hBO in disease models and drug screening in NDs. The pluripotent stem cells are induced in multiple stages to form cerebral organoids, brain region-specific organoids and their derived brain cells, which exhibit complex brain-like structures and perform electrophysiological activities. The brain region-specific organoids and their derived neurons or glial cells contribute to the understanding of the pathogenesis of NDs and the efficient development of drugs, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Glial-rich brain organoids facilitate the study of glial function and neuroinflammation, including astrocytes, microglia, and oligodendrocytes. Further research on the maturation enhancement, vascularization and multi-organoid assembly of hBO will help to enhance the research and application of NDs cellular models.}, }
@article {pmid39319809, year = {2024}, author = {Karra, R and Rice, AD and Hardcastle, A and V Lara, J and Hollen, A and Glenn, M and Munn, R and Hannan, P and Arcaris, B and Derksen, D and Spaite, DW and Gaither, JB}, title = {Telemedical Direction to Optimize Resource Utilization in a Rural Emergency Medical Services System.}, journal = {The western journal of emergency medicine}, volume = {25}, number = {5}, pages = {777-783}, pmid = {39319809}, issn = {1936-9018}, mesh = {Humans ; Retrospective Studies ; *Telemedicine ; *Emergency Medical Services ; *Rural Health Services ; Female ; *Emergency Medical Technicians ; Male ; Chest Pain/therapy ; Middle Aged ; Pilot Projects ; Adult ; }, abstract = {BACKGROUND: Telemedicine remains an underused tool in rural emergency medical servces (EMS) systems. Rural emergency medical technicians (EMT) and paramedics cite concerns that telemedicine could increase Advanced Life Support (ALS) transports, extend on-scene times, and face challenges related to connectivity as barriers to implementation. Our aim in this project was to implement a telemedicine system in a rural EMS setting and assess the impact of telemedicine on EMS management of patients with chest pain while evaluating some of the perceived barriers.<br><br>METHODS: This study was a mixed-methods, retrospective review of quality assurance data collected prior to and after implementation of a telemedicine program targeting patients with chest pain. We compared quantitative data from the 12-month pre-implementation phase to data from 15 months post-implementation. Patients were included if they had a chief complaint of chest pain or a 12-lead electrocardiogram had been obtained. The primary outcome was the rate of ALS transport before and after program implementation. Secondary outcomes included EMS call response times and EMS agency performance on quality improvement benchmarks. Qualitative data were also collected after each telemedicine encounter to evaluate paramedic/EMT and EMS physician perception of call quality.<br><br>RESULTS: The telemedicine pilot project was implemented in September 2020. Overall, there were 58 successful encounters. For this analysis, we included 38 patients in both the pre-implementation period (September 9, 2019-September 10, 2020) and the post-implementation period (September 11, 2020-December 5, 2021). Among this population, the ALS transport rate was 42% before and 45% after implementation (odds ratio 1.11; 95% confidence interval 0.45-2.76). The EMS median out-of-service times were 47 minutes before, and 33 minutes after (P&#x2009;=&#x2009;0.07). Overall, 64% of paramedics/EMTs and 89% of EMS physicians rated the telemedicine call quality as "good."<br><br>CONCLUSION: In this rural EMS system, a telehealth platform was successfully used to connect paramedics/EMTs to board-certified EMS physicians over a 15-month period. Telemedicine use did not alter rates of ALS transports and did not increase on-scene time. The majority of paramedics/EMTs and EMS physicians rated the quality of the telemedicine connection as "good."}, }
@article {pmid39318842, year = {2024}, author = {Emary, PC and Turner, AJ}, title = {Cervical spondylotic myelopathy in a 68-year-old man diagnosed with amyotrophic lateral sclerosis.}, journal = {The Journal of the Canadian Chiropractic Association}, volume = {68}, number = {2}, pages = {172-176}, pmid = {39318842}, issn = {0008-3194}, abstract = {Owing to similar clinical presentations, cervical spondylotic myelopathy can mimic other neurological disorders. In this imaging case review (ICR), we describe a case of cervical spondylotic myelopathy in a patient diagnosed with amyotrophic lateral sclerosis. The key clinical features, imaging findings and differential diagnoses of cervical spondylotic myelopathy compared with amyotrophic lateral sclerosis are also presented.}, }
@article {pmid39318236, year = {2025}, author = {Majewski, S and Klein, P and Boillée, S and Clarke, BE and Patani, R}, title = {Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis.}, journal = {Glia}, volume = {73}, number = {3}, pages = {591-607}, pmid = {39318236}, issn = {1098-1136}, support = {MR/S006591/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Amyotrophic Lateral Sclerosis/pathology/physiopathology ; Humans ; *Neuroglia/pathology/physiology ; Animals ; }, abstract = {Substantial advances in technology are permitting a high resolution understanding of the salience of glia, and have helped us to transcend decades of predominantly neuron-centric research. In particular, recent advances in 'omic' technologies have enabled unique insights into glial biology, shedding light on the cellular and molecular aspects of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques to attempt to understand the role of glia in ALS across different model systems and post mortem tissue. We also address caveats that should be considered when interpreting such studies, and how some of these may be mitigated through either using a multi-omic approach and/or careful low throughput, high fidelity orthogonal validation with particular emphasis on functional validation. Finally, we consider emerging technologies and their potential relevance in deepening our understanding of glia in ALS.}, }
@article {pmid39317854, year = {2024}, author = {Khoshdooz, S and Abbasi, H and Abbasi, MM}, title = {Iron-Status Indicators and HFE Gene Polymorphisms in Individuals with Amyotrophic Lateral Sclerosis: An Umbrella Review of Meta-analyses and Systematic Reviews.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39317854}, issn = {1559-0720}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Recent meta-analyses and systematic reviews suggest that HFE gene polymorphisms and iron-associated biomarkers may play a key role in the risk and occurrence of ALS. This umbrella study aimed to explore the roles of HFE gene polymorphisms and iron-associated biomarkers in individuals with ALS. A thorough search of three online scientific databases, namely Scopus, Web of Science, and PubMed, was conducted from their inception until September 13, 2024. The screening and selection processes were executed based on the PICO framework and eligibility criteria, followed by two independent reviewers. The Assessment of Multiple Systematic Reviews (AMSTAR)-2 and GRADE tools were utilized to assess the methodological quality and the certainty of evidence. Through an advanced search, 101 records were retrieved, of which eight meta-analyses and systematic reviews were selected for this umbrella review. A significant increase in iron concentrations was found in individuals with ALS compared to healthy controls (SMD, 0.26; 95% CI - 0.05, 0.57). Conversely, selected meta-analyses reported that serum transferrin concentrations in ALS patients were lower compared to healthy controls (SMD, - 0.15; 95% CI - 0.36, 0.05). Furthermore, mutations in H63D polymorphisms resulted in a 13% significant increase in the risk of ALS (OR, 1.13; 95% CI 1.05, 1.22). Our umbrella study of meta-analyses and systematic reviews reveals that individuals with ALS have lower serum concentrations of transferrin compared to healthy controls. Additionally, the H63D polymorphism in the HFE gene is associated with a slight increase in the risk of ALS. Future research should investigate broader aspects of iron-related biomarkers and HFE genes to elucidate their roles in ALS pathogenesis. Registration: Our umbrella study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42024559032 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024559032).}, }
@article {pmid39317352, year = {2025}, author = {Kleinerova, J and Garcia-Gallardo, A and Tacheva, A and Bede, P}, title = {Subcortical grey matter involvement in ALS and PLS - vulnerable hubs of cortico-cortical and cortico-basal circuits: extrapyramidal, cognitive, bulbar and respiratory correlates.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {1-4}, doi = {10.1080/21678421.2024.2405130}, pmid = {39317352}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology/diagnostic imaging/genetics ; *Gray Matter/diagnostic imaging/pathology/physiopathology ; Neural Pathways/physiopathology/diagnostic imaging/pathology ; Cerebral Cortex/diagnostic imaging/physiopathology/pathology ; }, abstract = {Evidence from neuroimaging studies suggests that the cardinal clinical manifestations of ALS stem from the dysfunction of specific neural networks. The majority of cortico-cortical and cortico-basal networks are physiologically relayed by deep cerebral and cerebellar grey matter nuclei which have been increasingly implicated in the pathophysiology of ALS. A series of recent human imaging papers revealed volume reductions, shape deformations, metabolic alterations and more recently, susceptibility changes in hippocampal subfields, thalamic, striatal, amygdalar and cerebellar nuclei. Thalamic changes have been identified in presymptomatic mutation carriers long before symptom onset and longitudinal studies have consistently confirmed progressive subcortical degeneration during the symptomatic phase of the disease. The dysfunction of circuits relayed by specific subcortical nuclei has been associated with apathy, amnestic deficits, limbic symptoms, extrapyramidal manifestations, sensory disturbances, pseudobulbar affect and cerebellar deficits. In light of emerging imaging data, the clinical heterogeneity of ALS is probably best approached from a network integrity perspective. Accordingly, the comprehensive assessment of subcortical grey matter nuclei seems imperative to untangle complex clinical phenomena in ALS.}, }
@article {pmid39316747, year = {2024}, author = {de Calbiac, H and Renault, S and Haouy, G and Jung, V and Roger, K and Zhou, Q and Campanari, ML and Chentout, L and Demy, DL and Marian, A and Goudin, N and Edbauer, D and Guerrera, C and Ciura, S and Kabashi, E}, title = {Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.}, journal = {Autophagy}, volume = {20}, number = {10}, pages = {2164-2185}, pmid = {39316747}, issn = {1554-8635}, mesh = {*Motor Neurons/metabolism/pathology ; Animals ; *C9orf72 Protein/genetics/metabolism ; *Zebrafish ; *Mitophagy/genetics ; *Apoptosis/genetics ; Humans ; *Autophagy/genetics/physiology ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; *Dipeptides/pharmacology/metabolism ; Loss of Function Mutation/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; }, abstract = {The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.}, }
@article {pmid39316061, year = {2025}, author = {Yang, W and Liu, X and Fan, D}, title = {Low CD3 level is a risk factor for amyotrophic lateral sclerosis: a Mendelian randomization study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {64-72}, doi = {10.1080/21678421.2024.2407408}, pmid = {39316061}, issn = {2167-9223}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Humans ; *Mendelian Randomization Analysis/methods ; *CD3 Complex/metabolism/genetics ; Risk Factors ; Genetic Predisposition to Disease/genetics ; Valosin Containing Protein/genetics ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by neuronal degeneration of the spinal cord and brain and believed to be related to the immune system. In this study, our aim is to use Mendelian randomization (MR) to search for immune markers related to ALS. A total of 731 immune cell traits were included in this study. MR analysis was used to identify the causality between 731 immune cell traits (with 3,757 Europeans) and ALS (with 138,086 Europeans). Colocalization analysis was used to verify the found causality, protein-protein interaction prediction was used to look for the interacting proteins that are known to be involved in ALS. We found low expression levels of CD3 on central memory CD8+ T cell is risk factor for ALS (OR = 0.90, 95% CI: 0.86-0.95, P = 0.0000303). CD3 can interact with three ALS-related proteins: VCP, HLA-DRA and HLA-DRB5, which are associated with adaptive immune response. Our study reported for the first time that low-level CD3 is a risk factor for ALS and the possible mechanism, which could provide a potential strategy for ALS diagnosis and therapy.}, }
@article {pmid39316038, year = {2025}, author = {Olsen, CG and Malmberg, VN and Fahlström, M and Alstadhaug, KB and Bjørnå, IK and Braathen, GJ and Bråthen, G and Demic, N and Hallerstig, E and Hogenesch, I and Horn, MA and Kampman, MT and Kleveland, G and Ljøstad, U and Maniaol, A and Morsund, &#xc5;H and Nakken, O and Schlüter, K and Schuler, S and Seim, E and Flemmen, H&#xd8; and Tysnes, OB and Holmøy, T and Høyer, H}, title = {Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway - prevalence, ancestry, clinical characteristics and sociodemographic status.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {132-140}, doi = {10.1080/21678421.2024.2405118}, pmid = {39316038}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; Norway/epidemiology ; *C9orf72 Protein/genetics ; Female ; Male ; Middle Aged ; Aged ; Prevalence ; Adult ; Proteins/genetics ; Genetic Predisposition to Disease/genetics ; DNA Repeat Expansion/genetics ; Aged, 80 and over ; Socioeconomic Factors ; }, abstract = {OBJECTIVE: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9pos). Further, we compared C9pos and C9neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status.<br><br>METHODS: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients.<br><br>RESULTS: The study enrolled 500 ALS patients, 8.8% of whom were C9pos, with half being sporadic ALS cases. The proportion of C9pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9pos patients had non-Finnish European descent and were not closely related. C9pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9neg patients.<br><br>CONCLUSION: C9pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9pos patients has proven to be challenging. Half of C9pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.}, }
@article {pmid39315390, year = {2024}, author = {Douglas, AGL and Thompson, AG and Turner, MR and Talbot, K}, title = {Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.}, journal = {BMJ neurology open}, volume = {6}, number = {2}, pages = {e000792}, pmid = {39315390}, issn = {2632-6140}, abstract = {BACKGROUND: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates.<br><br>METHODS: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years.<br><br>RESULTS: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases.<br><br>CONCLUSIONS: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.}, }
@article {pmid39315308, year = {2024}, author = {Abati, E and Gagliardi, D and Manini, A and Del Bo, R and Ronchi, D and Meneri, M and Beretta, F and Sarno, A and Rizzo, F and Monfrini, E and Di Fonzo, A and Pellecchia, MT and Brusati, A and Silani, V and Comi, GP and Ratti, A and Verde, F and Ticozzi, N and Corti, S}, title = {Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae312}, pmid = {39315308}, issn = {2632-1297}, abstract = {The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.}, }
@article {pmid39315251, year = {2024}, author = {Maitra, S and Baek, M and Choe, YJ and Kim, NC}, title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39315251}, issn = {2693-5015}, support = {R56 NS112296/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10[S59L], and human cell models expressing CHCHD10[S59L], we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10[S59L]. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10[S59L]-induced diseases.<br><br>METHODS: An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10[S59L] mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.<br><br>RESULTS: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10[S59L]-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10[S59L]-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H[S81L]. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10[S59L].<br><br>CONCLUSION: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10[S59L]-induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.}, }
@article {pmid39314515, year = {2025}, author = {He, D and Wang, X and Hao, M and Shen, D and Yang, X and Liu, M and Li, Y and Wang, J and Cui, L}, title = {Mutational and transcriptional profiling of cuproptosis-associated genes in amyotrophic lateral sclerosis.}, journal = {Genes &amp; diseases}, volume = {12}, number = {1}, pages = {101208}, pmid = {39314515}, issn = {2352-3042}, }
@article {pmid39314491, year = {2024}, author = {Guerra San Juan, I and Brunner, J and Eggan, K and Toonen, RF and Verhage, M}, title = {KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314491}, issn = {2692-8205}, support = {R01 NS089742/NS/NINDS NIH HHS/United States ; }, abstract = {Mutations in the microtubule binding motor protein, kinesin family member 5A (KIF5A), cause the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. While KIF5 family members transport a variety of cargos along axons, it is still unclear which cargos are affected by KIF5A mutations. We generated KIF5A null mutant human motor neurons to investigate the impact of KIF5A loss on the transport of various cargoes and its effect on motor neuron function at two different timepoints in vitro. The absence of KIF5A resulted in reduced neurite complexity in young motor neurons (DIV14) and significant defects in axonal regeneration capacity at all developmental stages. KIF5A loss did not affect neurofilament transport but resulted in decreased mitochondria motility and anterograde speed at DIV42. More prominently, KIF5A depletion strongly reduced anterograde transport of SFPQ-associated RNA granules in DIV42 motor neuron axons. We conclude that KIF5A most prominently functions in human motor neurons to promote axonal regrowth after injury as well as to anterogradely transport mitochondria and, to a larger extent, SFPQ-associated RNA granules in a time-dependent manner.}, }
@article {pmid39314333, year = {2024}, author = {Guha, A and Si, Y and Smith, R and Kazamel, M and Jiang, N and Smith, KA and Thalacker-Mercer, A and Singh, BK and Ho, R and Andrabi, SA and Pereira, JDTDS and Salgado, JS and Agrawal, M and Velic, EH and King, PH}, title = {The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39314333}, issn = {2692-8205}, support = {I01 BX002466/BX/BLRD VA/United States ; I01 BX006231/BX/BLRD VA/United States ; R01 NS092651/NS/NINDS NIH HHS/United States ; R21 NS111275/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1[G93A] mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1[G93A] or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.}, }
@article {pmid39314138, year = {2025}, author = {Lv, Y and Li, H}, title = {Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis.}, journal = {Neural regeneration research}, volume = {20}, number = {9}, pages = {2556-2570}, pmid = {39314138}, issn = {1673-5374}, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.}, }
@article {pmid39313512, year = {2024}, author = {Khan, AF and Iturria-Medina, Y}, title = {Beyond the usual suspects: multi-factorial computational models in the search for neurodegenerative disease mechanisms.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {386}, pmid = {39313512}, issn = {2158-3188}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/physiopathology ; *Neuroimaging/methods ; *Brain/diagnostic imaging/physiopathology ; Disease Progression ; Biomarkers ; Alzheimer Disease/diagnostic imaging/physiopathology ; Computer Simulation ; }, abstract = {From Alzheimer's disease to amyotrophic lateral sclerosis, the molecular cascades underlying neurodegenerative disorders remain poorly understood. The clinical view of neurodegeneration is confounded by symptomatic heterogeneity and mixed pathology in almost every patient. While the underlying physiological alterations originate, proliferate, and propagate potentially decades before symptomatic onset, the complexity and inaccessibility of the living brain limit direct observation over a patient's lifespan. Consequently, there is a critical need for robust computational methods to support the search for causal mechanisms of neurodegeneration by distinguishing pathogenic processes from consequential alterations, and inter-individual variability from intra-individual progression. Recently, promising advances have been made by data-driven spatiotemporal modeling of the brain, based on in vivo neuroimaging and biospecimen markers. These methods include disease progression models comparing the temporal evolution of various biomarkers, causal models linking interacting biological processes, network propagation models reproducing the spatial spreading of pathology, and biophysical models spanning cellular- to network-scale phenomena. In this review, we discuss various computational approaches for integrating cross-sectional, longitudinal, and multi-modal data, primarily from large observational neuroimaging studies, to understand (i) the temporal ordering of physiological alterations, i(i) their spatial relationships to the brain's molecular and cellular architecture, (iii) mechanistic interactions between biological processes, and (iv) the macroscopic effects of microscopic factors. We consider the extents to which computational models can evaluate mechanistic hypotheses, explore applications such as improving treatment selection, and discuss how model-informed insights can lay the groundwork for a pathobiological redefinition of neurodegenerative disorders.}, }
@article {pmid39313484, year = {2025}, author = {Funai, A and Hayashi, K and Kawata, A and Nakayama, Y and Matsuda, C and Haraguchi, M and Takahashi, K and Komori, T}, title = {An autopsy report of a long-survival case of familial amyotrophic lateral sclerosis with SOD1 G93S gene mutation: Lack of SOD1-positive inclusion in the remaining neurons.}, journal = {Neuropathology : official journal of the Japanese Society of Neuropathology}, volume = {45}, number = {1}, pages = {60-65}, doi = {10.1111/neup.13004}, pmid = {39313484}, issn = {1440-1789}, support = {22H03398//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Male ; Aged ; *Superoxide Dismutase-1/genetics ; *Autopsy ; *Mutation ; Motor Neurons/pathology/metabolism ; Superoxide Dismutase/genetics ; }, abstract = {We describe the case of a 70-year-old Japanese man with familial amyotrophic lateral sclerosis (fALS) associated with a p.Gly93Ser mutation in the copper/zinc superoxide dismutase (SOD1) gene. This mutation is one of the relatively rare SOD1 mutations, with only one previous autopsy report, and is known for its longer disease duration. As previously reported, the patient had weakness in the lower limbs at age 33, followed by dysphagia, dysesthesia in the lower limbs, and autonomic dysfunction. He required mechanical ventilation at age 44 and died of acute pancreatitis at age 70. Neuropathologically, multisystem degeneration was observed beyond lesions typical of familial ALS with posterior column involvement. In addition, there was no SOD1-positive inclusion in the remaining motor neurons. The absence of SOD1-positive inclusion is a rare feature observed predominantly in long survival cases with SOD1 gene mutations. We hypothesize that the considerably lower amount of abnormal SOD1 protein in the motor neuron cells might explain our patient's extraordinarily long clinical course.}, }
@article {pmid39313211, year = {2025}, author = {Rahimi, M and Al Masry, Z and Templeton, JM and Schneider, S and Poellabauer, C}, title = {A Comprehensive Multifunctional Approach for Measuring Parkinson's Disease Severity.}, journal = {Applied clinical informatics}, volume = {16}, number = {1}, pages = {11-23}, pmid = {39313211}, issn = {1869-0327}, mesh = {Humans ; *Parkinson Disease/diagnosis/physiopathology ; Male ; Female ; *Severity of Illness Index ; Aged ; Middle Aged ; Neuropsychological Tests ; Machine Learning ; }, abstract = {OBJECTIVES: This research study aims to advance the staging of Parkinson's disease (PD) by incorporating machine learning to assess and include a broader multifunctional spectrum of neurocognitive symptoms in the staging schemes beyond motor-centric assessments. Specifically, we provide a novel framework to modernize and personalize PD staging more objectively by proposing a hybrid feature scoring approach.<br><br>METHODS: &#x2003;We recruited 37 individuals diagnosed with PD, each of whom completed a series of tablet-based neurocognitive tests assessing motor, memory, speech, executive functions, and tasks ranging in complexity from single to multifunctional. Then, the collected data were used to develop a hybrid feature scoring system to calculate a weighted vector for each function. We evaluated the current PD staging schemes and developed a new approach based on the features selected and extracted using random forest and principal component analysis.<br><br>RESULTS: &#x2003;Our findings indicate a substantial bias in current PD staging systems toward fine motor skills, that is, other neurological functions (memory, speech, executive function, etc.) do not map into current PD stages as well as fine motor skills do. The results demonstrate that a more accurate and personalized assessment of PD severity could be achieved by including a more exhaustive range of neurocognitive functions in the staging systems either by involving multiple functions in a unified staging score or by designing a function-specific staging system.<br><br>CONCLUSION: &#x2003;The proposed hybrid feature score approach provides a comprehensive understanding of PD by highlighting the need for a staging system that covers various neurocognitive functions. This approach could potentially lead to more effective, objective, and personalized treatment strategies. Further, this proposed methodology could be adapted to other neurodegenerative conditions such as Alzheimer's disease or amyotrophic lateral sclerosis.}, }
@article {pmid39312574, year = {2024}, author = {Plessis-Belair, J and Ravano, K and Han, E and Janniello, A and Molina, C and Sher, RB}, title = {NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.}, journal = {PLoS genetics}, volume = {20}, number = {9}, pages = {e1011411}, pmid = {39312574}, issn = {1553-7404}, support = {R01 AG079898/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *beta Karyopherins/metabolism/genetics ; *Active Transport, Cell Nucleus/genetics ; Mice ; Humans ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; *Disease Models, Animal ; Mutation ; ran GTP-Binding Protein/metabolism/genetics ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Cell Nucleus/metabolism/genetics ; Frontotemporal Dementia/genetics/metabolism/pathology ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; Alzheimer Disease/genetics/metabolism/pathology ; }, abstract = {Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.}, }
@article {pmid39312484, year = {2024}, author = {Okada, K and Ito, D and Morimoto, S and Kato, C and Oguma, Y and Warita, H and Suzuki, N and Aoki, M and Kuramoto, J and Kobayashi, R and Shinozaki, M and Ikawa, M and Nakahara, J and Takahashi, S and Nishimoto, Y and Shibata, S and Okano, H}, title = {Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {11}, pages = {3933-3948}, pmid = {39312484}, issn = {1460-2156}, support = {21H02812//Japan Society for the Promotion of Science/ ; JP20ek0109395//Japan Agency for Medical Research and Development/ ; //Takeda Science Foundation/ ; //The Yukihiko Miyata Memorial Trust for ALS Research/ ; //Yoshio Koide/ ; //Japan ALS Association/ ; //Daiichi Sankyo Foundation of Life Science/ ; //Keio Medical Association and Keio University Grant-in-Aid for Encouragement of Young Medical Scientists/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *RNA-Binding Protein FUS/genetics/metabolism ; Mice ; Humans ; *Nuclear Pore Complex Proteins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; *Nuclear Lamina/metabolism ; Disease Models, Animal ; Male ; Mice, Transgenic ; Spinal Cord/metabolism/pathology ; Female ; Mutation ; }, abstract = {Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.}, }
@article {pmid39311426, year = {2024}, author = {Azzolino, D and Piras, R and Zulueta, A and Lucchi, T and Lunetta, C}, title = {Amyotrophic lateral sclerosis as a disease model of sarcopenia.}, journal = {Age and ageing}, volume = {53}, number = {9}, pages = {}, doi = {10.1093/ageing/afae209}, pmid = {39311426}, issn = {1468-2834}, mesh = {Humans ; *Sarcopenia/physiopathology/diagnosis ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/diagnosis ; *Muscle, Skeletal/pathology/physiopathology ; Aging/pathology ; Animals ; Age Factors ; Aged ; Risk Factors ; }, abstract = {Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.}, }
@article {pmid39311315, year = {2025}, author = {Ortiz-Corredor, F and Correa-Arrieta, C and Forero Diaz, JJ and Castellar-Leones, S and Gil-Salcedo, A}, title = {Profiles of disease progression and predictors of mortality in Colombian patients with amyotrophic lateral sclerosis: a comprehensive longitudinal study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {141-148}, doi = {10.1080/21678421.2024.2405587}, pmid = {39311315}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis ; *Disease Progression ; Colombia/epidemiology ; Male ; Female ; Middle Aged ; Longitudinal Studies ; Aged ; Retrospective Studies ; Adult ; Prognosis ; }, abstract = {OBJECTIVE: This study aimed to assess the prognostic value of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) in predicting mortality and characterizing disease progression patterns in ALS patients in Colombia.<br><br>METHODS: We conducted a retrospective longitudinal analysis of 537 ALS patients from the Roosevelt Institute Rehabilitation Service between October 2008 and October 2022. The study excluded nine patients due to incomplete data, resulting in 528 individuals in the analysis. ALS diagnoses were confirmed using the revised El Escorial and Gold Coast criteria. Disease progression was assessed using the ALSFRS-R, and mortality data were sourced from follow-up calls and a national database. Statistical analysis included Cox proportional hazards models to identify mortality predictors and Growth Mixture Modeling (GMM) to explore ALS progression trajectories.<br><br>RESULTS: The majority of the cohort (63.8%) deceased within the 84-month follow-up period. Survival analysis revealed that each point increase in the ALSFRS-R rate was associated with a 2.22-fold (95% CI =1.99-2.48, p&#x2009;<&#x2009;0.001) increased risk of mortality. In the population with data from two clinical visits, the ALSFRS-R rate based on initial assessments predicted mortality more effectively over 36 months than the rate based on two evaluations. GMM identified three distinct progression trajectories: slow, intermediate, and rapid decliners.<br><br>CONCLUSIONS: The ALSFRS-R rate, derived from self-reported symptom onset, significantly predicts mortality, underscoring its value in clinical assessments. This study highlights the heterogeneity in disease progression among Colombian ALS patients, indicating the necessity for personalized treatment approaches based on individual progression trajectories. Further studies are needed to refine these predictive models and improve patient management and outcomes.}, }
@article {pmid39311028, year = {2024}, author = {Driver, MD and Postema, J and Onck, PR}, title = {The Effect of Dipeptide Repeat Proteins on FUS/TDP43-RNA Condensation in C9orf72 ALS/FTD.}, journal = {The journal of physical chemistry. B}, volume = {128}, number = {39}, pages = {9405-9417}, pmid = {39311028}, issn = {1520-5207}, mesh = {*RNA-Binding Protein FUS/chemistry/metabolism/genetics ; *C9orf72 Protein/chemistry/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Dipeptides/chemistry/metabolism ; *RNA/chemistry/metabolism ; Humans ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism ; }, abstract = {Condensation of RNA binding proteins (RBPs) with RNA is essential for cellular function. The most common familial cause of the diseases ALS and FTD is C9orf72 repeat expansion disorders that produce dipeptide repeat proteins (DPRs). We explore the hypothesis that DPRs disrupt the native condensation behavior of RBPs and RNA through molecular interactions resulting in toxicity. FUS and TDP43 are two RBPs known to be affected in ALS/FTD. We use our previously developed 1-bead-per-amino acid and a newly developed 3-bead-per-nucleotide molecular dynamics model to explore ternary phase diagrams of FUS/TDP43-RNA-DPR systems. We show that the most toxic arginine containing DPRs (R-DPRs) can disrupt the RBP condensates through cation-π interactions and can strongly sequester RNA through electrostatic interactions. The native droplet morphologies are already modified at small additions of R-DPRs leading to non-native FUS/TDP43-encapsulated condensates with a marbled RNA/DPR core.}, }
@article {pmid39310990, year = {2024}, author = {Vallejo Herrera, MJ and Vallejo Herrera, V and Del Toro Ortega, A and Tapia Guerrero, MJ}, title = {[Radiological versus endoscopic gastrostomy in patients with amyotrophic lateral sclerosis].}, journal = {Nutricion hospitalaria}, volume = {41}, number = {6}, pages = {1160-1164}, doi = {10.20960/nh.05190}, pmid = {39310990}, issn = {1699-5198}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Gastrostomy/methods/adverse effects ; Middle Aged ; Retrospective Studies ; Male ; Female ; *Enteral Nutrition/methods ; Aged ; Deglutition Disorders/etiology ; Adult ; Treatment Outcome ; Radiography ; }, abstract = {IIntroduction: patients with amyotrophic lateral sclerosis (ALS) require nutritional support, in most cases with enteral nutrition through gastrostomy, either endoscopic (PEG) or radiological (PRG). Objectives: to analyze the characteristics of patients with ALS at the time of PEG/PRG placement, and to compare the efficacy and safety of PRG versus PEG. Methods: a retrospective descriptive study. All patients with ALS who required gastrostomy in the last 3 years (2021-2023) in our hospital were recruited (4 PEG and 6 PRG). Demographic and nutritional parameters were analyzed. Results: ten patients were included, with an average age of 57 years. All patients presented with dysphagia and received oral or tube supplements prior to gastrostomy placement. The average duration of enteral nutrition was approximately 50 months, with a mortality rate of 30 % at 12 months after gastrostomy. The success rate of PEG and PRG was similar, with no complications. All patients developed deterioration of respiratory function, even after nutritional support. Conclusion: gastrostomy should be indicated as soon as a patient is at risk of aspiration pneumonia or when weight loss begins. Although the nutritional benefit of gastrostomy is well established, there is currently a delay between diagnosis and placement of approximately 4 years. PRG appears to be safer than PEG in patients with ALS and respiratory failure.}, }
@article {pmid39310519, year = {2024}, author = {Albadawi, EA}, title = {Microstructural Changes in the Corpus Callosum in Neurodegenerative Diseases.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e67378}, pmid = {39310519}, issn = {2168-8184}, abstract = {The corpus callosum, the largest white matter structure in the brain, plays a crucial role in interhemispheric communication and cognitive function. This review examines the microstructural changes observed in the corpus callosum across various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). New neuroimaging studies, mainly those that use diffusion tensor imaging (DTI) and advanced tractography methods, were put together to show how changes have happened in the organization of white matter and the connections between them. Some of the most common ways the corpus callosum breaks down are discussed, including less fractional anisotropy, higher mean diffusivity, and atrophy in certain regions. The relationship between these microstructural changes and cognitive decline, motor dysfunction, and disease progression is explored. Additionally, we consider the potential of corpus callosum imaging as a biomarker for early disease detection and monitoring. Studies show that people with these disorders have lower fractional anisotropy and higher mean diffusivity in the corpus callosum, often in ways that are specific to the disease. These changes often happen before gray matter atrophy and are linked to symptoms, which suggests that the corpus callosum could be used as an early sign of neurodegeneration. The review also highlights the implications of these findings for understanding disease mechanisms and developing therapeutic strategies. Future directions, including the application of advanced imaging techniques and longitudinal studies, are discussed to elucidate the role of corpus callosum degeneration in neurodegenerative processes. This review underscores the importance of the corpus callosum in understanding the pathophysiology of neurodegenerative diseases and its potential as a target for therapeutic interventions.}, }
@article {pmid39307464, year = {2024}, author = {Kalykaki, M and Rubio-Tomás, T and Tavernarakis, N}, title = {The role of mitochondria in cytokine and chemokine signalling during ageing.}, journal = {Mechanisms of ageing and development}, volume = {222}, number = {}, pages = {111993}, doi = {10.1016/j.mad.2024.111993}, pmid = {39307464}, issn = {1872-6216}, mesh = {Humans ; *Mitochondria/metabolism ; *Aging/metabolism ; *Signal Transduction ; *Inflammation/metabolism ; *Cytokines/metabolism ; Animals ; Chemokines/metabolism ; Cellular Senescence/physiology ; }, abstract = {Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPR[mt], in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.}, }
@article {pmid39307154, year = {2024}, author = {Pal, S and Chataway, J and Swingler, R and Macleod, MR and Carragher, NO and Hardingham, G and Selvaraj, BT and Smith, C and Wong, C and Newton, J and Lyle, D and Stenson, A and Dakin, RS and Ihenacho, A and Colville, S and Mehta, AR and Stallard, N and Carpenter, JR and Parker, RA and Keerie, C and Weir, CJ and Virgo, B and Morris, S and Waters, N and Gray, B and MacDonald, D and MacDonald, E and Parmar, MKB and Chandran, S and , }, title = {Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.}, journal = {The Lancet. Neurology}, volume = {23}, number = {11}, pages = {1097-1107}, doi = {10.1016/S1474-4422(24)00326-0}, pmid = {39307154}, issn = {1474-4465}, mesh = {Humans ; *Trazodone/therapeutic use/pharmacology ; Male ; Middle Aged ; Female ; Aged ; *Memantine/therapeutic use ; Double-Blind Method ; *Motor Neuron Disease/drug therapy ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.<br><br>METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.<br><br>FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0&#xb7;650 for memantine, -0&#xb7;625 for trazodone, and -0&#xb7;655 for placebo (memantine versus placebo estimated mean difference 0&#xb7;033, one-sided 90% CI lower level -0&#xb7;085; one-sided p=0&#xb7;36; trazodone vs placebo: 0&#xb7;065, -0&#xb7;051; one-sided p=0&#xb7;24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.<br><br>INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result.<br><br>FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.}, }
@article {pmid39307005, year = {2024}, author = {Austin, JM and Bailey, R and Velazquez, SG and Sainath, H and Jackson, C}, title = {Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123243}, doi = {10.1016/j.jns.2024.123243}, pmid = {39307005}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/complications ; *Medical Marijuana/therapeutic use ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; Disease Progression ; Cohort Studies ; Adult ; Anxiety/drug therapy/etiology ; }, abstract = {Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.}, }
@article {pmid39305776, year = {2024}, author = {Lichtfouse, J and Courtier, A and Vergunst, AC and Giannoni, P}, title = {Effects of environmental concentrations of toxins BMAA and its isomers DAB and AEG on zebrafish larvae.}, journal = {Ecotoxicology and environmental safety}, volume = {285}, number = {}, pages = {117045}, doi = {10.1016/j.ecoenv.2024.117045}, pmid = {39305776}, issn = {1090-2414}, mesh = {Animals ; *Zebrafish ; *Amino Acids, Diamino/toxicity ; *Cyanobacteria Toxins ; *Water Pollutants, Chemical/toxicity ; *Larva/drug effects ; Aminobutyrates/toxicity ; Glycine/toxicity/analogs &amp; derivatives ; Embryo, Nonmammalian/drug effects ; Toxicity Tests, Acute ; Embryonic Development/drug effects ; Isomerism ; }, abstract = {The increasing concern over the environmental presence of β-N-Methylamino-L-alanine (BMAA), a toxin primarily produced by cyanobacteria and diatoms, has stimulated numerous studies to evaluate the risk for exposed populations, mainly aquatic organisms and humans. This study focuses on the toxicity of environmental concentrations of BMAA and its isomers, l-2,4 diaminobutyric acid dihydrochloride (DAB) and N-(2-aminoethyl) glycine (AEG) on zebrafish embryo development (ng.L[-1]). Presence of BMAA in various environments, including aquatic sources, air, and desert crusts, has raised concerns due to its potential link to neurodegenerative diseases such as the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Despite its known toxicity at high concentrations, there is limited information on the effects of environmental concentrations of BMAA and its isomers. These isomers are often found in association with BMAA and have been detected in seafood intended for human consumption, indicating potential risks from bioaccumulation and biomagnification. Zebrafish embryos have been chosen as a model due to their relevance for embryonic development and toxicity studies. The study employed fish embryo acute toxicity tests and behavioural analyses to specifically assess the sublethal effects of BMAA, DAB, and AEG. The results demonstrated larval mortality rates between 0 % and 3.75 %, while morphological defects were detected across all tested concentrations for each molecule. Behavioural analyses showed alterations in swimming behaviour. Unexpectedly, the changes in morphology and locomotion of the zebrafish larvae were detected more frequently at the lowest concentrations tested, suggesting potential non-monotonic dose responses. Overall, this research underscores the environmental risks associated with BMAA and its isomers, highlighting the importance of continuous monitoring and understanding of their sublethal effects on aquatic organisms and potential implications for human health. Further studies are warranted to elucidate the mechanisms of toxicity, evaluate long-term effects, and assess the risks associated with chronic exposure to these toxins.}, }
@article {pmid39297678, year = {2024}, author = {Paoletti, O and Hyeraci, G and Finochietti, M and Celani, MG and Bacigalupo, I and Lombardi, N and Crescioli, G and Tuccori, M and Cascini, S and Gini, R and Addis, A and Kirchmayer, U and , }, title = {Pharmacological and non-pharmacological treatments in amyotrophic lateral sclerosis: an Italian real-world data study.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16470}, pmid = {39297678}, issn = {1468-1331}, support = {//Agenzia Italiana del Farmaco, Ministero della Salute/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/epidemiology/drug therapy ; Italy/epidemiology ; *Riluzole/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; Neuroprotective Agents/therapeutic use ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions.<br><br>METHODS: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2&#x2009;years before and 1&#x2009;year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12&#x2009;months after the index date. Determinants of riluzole use were also investigated.<br><br>RESULTS AND CONCLUSIONS: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74&#x2009;years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12&#x2009;months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole.}, }
@article {pmid39297377, year = {2024}, author = {Akyuz, E and Aslan, FS and Gokce, E and Ilmaz, O and Topcu, F and Kakac, S}, title = {Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.}, journal = {The European journal of neuroscience}, volume = {60}, number = {8}, pages = {6057-6090}, doi = {10.1111/ejn.16541}, pmid = {39297377}, issn = {1460-9568}, mesh = {Humans ; *Genetic Therapy/methods ; *Extracellular Vesicles/metabolism/genetics ; *CRISPR-Cas Systems ; *Huntington Disease/therapy/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; Animals ; Gene Editing/methods ; Neurodegenerative Diseases/therapy/genetics ; }, abstract = {Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.}, }
@article {pmid39305312, year = {2024}, author = {Torres, P and Rico-Rios, S and Ceron-Codorniu, M and Santacreu-Vilaseca, M and Seoane-Miraz, D and Jad, Y and Ayala, V and Mariño, G and Beltran, M and Miralles, MP and Andrés-Benito, P and Fernandez-Irigoyen, J and Santamaria, E and López-Otín, C and Soler, RM and Povedano, M and Ferrer, I and Pamplona, R and Wood, MJA and Varela, MA and Portero-Otin, M}, title = {TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {45}, pmid = {39305312}, issn = {1432-0533}, support = {PI 20-00155//Instituto de Salud Carlos III/ ; 23-00176//Instituto de Salud Carlos III/ ; Programa Margarita Salas//Ministerio de Universidades/ ; SGR//Departament d'Innovaci&#xf3;, Universitats i Empresa, Generalitat de Catalunya/ ; Ayuda Unzue//Fundaci&#xf3;n Luzon/ ; }, mesh = {Animals ; *Autophagy-Related Proteins/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Microtubule-Associated Proteins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cysteine Endopeptidases/metabolism/genetics ; Male ; Spinal Cord/metabolism/pathology ; Autophagy/physiology ; Mice, Knockout ; RNA Splicing/genetics ; Female ; Mice, Transgenic ; Motor Neurons/metabolism/pathology ; Oligonucleotides, Antisense/pharmacology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b[-/-] mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.}, }
@article {pmid39305271, year = {2024}, author = {Panzetta, ME and Valdivia, RH}, title = {Akkermansia in the gastrointestinal tract as a modifier of human health.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2406379}, pmid = {39305271}, issn = {1949-0984}, support = {R01 AI142376/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; *Akkermansia/physiology ; Animals ; *Gastrointestinal Tract/microbiology ; Gastrointestinal Diseases/microbiology ; }, abstract = {Akkermansia sp are common members of the human gut microbiota. Multiple reports have emerged linking the abundance of A. muciniphila to health benefits and disease risk in humans and animals. This review highlights findings linking Akkermansia species in the gastrointestinal (GI) tract to health outcomes across a spectrum of disorders, encompassing those that affect the digestive, respiratory, urinary, and central nervous systems. The mechanism through which Akkermansia exerts a beneficial versus a detrimental effect on health is likely dependent on the genetic makeup of the host metabolic capacity and immunomodulatory properties of the strain, the competition or cooperation with other members of the host microbiota, as well as synergy with co-administered therapies.}, }
@article {pmid39304897, year = {2024}, author = {Ortiz, DA and Peregrín, N and Valencia, M and Vinueza-Gavilanes, R and Marín-Ordovas, E and Ferrero, R and Nicolás, MJ and González-Aseguinolaza, G and Arrasate, M and Aragón, T}, title = {GCN2 inhibition reduces mutant SOD1 clustering and toxicity and delays disease progression in an amyotrophic lateral sclerosis mouse model.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {49}, pmid = {39304897}, issn = {2047-9158}, support = {BFU2017-90043-P//Ministerio de Ciencia e Innovaci&#xf3;n, Gobierno de Espa&#xf1;a/ ; PID2020-120497RB-I00//Ministerio de Ciencia y Universidades, Gobierno de Espa&#xf1;a/ ; Proyecto Intramural IdisNa 2022//Navarra Institute for Health Research (IdiSNA)/ ; Proyectos I+D, 2017//Fundaci&#xf3;n para la Investigaci&#xf3;n M&#xe9;dica Aplicada/ ; AC Predoctoral Fellowship//Fundaci&#xf3;n para la Investigaci&#xf3;n M&#xe9;dica Aplicada/ ; 270-2018-922//Rep&#xfa;blica de Panam&#xe1;, Programa de Becas IFARHU-SENACYT/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/drug therapy ; Animals ; *Disease Progression ; *Disease Models, Animal ; Mice ; *Superoxide Dismutase-1/genetics ; *Mice, Transgenic ; Protein Serine-Threonine Kinases/genetics/antagonists &amp; inhibitors ; Humans ; Mutation/genetics ; }, }
@article {pmid39302099, year = {2024}, author = {Haider, R and Shipley, B and Surewicz, K and Hinczewski, M and Surewicz, WK}, title = {Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.}, journal = {Protein science : a publication of the Protein Society}, volume = {33}, number = {10}, pages = {e5179}, pmid = {39302099}, issn = {1469-896X}, support = {F30 AG071339/AG/NIA NIH HHS/United States ; F30 AG071339-03/NH/NIH HHS/United States ; T32 GM007250/GM/NIGMS NIH HHS/United States ; T32 NS077888/NH/NIH HHS/United States ; T32 GM007250/NH/NIH HHS/United States ; RF1 AG061797/NH/NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; Humans ; Phosphorylation ; *Protein Domains ; Molecular Dynamics Simulation ; Amino Acid Substitution ; Liquid-Liquid Extraction ; Phase Separation ; }, abstract = {C-terminally phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) marks the proteinaceous inclusions that characterize a number of age-related neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration and Alzheimer's disease. TDP-43 phosphorylation at S403/S404 and (especially) at S409/S410 is, in fact, accepted as a biomarker of proteinopathy. These residues are located within the low complexity domain (LCD), which also drives the protein's liquid-liquid phase separation (LLPS). The impact of phosphorylation at these LCD sites on phase separation of the protein is a topic of great interest, as these post-translational modifications and LLPS are both implicated in proteinopathies. Here, we employed a combination of experimental and simulation-based approaches to explore this question on a phosphomimetic model of the TDP-43 LCD. Our turbidity and fluorescence microscopy data show that phosphomimetic Ser-to-Asp substitutions at residues S403, S404, S409 and S410 alter the LLPS behavior of TDP-43 LCD. In particular, unlike the LLPS of unmodified protein, LLPS of the phosphomimetic variants displays a biphasic dependence on salt concentration. Through coarse-grained modeling, we find that this biphasic salt dependence is derived from an altered mechanism of phase separation, in which LLPS-driving short-range intermolecular hydrophobic interactions are modulated by long-range attractive electrostatic interactions. Overall, this in vitro and in silico study provides a physiochemical foundation for understanding the impact of pathologically relevant C-terminal phosphorylation on the LLPS of TDP-43 in a more complex cellular environment.}, }
@article {pmid39302063, year = {2024}, author = {Khanna, RK and Catanese, S and Mortemousque, G and Mureau, N and Emond, P and Pisella, PJ and Blasco, H and Corcia, P}, title = {Exploring amyotrophic lateral sclerosis through the visual system: A systematic review.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16475}, pmid = {39302063}, issn = {1468-1331}, mesh = {*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Humans ; Vision Disorders/etiology/physiopathology ; Visual Pathways/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: The human visual system relies on neural networks throughout the brain that are easily accessible for tests exploring eye structures and movements. Over the past two decades, investigations have been carried out on both afferent and efferent components of the visual system in people with amyotrophic lateral sclerosis (ALS). This approach might represent an innovative biomarker research strategy to better characterise the phenotypic variability of ALS. The purpose of this review was to determine whether exploring the visual system of patients with ALS (pwALS) is an effective strategy.<br><br>METHODS: The Medline and Web of science databases were searched for studies with terms relating to ALS and vision. Of 1146 references identified, 43 articles were included.<br><br>RESULTS: In this review article, both afferent and efferent components of the visual system were found to be impaired in pwALS in the absence of visual complaint, thereby contributing to the hypothesis that ALS is a multisystem disease with sensory involvement. Of note, some areas of the eye remain unexplored (i.e., tears, and retinal function using electroretinography).<br><br>CONCLUSIONS: According to the findings available in the literature, investigating the oculomotor system and exploring the ocular surface could represent two key promising strategies to identify new diagnostic biomarkers in pwALS. Further longitudinal studies are needed to identify relevant indicators of disease progression and response to therapeutic intervention.}, }
@article {pmid39301564, year = {2024}, author = {Barnard, J and Hunt, R and Yucel, M and Mazaud, D and Smith, BN and Fanto, M}, title = {Human TDP43 is required for ALS‑related annexin A11 toxicity in Drosophila.}, journal = {Biomedical reports}, volume = {21}, number = {5}, pages = {165}, pmid = {39301564}, issn = {2049-9442}, abstract = {Genomics allows identification of genes and mutations associated with amyotrophic lateral sclerosis (ALS). Mutations in annexin A11 (ANXA11) are responsible for ~1% of all familial ALS and fronto-temporal dementia cases. The present study used the fruit fly, Drosophila melanogaster, to assess the mechanism of toxicity of ANXA11 mutants in residues that are conserved in the fly ANXB11 protein, the closest homolog to human ANXA11. In immune fluorescence, lifespan and negative geotaxis assays ANXA11 mutants, while displaying some degree of alteration in localization and function, did not exert any relevant organism toxicity in Drosophila. However, they showed a specific interaction with human TAR DNA-binding protein (TDP43). The present study illustrated that the ANXA11 mutants interact with human TDP43, but not the fly TAR DNA-binding protein-43 homolog (TBPH) or other ALS-associated genes such as super oxide dismutase 1, to shorten lifespan and increase negative geotaxis defects. This sheds light both on the mechanisms underlying ALS, further elucidating the intricate molecular network implicated in ALS and placing ANXA11 as a key player in its pathology, and on the complexity of using Drosophila as a model organism for researching genes in ALS.}, }
@article {pmid39300745, year = {2024}, author = {Guo, Y and Ma, G and Wang, Y and Lin, T and Hu, Y and Zang, T}, title = {Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity.}, journal = {Aging cell}, volume = {23}, number = {11}, pages = {e14271}, pmid = {39300745}, issn = {1474-9726}, support = {62371161//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Longevity/genetics ; *Neurodegenerative Diseases/genetics ; *Epigenesis, Genetic ; *Aging/genetics ; *Genome-Wide Association Study ; Mendelian Randomization Analysis ; }, abstract = {The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.}, }
@article {pmid39302926, year = {2024}, author = {Chung, YM and Hu, CS and Sun, E and Tseng, HC}, title = {Morphological multiparameter filtration and persistent homology in mitochondrial image analysis.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310157}, pmid = {39302926}, issn = {1932-6203}, mesh = {Humans ; *Mitochondria/metabolism/genetics ; *Membrane Transport Proteins/genetics/metabolism ; *Image Processing, Computer-Assisted/methods ; Cell Cycle Proteins/genetics/metabolism ; Transcription Factor TFIIIA/genetics/metabolism ; Mutation ; Software ; }, abstract = {The complexity of branching and curvilinear morphology of a complete mitochondrial network within each cell is challenging to analyze and quantify. To address this challenge, we developed an image analysis technique using persistent homology with a multiparameter filtration framework, combining image processing techniques in mathematical morphology. We show that such filtrations contain both topological and geometric information about complex cellular organelle structures, which allows a software program to extract meaningful features. Using this information, we also develop a connectivity index that describes the morphology of the branching patterns. As proof of concept, we utilize this approach to study how mitochondrial networks are altered by genetic changes in the Optineurin gene. Mutations in the autophagy gene Optineurin (OPTN) are associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), and Paget's disease of the bone, but the pathophysiological mechanism is unclear. We utilized the proposed mathematical morphology-based multiparameter filtration and persistent homology approach to analyze and quantitatively compare how changes in the OPTN gene alter mitochondrial structures from their normal interconnected, tubular morphology into scattered, fragmented pieces.}, }
@article {pmid39300574, year = {2024}, author = {Ashkaran, F and Seyedalipour, B and Baziyar, P and Hosseinkhani, S}, title = {Mutation/metal deficiency in the "electrostatic loop" enhanced aggregation process in apo/holo SOD1 variants: implications for ALS diseases.}, journal = {BMC chemistry}, volume = {18}, number = {1}, pages = {177}, pmid = {39300574}, issn = {2661-801X}, abstract = {Despite the many mechanisms it has created to prevent unfolding and aggregation of proteins, many diseases are caused by abnormal folding of proteins, which are called misfolding diseases. During this process, proteins undergo structural changes and become stable, insoluble beta-sheet aggregates called amyloid fibrils. Mutations/disruptions in metal ion homeostasis in the ALS-associated metalloenzyme superoxide dismutase (SOD1) reduce conformational stability, consistent with the protein aggregation hypothesis for neurodegenerative diseases. However, the exact mechanism of involvement is not well understood. Hence, to understand the role of mutation/ metal deficiency in SOD1 misfolding and aggregation, we investigated the effects of apo/holo SOD1 variants on structural properties using biophysical/experimental techniques. The MD results support the idea that the mutation/metal deficiency can lead to a change in conformation. The increased content of β-sheet structures in apo/holo SOD1 variants can be attributed to the aggregation tendency, which was confirmed by FTIR spectroscopy and dictionary of secondary structure in proteins (DSSP) results. Thermodynamic studies of GdnHCl showed that metal deficiency/mutation/intramolecular S-S reduction together are required to initiate misfolding/aggregation of SOD1. The results showed that apo/holo SOD1 variants under destabilizing conditions induced amyloid aggregates at physiological pH, which were detected by ThT/ANS fluorescence, as well as further confirmation of amyloid/amorphous species by TEM. This study confirms that mutations in the electrostatic loop of SOD1 lead to structural abnormalities, including changes in hydrophobicity, reduced disulfide bonds, and an increased propensity for protein denaturation. This process facilitates the formation of amyloid/amorphous aggregates ALS-associated.}, }
@article {pmid39300421, year = {2024}, author = {Koçkaya, PD and Alvur, TM and Odabaşı, O}, title = {Empowering medical students: bridging gaps with high-fidelity simulations; a mixed-methods study on self-efficacy.}, journal = {BMC medical education}, volume = {24}, number = {1}, pages = {1026}, pmid = {39300421}, issn = {1472-6920}, mesh = {Humans ; *Self Efficacy ; *Students, Medical/psychology ; Prospective Studies ; *Clinical Competence ; Male ; Female ; Cardiopulmonary Resuscitation/education ; Simulation Training ; Adult ; Emergency Medicine/education ; High Fidelity Simulation Training ; Young Adult ; Focus Groups ; Education, Medical, Undergraduate/methods ; Empowerment ; }, abstract = {BACKGROUND: High-fidelity simulations play a crucial role in preparing for high-mortality events like cardiopulmonary arrest, emphasizing the need for rapid and accurate intervention. Proficiency in cardiopulmonary resuscitation(CPR) requires a strong self-efficacy(SE); training for both is crucial. This study assesses the impact of Advanced Life Support(ALS) simulation on SE changes in final-year medical students.<br><br>METHODS: This mixed-methods prospective simulation study involved medical students in emergency medicine internships, examining self-efficacy perceptions regarding ALS technical skills(ALS-SEP). A comparison was made between students who underwent scenario-based ALS simulation training and those who did not. Competencies in chest compression skills were assessed, and the concordance between ALS-SEP scores and observed CPR performances were evaluated. Focus group interviews were conducted and analyzed using content analysis techniques.<br><br>RESULTS: The study involved 80 students, with 53 in the experimental group(EG) and 27 in the control group(CG). The EG, underwent simulation training, showed a significantly higher ALS-SEP change than the CG(p&#x2009;<&#x2009;0.05). However, there was low concordance between pre-simulation SEP and actual performance. Compression skills success rates were inadequate. Qualitative analysis revealed main themes as"learning"(32.6%), "self-efficacy"(29%), "simulation method"(21.3%), and "development"(16.5%).<br><br>DISCUSSION: Post-simulation, students reported improved SEP and increased readiness for future interventions. The findings and qualitative statements support the effectiveness of simulation practices in bridging the gap between SEP and performance. Utilizing simulation-based ALS training enhances learners' belief in their capabilities, raises awareness of their competencies, and encourages reflective thinking. Given the importance of high SEP for ALS, simulation trainings correlating self-efficacy perception and performance may significantly reduce potential medical errors stemming from a disparity between perceived capability and actual performance.}, }
@article {pmid39300071, year = {2024}, author = {Castelli, S and Desideri, E and Laureti, L and Felice, F and De Cristofaro, A and Scaricamazza, S and Lazzarino, G and Ciriolo, MR and Ciccarone, F}, title = {N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.}, journal = {Cell death &amp; disease}, volume = {15}, number = {9}, pages = {686}, pmid = {39300071}, issn = {2041-4889}, support = {GR-2019-1236998//Ministero della Salute (Ministry of Health, Italy)/ ; MNESYS PNRR - MUR PE00000006//Ministero della Salute (Ministry of Health, Italy)/ ; }, mesh = {Animals ; *Glycolysis/drug effects ; *Muscle Fibers, Skeletal/metabolism/drug effects ; Mice ; *Aspartic Acid/metabolism/analogs &amp; derivatives ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Humans ; Oxidation-Reduction ; Cell Line ; Mice, Transgenic ; }, abstract = {N-acetylaspartate (NAA) is a neuronal metabolite that can be extruded in extracellular fluids and whose blood concentration increases in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Aspartoacylase (ASPA) is the enzyme responsible for NAA breakdown. It is abundantly expressed in skeletal muscle and most other human tissues, but the role of NAA catabolism in the periphery is largely neglected. Here we demonstrate that NAA treatment of differentiated C2C12 muscle cells increases lipid turnover, mitochondrial biogenesis and oxidative metabolism at the expense of glycolysis. These effects were ascribed to NAA catabolism, as CRISPR/Cas9 ASPA KO cells are insensitive to NAA administration. Moreover, the metabolic switch induced by NAA was associated with an augmented resistance to atrophic stimuli. Consistently with in vitro results, SOD1-G93A ALS mice show an increase in ASPA levels in those muscles undergoing the glycolytic to oxidative switch during the disease course. The impact of NAA on the metabolism and resistance capability of myotubes supports a role for this metabolite in the phenotypical adaptations of skeletal muscle in neuromuscular disorders.}, }
@article {pmid39299905, year = {2024}, author = {Hetz, C and Thielen, P and Matus, S and Nassif, M and Court, F and Kiffin, R and Martinez, G and Cuervo, AM and Brown, RH and Glimcher, LH}, title = {Corrigendum: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.}, journal = {Genes &amp; development}, volume = {38}, number = {15-16}, pages = {785}, doi = {10.1101/gad.352249.124}, pmid = {39299905}, issn = {1549-5477}, }
@article {pmid39299508, year = {2024}, author = {Shetty, P and Ren, Y and Dillon, D and Mcleod, A and Nishijima, D and Taylor, SL and , }, title = {Derivation of a clinical decision rule for termination of resuscitation in non-traumatic pediatric out-of-hospital cardiac arrest.}, journal = {Resuscitation}, volume = {204}, number = {}, pages = {110400}, pmid = {39299508}, issn = {1873-1570}, support = {K38 HL165363/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; Retrospective Studies ; Child ; *Clinical Decision Rules ; *Cardiopulmonary Resuscitation/methods ; Child, Preschool ; Emergency Medical Services/methods ; Medical Futility ; Adolescent ; Infant ; Resuscitation Orders ; Withholding Treatment/standards ; }, abstract = {AIM: Prehospital termination of resuscitation (ToR) rules are used to predict medical futility in adult out-of-hospital cardiac arrest (OHCA), however, the available evidence for pediatric patients is limited. The primary aim of this study is to derive a Pediatric Termination of Resuscitation (PToR) prediction rule for use in pediatric non-traumatic OHCA patients.<br><br>METHODS: We analyzed a retrospective cohort of pediatric OHCA patients within the CARES database over a 10-year period (2013-2022). We split the dataset into training and test datasets and fit logistic regressions with Least Absolute Shrinkage and Selection Operator (LASSO) to select predictor variables and estimate predictive test characteristics for the primary outcome of death and a secondary composite outcome of death or survival to hospital discharge with unfavorable neurologic status.<br><br>RESULTS: We analyzed a sample of 21,240 children where 2,326 (11.0%) survived to hospital discharge, and 1,894 (8.9%) survived to hospital discharge with favorable neurologic status. We derived a PToR rule for death demonstrating a specificity of 99.1% and a positive predictive value (PPV) of 99.8% and a PToR rule for death or survival with poor neurologic status with a specificity of 99.7% and PPV of 99.9% within the test dataset.<br><br>CONCLUSION: We derived a clinical prediction rule with high specificity and positive predictive value in prehospital settings utilizing Advanced Life Support (ALS) providers which may inform termination of resuscitation considerations in pediatric patients. Further prospective and validation studies will be necessary to define the appropriateness and applicability of these PToR criteria for routine use.}, }
@article {pmid39299489, year = {2024}, author = {Le, NT and Chu, N and Joshi, G and Higgins, NR and Nebie, O and Adelakun, N and Butts, M and Monteiro, MJ}, title = {Prion protein pathology in Ubiquilin 2 models of ALS.}, journal = {Neurobiology of disease}, volume = {201}, number = {}, pages = {106674}, pmid = {39299489}, issn = {1095-953X}, support = {K22 CA241105/CA/NCI NIH HHS/United States ; R01 NS098243/NS/NINDS NIH HHS/United States ; R35 GM151124/GM/NIGMS NIH HHS/United States ; RF1 NS098243/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; Humans ; *Autophagy-Related Proteins/metabolism/genetics ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Mutation ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism/pathology ; Prion Proteins/metabolism/genetics ; Inclusion Bodies/metabolism/pathology ; Neurons/metabolism/pathology ; Mice, Transgenic ; }, abstract = {Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrP[C]) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrP[C] with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrP[C] protein degradation and leads to mislocalization of PrP[C] in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrP[C] bind together in a complex. The abnormalities in PrP[C] caused by UBQLN2 mutations may be relevant in disease pathogenesis.}, }
@article {pmid39299156, year = {2024}, author = {Caswell, G and Wilson, E}, title = {The impact of home mechanical ventilation on the time and manner of death for those with Motor neurone disease (MND): A qualitative study of bereaved family members.}, journal = {Social science &amp; medicine (1982)}, volume = {360}, number = {}, pages = {117345}, doi = {10.1016/j.socscimed.2024.117345}, pmid = {39299156}, issn = {1873-5347}, mesh = {Humans ; *Motor Neuron Disease/psychology/complications ; *Qualitative Research ; Male ; Female ; *Respiration, Artificial/psychology ; Middle Aged ; *Family/psychology ; United Kingdom ; Aged ; *Bereavement ; Attitude to Death ; Adult ; Terminal Care/psychology/methods ; Home Care Services ; Time Factors ; Aged, 80 and over ; }, abstract = {Motor neurone disease (MND) is a progressive neurodegenerative disorder which is ultimately terminal. It causes muscle weakness which can lead to the need for assistance in breathing, for some with the disease. This paper draws on qualitative research using semi-structured interviews with 32 people bereaved by the death of a family member with MND who was dependent on home mechanical ventilation, from across the United Kingdom. Interviews explored how the end-of-life of a person who had used non-invasive ventilation to assist their breathing was experienced by participants, who had cared about, and for them. Four themes are used to examine the impact of dependent ventilation technology on the experience of dying on the part of bereaved family members. Themes are: accompanied dying, planned withdrawal of ventilation, blurred time of death, time post-death. The perception and experience of time was a key component across all four themes. Ventilator technology played a critical role in sustaining life, but it could also contribute to a complex dynamic where the realities of death were mediated or obscured. This raises ethical, emotional, and existential considerations, both for the individuals receiving ventilator support and their families, as well as for healthcare professionals involved in end-of-life care.}, }
@article {pmid39299050, year = {2024}, author = {Eshak, D and Arumugam, M}, title = {Unveiling therapeutic biomarkers and druggable targets in ALS: An integrative microarray analysis, molecular docking, and structural dynamic studies.}, journal = {Computational biology and chemistry}, volume = {113}, number = {}, pages = {108211}, doi = {10.1016/j.compbiolchem.2024.108211}, pmid = {39299050}, issn = {1476-928X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; *Molecular Docking Simulation ; *Biomarkers/metabolism/analysis/blood ; Microarray Analysis ; Molecular Dynamics Simulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder characterized by the progressive degeneration of nerve cells in the brain and spinal cord. Despite extensive research, its precise etiology remains elusive, and early diagnosis is challenging due to the absence of specific tests. This study aimed to identify potential blood-based biomarkers for early ALS detection and monitoring using datasets from whole blood samples (GSE112680) and oligodendrocytes, astrocytes, and fibroblasts (GSE87385) obtained from the NCBI-GEO repository. Through bioinformatics analysis, including protein-protein interactions and molecular pathway analyses, we identified differentially expressed genes (DEGs) associated with ALS. Notably, ALS2, ADH7, ALDH8A1, ALDH3B1, ABHD2, ABHD17B, ABHD12, ABHD13, PGAM2, AURKB, ANAPC11, VAPA, UNC45B, and TNNT2 emerged as top-ranked DEGs, implicated in drug metabolism, protein depalmytilation, and the AKT/mTOR signaling pathways. Among these, AurKB established as a potential therapeutic biomarker with relevance to various neurological conditions. Consequently, AurKB was selected for identifying potential therapeutic molecules and utilized for in silico structural characterization studies. Exploration of the IMPATT database led to the discovery of a lead compound similar to Fostamatinib, currently used for AurKB. Initial molecular docking and MMGBSA-based binding energy analysis were followed by molecular dynamics simulation (MDS) and free energy landscape (FEL) analysis to validate the ligand's binding efficacy and understand dynamic processes within the biological system. The identified potential biomarkers and lead molecule provide novel insights into the correlation between blood cell transcripts and ALS pathology, paving the way for blood-based diagnostic tools for early ALS detection and ongoing disease monitoring.}, }
@article {pmid39297270, year = {2024}, author = {Doğan, V and Şenormanci, &#xd6;}, title = {Validity and Reliability of the Affective Lability Scale-18 (ALS-18) Turkish Form in the Non-Clinical Group.}, journal = {Turk psikiyatri dergisi = Turkish journal of psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.5080/u27329}, pmid = {39297270}, issn = {2651-3463}, abstract = {OBJECTIVE: Affective lability, which is an important aspect of mood dysregulation, is seen in many psychiatric conditions. The aim of this study is to examine the psychometric properties of the Affective Lability Scale-18 in the Turkish sample of the non-clinical group.<br><br>METHOD: A total of 615 individuals (312 females and 303 males) who did not have a past or current psychiatric disorder were included in the study. The participants were administered sociodemographic data form, Affective Lability Scale-18, Difficulties in Emotion Regulation Scale, and Beck Depression Inventory. The participants were divided into 4 groups; a pilot group, EFA (exploratory factor analysis) group, CFA (confirmatory factor analysis) group and test-retest group.<br><br>RESULTS: The factor analysis conducted for the construct validity of the scale, revealed similar results to that of the original scale. The Cronbach's alpha internal consistency coefficient was 0.92 for the EFA group and 0.92 for the CFA group. The test-retest reliability coefficient was 0.82. Difficulties in Emotion Regulation Scale (DERS) and Beck's Depression Inventory (BDI) were used tp measure validity. The correlation between the total scores of participants on the ALS-18 and their scores on the DERS and BDI was determined to be positive and moderate (r=0.38, r=41).<br><br>CONCLUSION: The Affective Lability Scale-18 in the Turkish sample, three sub-dimensions, anxiety/depression, depression/elevation, anger and the general factor all have sufficient internal consistency and it has been demonstrated that the scale can be applied in our country to evaluate the situations in which affect variability is evaluated.}, }
@article {pmid39296960, year = {2024}, author = {Keilholz, AN and Pathak, I and Smith, CL and Osman, KL and Smith, L and Oti, G and Golzy, M and Ma, L and Lever, TE and Nichols, NL}, title = {Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1441529}, pmid = {39296960}, issn = {1664-2295}, abstract = {INTRODUCTION: Tongue weakness and atrophy can lead to deficits in the vital functions of breathing and swallowing in patients with motor neuron diseases (MNDs; e.g., amyotrophic lateral sclerosis (ALS) and pseudobulbar palsy), often resulting in aspiration pneumonia, respiratory failure, and death. Available treatments for patients with MNDs are largely palliative; thus, there is a critical need for therapies targeting preservation of upper airway function and suggesting a role for tongue exercise in patients with MNDs. Here, we leveraged our inducible rodent model of hypoglossal (XII) motor neuron degeneration to investigate the effects of a strength endurance tongue exercise program on upper airway structure and function. Our model was created through intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue to induce targeted death of XII motor neurons.<br><br>METHODS: Rats in this study were allocated to 4 experimental groups that received intralingual injection of either CTB-SAP or unconjugated CTB + SAP (i.e., control) +/- tongue exercise. Following tongue exercise exposure, we evaluated the effect on respiratory function (via plethysmography), macrostructure [via magnetic resonance imaging (MRI) of the upper airway and tongue], and ultrafine structure [via ex vivo magnetic resonance spectroscopy (MRS) of the tongue] with a focus on lipid profiles.<br><br>RESULTS: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to CTB-SAP + exercise rats and control rats +/- tongue exercise, which was ameliorated with tongue exercise. Additionally, CTB-SAP + sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP + exercise rats or control rats +/- tongue exercise.<br><br>CONCLUSION: These findings provide further evidence that a strength endurance tongue exercise program may be a viable therapeutic treatment option in patients with XII motor neuron degeneration in MNDs such as ALS. Future directions will focus on investigating the underlying mechanism responsible for tongue exercise-induced plasticity in the hypoglossal-tongue axis, particularly inflammatory associated factors such as BDNF.}, }
@article {pmid39296911, year = {2024}, author = {Odat, RM and Alomari, O and Elgenidy, A}, title = {Evaluation of the gold cost criteria as a diagnostic criteria of amyotrophic lateral sclerosis.}, journal = {eNeurologicalSci}, volume = {37}, number = {}, pages = {100524}, pmid = {39296911}, issn = {2405-6502}, }
@article {pmid39295200, year = {2025}, author = {Zhang, Z and He, X and Wang, J and Cui, J and Shi, B}, title = {The correlation between social support, coping style, advance care planning readiness, and quality of life in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {40-47}, doi = {10.1080/21678421.2024.2400520}, pmid = {39295200}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Quality of Life/psychology ; Male ; Female ; Middle Aged ; *Adaptation, Psychological ; Cross-Sectional Studies ; *Social Support ; *Advance Care Planning ; Aged ; Adult ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: The primary goal for clinical healthcare professionals is to enhance the quality of life (QOL) of patients with amyotrophic lateral sclerosis (ALS). This study aimed to explore the correlation between social support, coping style, advance care planning (ACP) readiness, and QOL in patients with ALS. We also sought to analyze the mediating effect of coping style and ACP readiness between social support and QOL, and to provide insights for developing targeted interventions to improve patients' QOL.<br><br>METHODS: A cross-sectional design was used, with participants recruited through convenience sampling in Tianjin, China. Statistical analysis included the t-test, analysis of variance, correlation analysis, and mediating effect analysis.<br><br>RESULTS: The study included 215 participants. The QOL of patients with ALS was at a medium level, with significant correlations between social support, coping style, ACP readiness, and QOL (all p&#x2009;<&#x2009;0.01). The direct effect of social support on QOL was 0.403 (p&#x2009;=&#x2009;0.018), accounting for 41.85% of the total effect. The total indirect effect of social support on QOL through coping style and ACP readiness was 0.560 (p&#x2009;<&#x2009;0.001), accounting for 58.15% of the total effect. The chain mediating effect involving facing, avoiding, and ACP readiness accounted for 16.72%.<br><br>CONCLUSION: Social support directly influenced QOL and had an indirect impact through coping style and ACP readiness. Healthcare professionals can improve the QOL of patients with ALS by enhancing social support, disease-coping ability, and ACP readiness in clinical practice.}, }
@article {pmid39295118, year = {2024}, author = {Berry, JD and Paganoni, S and Harms, MB and Shneider, N and Andrews, J and Miller, TM and Babu, S and Sherman, AV and Harris, BT and Provenzano, FA and Phatnani, HP and Shefner, J and Garret, MA and Ladha, SS and Tsou, AY and Mohan, P and Igne, C and ,  and Bowser, R}, title = {Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {6}, pages = {1140-1150}, doi = {10.1002/mus.28244}, pmid = {39295118}, issn = {1097-4598}, support = {OT2 NS136938/NS/NINDS NIH HHS/United States ; OT2 NS136939/NS/NINDS NIH HHS/United States ; 1OT2NS136939-01//National Institute of Neurological Disorders and Stroke, NIH/ ; 1OT2NS136938-01//National Institute of Neurological Disorders and Stroke, NIH/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Humans ; United States ; Biomedical Research ; National Institutes of Health (U.S.) ; }, abstract = {Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.}, }
@article {pmid39294194, year = {2024}, author = {Luthi-Carter, R and Cappelli, S and Le Roux-Bourdieu, M and Tentillier, N and Quinn, JP and Petrozziello, T and Gopalakrishnan, L and Sethi, P and Choudhary, H and Bartolini, G and Gebara, E and Stuani, C and Font, L and An, J and Ortega, V and Sage, J and Kosa, E and Trombetta, BA and Simeone, R and Seredenina, T and Afroz, T and Berry, JD and Arnold, SE and Carlyle, BC and Adolfsson, O and Sadri-Vakili, G and Buratti, E and Bowser, R and Agbas, A}, title = {Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21837}, pmid = {39294194}, issn = {2045-2322}, support = {P30 AG062421/AG/NIA NIH HHS/United States ; Industry-Led Consortium Project Grant//Target ALS Foundation/ ; BB-2022-C5//Target ALS Foundation/ ; }, mesh = {Humans ; *Blood Platelets/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurodegenerative Diseases/blood/metabolism ; *Biological Specimen Banks ; Amyotrophic Lateral Sclerosis/blood/metabolism/pathology ; Biomarkers/blood ; Cytosol/metabolism ; }, abstract = {The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system.}, }
@article {pmid39293800, year = {2024}, author = {Gao, J and Chai, N and Wang, T and Han, Z and Chen, J and Lin, G and Wu, Y and Bi, L}, title = {A new technique of percutaneous minimally invasive surgery assisted by magnetic resonance neurography.}, journal = {Bone &amp; joint open}, volume = {5}, number = {9}, pages = {776-784}, pmid = {39293800}, issn = {2633-1462}, abstract = {AIMS: In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.<br><br>METHODS: A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients' clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al's objective assessments, respectively.<br><br>RESULTS: The contracture bands exhibited three typical types of shape - feather-like, striped, and mixed shapes - in MR images. Guided by MRN images, we designed minimally invasive approaches directed to each hip. These approaches resulted in a shortened incision length in each hip (0.3 cm (SD 0.1)), shorter surgery duration (25.3 minutes (SD 5.8)), less intraoperative bleeding (8.0 ml (SD 3.6)), and shorter time between the end of the operation and the patient's first off-bed activity (17.2 hours (SD 2.0)) in each patient. Meanwhile, no serious postoperative complications occurred in all patients. The mean HOS-Sports subscale of patients increased from 71.0 (SD 5.3) to 94.83 (SD 4.24) at six months postoperatively (p < 0.001). The follow-up outcomes from all patients were "good" and "excellent", based on objective assessments.<br><br>CONCLUSION: Preoperative MRN analysis can be used to facilitate the determination of the relationship between contracture band and normal tissues. The minimally invasive surgical design via MRN can avoid nerve damage and improve the release effect.}, }
@article {pmid39293008, year = {2024}, author = {Ramirez, V and Kittrell, P and Jackson, C and Clegg, A and Allegretti, A}, title = {Sexual Intimacy in Persons with Amyotrophic Lateral Sclerosis and their Partners: A Pilot Study.}, journal = {Journal of allied health}, volume = {53}, number = {3}, pages = {212-217}, pmid = {39293008}, issn = {1945-404X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Pilot Projects ; Male ; Female ; Middle Aged ; *Sexual Partners/psychology ; Aged ; Sexual Behavior ; Adult ; Quality of Life ; }, abstract = {OBJECTIVE: The objective of this study was to describe concerns experienced among persons with amyotrophic lateral sclerosis (PALS) and their partners regarding sexual intimacy, as well as preferences regarding discussion of the topic with healthcare providers.<br><br>METHODS: A total of 27 survey responses including 13 PALS and 14 partners were received. Surveys included both quantitative and qualitative data addressing the importance of sexual intimacy to quality of life, assistance required to participate in sexual intimacy, concerns for safety, and preferred timing and method of discussing/receiving information from healthcare professionals.<br><br>RESULTS: 100% of respondents stated they had never been asked about sexual intimacy by any healthcare provider. 92% of participants agreed ALS had affected their ability to express sexual intimacy. Participants discussed loss of intimacy as due to muscle weakness, respiratory concerns, and role change among other contributors to the overall experienced change in expression of sexual intimacy. With regards to their preferred method of receiving/discussing information on the effect of ALS on sexual intimacy, 48% of participants preferred use of an online video series, 44% chose a pamphlet, 24% chose a one-on-one discussion with a healthcare provider, and 12% chose a private conversation with their partner and healthcare provider.<br><br>CONCLUSIONS: The findings greatly illustrate the difficulties and concerns experienced with sexual intimacy among PALS and their partners as well as the preferred methods for receiving information on the topic.}, }
@article {pmid39292705, year = {2024}, author = {Minnella, A and McCusker, KP and Amagata, A and Trias, B and Weetall, M and Latham, JC and O'Neill, S and Wyse, RK and Klein, MB and Trimmer, JK}, title = {Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0309893}, pmid = {39292705}, issn = {1932-6203}, mesh = {Animals ; *Ferroptosis/drug effects ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Humans ; *Parkinson Disease/drug therapy/metabolism/pathology ; Rats ; Mice ; alpha-Synuclein/metabolism ; Lipid Peroxidation/drug effects ; Neurons/drug effects/metabolism/pathology ; Fibroblasts/drug effects/metabolism ; Arachidonate 15-Lipoxygenase/metabolism ; Cells, Cultured ; Male ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.}, }
@article {pmid39292682, year = {2024}, author = {Tang, X and Li, Q and Huang, G and Pei, X and Chen, Z and Huang, Y and Zhao, S and Guo, T and Liu, Z}, title = {Immediate efficacy of auricular acupuncture combined with active exercise in the treatment of acute lumbar sprains in 10 minutes: Protocol of a randomized controlled trial.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0308801}, pmid = {39292682}, issn = {1932-6203}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acupuncture, Ear/methods ; Combined Modality Therapy ; *Exercise Therapy/methods ; Low Back Pain/therapy ; Lumbar Vertebrae/physiopathology ; Lumbosacral Region ; Pain Measurement ; Prospective Studies ; Range of Motion, Articular ; Sprains and Strains/therapy ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes.<br><br>METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle.<br><br>DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical.<br><br>TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.}, }
@article {pmid39292611, year = {2024}, author = {Xu, Z and Tang, J and Gong, Y and Zhang, J and Zou, Y}, title = {Atomistic Insights into the Stabilization of TDP-43 Protofibrils by ATP.}, journal = {Journal of chemical information and modeling}, volume = {64}, number = {19}, pages = {7639-7649}, doi = {10.1021/acs.jcim.4c01140}, pmid = {39292611}, issn = {1549-960X}, mesh = {*Adenosine Triphosphate/metabolism ; *Molecular Dynamics Simulation ; *DNA-Binding Proteins/chemistry/metabolism ; Humans ; Protein Stability ; Hydrogen Bonding ; }, abstract = {The aberrant accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates in the cytoplasm of motor neurons is the main pathological hallmark of amyotrophic lateral sclerosis (ALS). Previous experiments reported that adenosine triphosphate (ATP), the universal energy currency for all living cells, could induce aggregation and enhance the folding of TDP-43 fibrillar aggregates. However, the significance of ATP on TDP-43 fibrillation and the mechanism behind it remain elusive. In this work, we conducted multiple atomistic molecular dynamics (MD) simulations totaling 20 μs to search the critical nucleus size of TDP-43282-360 and investigate the impact of ATP molecules on preformed protofibrils. The results reveal that the trimer is the critical nucleus for TDP-43282-360 fibril formation and the tetramer is the minimal stable nucleus. When ATP molecules bind to the TDP-43282-360 trimer and tetramer, they can consolidate the TDP-43282-360 protofibrils by increasing the content of the β-sheet structure and promoting the formation of hydrogen bonds (H-bonds). Binding site analyses show that the N-terminus of TDP-43282-360 protofibrils is the main binding site of ATP, and R293 dominates the direct binding of ATP. Further analyses reveal that the π-π, cation-π, salt bridge, and H-bonding interactions together contribute to the binding of ATP to TDP-43282-360 protofibrils. This study decoded the detailed stabilization mechanism of protofibrillar TDP-43282-360 oligomers by ATP, and may provide new avenues for the development of drug design against ALS.}, }
@article {pmid39292414, year = {2024}, author = {Ataman, R and Alhasani, R and Auneau-Enjalbert, L and Quigley, A and Michael, HU and Ahmed, S}, title = {The psychometric properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system in neurorehabilitation populations: a systematic review.}, journal = {Journal of patient-reported outcomes}, volume = {8}, number = {1}, pages = {106}, pmid = {39292414}, issn = {2509-8020}, support = {36053//Canadian Foundation of Innovation and the Ministry of Health of Quebec/ ; }, mesh = {Humans ; *Nervous System Diseases/rehabilitation/psychology/diagnosis ; *Neurological Rehabilitation/methods ; *Psychometrics/methods ; *Quality of Life/psychology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To systematically review the literature of existing evidence on the measurement properties of the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system among neurorehabilitation populations.<br><br>DATA SOURCES: The Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guided this systematic review in which we searched nine electronic databases and registries, and hand-searched reference lists of included articles.<br><br>STUDY SELECTION: Two independent reviewers screened selected articles and extracted data from 28 included studies.<br><br>DATA EXTRACTION: COSMIN's approach guided extraction and synthesizing measurement properties evidence (insufficient, sufficient), and the modified GRADE approach guided synthesizing evidence quality (very-low, low, moderate, high) by diagnosis.<br><br>DATA SYNTHESIS: Neuro-QoL has sufficient measurement properties when used by individuals with Huntington's disease, Multiple Sclerosis, Parkinson's disease, stroke, lupus, cognitive decline, and amyotrophic lateral sclerosis. The strongest evidence is for the first four conditions, where test-retest reliability, construct validity, and responsiveness are nearly always sufficient (GRADE: moderate-high). Structural validity is assessed only in multiple sclerosis and stroke but is often insufficient (GRADE: moderate-high). Criterion validity is sufficient in some stroke and Huntington's disease domains (GRADE: high). Item response theory analyses were reported for some stroke domains only. There is limited, mixed evidence for responsiveness and measurement error (GRADE: moderate-high), and no cross-cultural validity evidence CONCLUSIONS: Neuro-QoL domains can describe and evaluate patients with Huntington's disease, multiple sclerosis, Parkinson's disease, and stroke, but predictive validity evidence would be beneficial. In the other conditions captured in this review, a limited number of Neuro-QoL domains have evidence for descriptive use only. For these conditions, further evidence of structural validity, measurement error, cross-cultural validity and predictive validity would enhance the use and interpretation of Neuro-QoL.}, }
@article {pmid39292338, year = {2024}, author = {Zhang, H and Gao, C and Yang, D and Nie, L and He, K and Chen, C and Li, S and Huang, G and Zhou, L and Huang, X and Wu, D and Liu, J and Huang, Z and Wang, J and Li, W and Zhang, Z and Yang, X and Zou, L}, title = {Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1[G93A] Transgenic Mice Via Activation of Mitophagy.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {39292338}, issn = {1559-1182}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1[G93A] transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&amp;E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1[G93A] mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1[G93A] mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.}, }
@article {pmid39291248, year = {2024}, author = {Senerchia, G and Dubbioso, R}, title = {Non-invasive brain stimulation therapy in amyotrophic lateral sclerosis: are we ready for clinical use?.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101055}, pmid = {39291248}, issn = {2666-7762}, }
@article {pmid39291166, year = {2024}, author = {Gianferrari, G and Cuoghi Costantini, R and Crippa, V and Carra, S and Bonetto, V and Pansarasa, O and Cereda, C and Zucchi, E and Martinelli, I and Simonini, C and Vicini, R and Fini, N and Trojsi, F and Passaniti, C and Ticozzi, N and Doretti, A and Diamanti, L and Fiamingo, G and Conte, A and Dalla Bella, E and D'Errico, E and Scarian, E and Pasetto, L and Antoniani, F and Galli, V and Casarotto, E and ,  and D'Amico, R and Poletti, A and Mandrioli, J}, title = {Colchicine treatment in amyotrophic lateral sclerosis: safety, biological and clinical effects in a randomized clinical trial.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae304}, pmid = {39291166}, issn = {2632-1297}, abstract = {In preclinical studies, the anti-inflammatory drug colchicine, which has never been tested in amyotrophic lateral sclerosis, enhanced the expression of autophagy factors and inhibited accumulation of transactive response DNA-binding protein 43 kDa, a known histopathological marker of amyotrophic lateral sclerosis. This multicentre, randomized, double-blind trial enrolled patients with probable or definite amyotrophic lateral sclerosis who experienced symptom onset within the past 18 months. Patients were randomly assigned in a 1:1:1 ratio to receive colchicine at a dose of 0.005 mg/kg/day, 0.01 mg/kg/day or placebo for a treatment period of 30 weeks. The number of positive responders, defined as patients with a decrease lesser than 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score during the 30-week treatment period, was the primary outcome. Disease progression, survival, safety and quality of life at the end of treatment were the secondary clinical outcomes. Secondary biological outcomes included changes from baseline to treatment end of stress granule and autophagy responses, transactive response DNA-binding protein 43 kDa, neurofilament accumulation and extracellular vesicle secretion, between the colchicine and placebo groups. Fifty-four patients were randomized to receive colchicine (n = 18 for each colchicine arm) or placebo (n = 18). The number of positive responders did not differ between the placebo and colchicine groups: 2 out of 18 patients (11.1%) in the placebo group, 5 out of 18 patients (27.8%) in the colchicine 0.005 mg/kg/day group (odds ratio = 3.1, 97.5% confidence interval 0.4-37.2, P = 0.22) and 1 out of 18 patients (5.6%) in the colchicine 0.01 mg/kg/day group (odds ratio = 0.5, 97.5% confidence interval 0.01-10.2, P = 0.55). During treatment, a slower Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised decline was detected in patients receiving colchicine 0.005 mg/kg/day (mean difference = 0.53, 97.5% confidence interval 0.07-0.99, P = 0.011). Eight patients experienced adverse events in placebo arm (44.4%), three in colchicine 0.005 mg/kg/day (16.7%) and seven in colchicine 0.01 mg/kg/day arm (35.9%). The differences in adverse events were not statistically significant. In conclusion, colchicine treatment was safe for amyotrophic lateral sclerosis patients. Further studies are required to better understand mechanisms of action and clinical effects of colchicine in this condition.}, }
@article {pmid39290830, year = {2024}, author = {Noches, V and Campos-Melo, D and Droppelmann, CA and Strong, MJ}, title = {Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis.}, journal = {Frontiers in molecular neuroscience}, volume = {17}, number = {}, pages = {1417961}, pmid = {39290830}, issn = {1662-5099}, abstract = {The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.}, }
@article {pmid39290715, year = {2024}, author = {Huang, L and Liu, M and Tang, J and Gong, Z and Li, Z and Yang, Y and Zhang, M}, title = {The role of ALDH2 rs671 polymorphism and C-reactive protein in the phenotypes of male ALS patients.}, journal = {Frontiers in neuroscience}, volume = {18}, number = {}, pages = {1397991}, pmid = {39290715}, issn = {1662-4548}, abstract = {BACKGROUND: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients.<br><br>METHODS: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects.<br><br>RESULTS: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (&#x3b2; = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses.<br><br>CONCLUSION: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients.}, }
@article {pmid39289761, year = {2024}, author = {van der Geest, AT and Jakobs, CE and Ljubikj, T and Huffels, CFM and Cañizares Luna, M and Vieira de Sá, R and Adolfs, Y and de Wit, M and Rutten, DH and Kaal, M and Zwartkruis, MM and Carcolé, M and Groen, EJN and Hol, EM and Basak, O and Isaacs, AM and Westeneng, HJ and van den Berg, LH and Veldink, JH and Schlegel, DK and Pasterkamp, RJ}, title = {Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {152}, pmid = {39289761}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; ALS-on-a-chip//Stichting ALS Nederland/ ; MUS-ALS//Stichting ALS Nederland/ ; ATAXALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; INTEGRALS//E-Rare/ ; TRIAGE//JPND/ ; EScORIAL/ERC_/European Research Council/International ; }, mesh = {Humans ; *Organoids/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics ; *Induced Pluripotent Stem Cells/pathology ; *Synapses/pathology/genetics ; Male ; Female ; Cerebral Cortex/pathology ; DNA Repeat Expansion/genetics ; }, abstract = {A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.}, }
@article {pmid39289471, year = {2024}, author = {Jawdat, O and Rucker, J and Nakano, T and Takeno, K and Statland, J and Pasnoor, M and Dimachkie, MM and Sabus, C and Badawi, Y and Hunt, SL and Tomioka, NH and Gunewardena, S and Bloomer, C and Wilkins, HM and Herbelin, L and Barohn, RJ and Nishimune, H}, title = {Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: a pilot study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21729}, pmid = {39289471}, issn = {2045-2322}, support = {P30 GM122731/GM/NIGMS NIH HHS/United States ; R01NS078214/NS/NINDS NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; R01 NS078214/NS/NINDS NIH HHS/United States ; U54 HD090216/HD/NICHD NIH HHS/United States ; S10 OD021743/OD/NIH HHS/United States ; 19K24690//Japan Society for the Promotion of Science/ ; UL1 TR002366/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/physiopathology ; Pilot Projects ; Male ; *Resistance Training ; Female ; Middle Aged ; *Transcriptome ; *Muscle Strength ; Aged ; Adult ; Quadriceps Muscle/metabolism/physiopathology ; Muscle, Skeletal/metabolism/physiopathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients' muscle transcriptome.}, }
@article {pmid39289025, year = {2024}, author = {Dunlop, CL and Kilpatrick, C and Jones, L and Bonet, M and Allegranzi, B and Brizuela, V and Graham, W and Thompson, A and Cheshire, J and Lissauer, D}, title = {Adapting the WHO hand hygiene 'reminders in the workplace' to improve acceptability for healthcare workers in maternity settings worldwide: a mixed methods study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e083132}, pmid = {39289025}, issn = {2044-6055}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Hand Hygiene ; *Focus Groups ; Female ; *World Health Organization ; *Health Personnel/psychology ; Workplace ; Attitude of Health Personnel ; Reminder Systems ; Adult ; Male ; Cross Infection/prevention &amp; control ; Surveys and Questionnaires ; Hospitals, Maternity ; Developing Countries ; Guideline Adherence ; Interviews as Topic ; }, abstract = {INTRODUCTION: Hand hygiene is key in preventing healthcare-associated infections, but it is challenging in maternity settings due to high patient turnover, frequent emergencies and volume of aseptic procedures. We sought to investigate if adaptions to the WHO hand hygiene reminders could improve their acceptability in maternity settings globally, and use these findings to develop new reminders specific to maternity settings.<br><br>METHODS: Informed by Sekhon et al's acceptability framework, we conducted an online survey, semi-structured interviews and a focus group examining the three WHO central hand hygiene reminders ('your five moments of hand hygiene', 'how to hand wash' and 'how to hand rub') and their acceptability in maternity settings. A convergent mixed-methods study design was followed. Findings were examined overall and by country income status. A WHO expert working group tested the integrated findings, further refined results and developed recommendations to improve acceptability for use in the global maternity community. Findings were used to inform the development of two novel and acceptable hand hygiene reminders for use in high-income country (HIC) and low- and middle-income country (LMIC) maternity settings.<br><br>RESULTS: Participation in the survey (n=342), semi-structured interviews (n=12) and focus group (n=7) spanned 51 countries (14 HICs and 37 LMICs). The highest scoring acceptability constructs were clarity of the intervention (intervention coherence), confidence in performance (self-efficacy), and alignment with personal values (ethicality). The lowest performing were perceived difficulty (burden) and how the intervention made the participant feel (affective attitude). Overfamiliarity reduced acceptability in HICs (perceived effectiveness). In LMICs, resource availability was a barrier to implementation (opportunity cost). Two new reminders were developed based on the findings, using inclusive female images, and clinical examples from maternity settings.<br><br>CONCLUSION: Following methodologically robust adaptation, two novel and inclusive maternity-specific hand hygiene reminders have been developed for use in both HIC and LMICs.}, }
@article {pmid39288267, year = {2024}, author = {Liu, H and Zhao, XF and Lu, YN and Hayes, LR and Wang, J}, title = {CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {21}, pages = {}, pmid = {39288267}, issn = {1558-8238}, support = {R01 NS123538/NS/NINDS NIH HHS/United States ; R01 NS128494/NS/NINDS NIH HHS/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; }, mesh = {*C9orf72 Protein/genetics/metabolism ; Humans ; Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *CRISPR-Cas Systems ; Mice ; *Frontotemporal Dementia/genetics/pathology/metabolism ; *DNA Repeat Expansion/genetics ; *Mice, Transgenic ; Protein Biosynthesis ; Induced Pluripotent Stem Cells/metabolism ; RNA/genetics/metabolism ; Motor Neurons/metabolism/pathology ; }, abstract = {A hexanucleotide GGGGCC repeat expansion in the non-coding region of the C9orf72 gene is the most common genetic mutation identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The resulting repeat RNA and dipeptide repeat proteins from non-conventional repeat translation have been recognized as important markers associated with the diseases. CRISPR/Cas13d, a powerful RNA-targeting tool, has faced challenges in effectively targeting RNA with stable secondary structures. Here we report that CRISPR/Cas13d can be optimized to specifically target GGGGCC repeat RNA. Our results demonstrate that the CRISPR/Cas13d system can be harnessed to significantly diminish the translation of poly-dipeptides originating from the GGGGCC repeat RNA. This efficacy has been validated in various cell types, including induced pluripotent stem cells and differentiated motor neurons originating from C9orf72-ALS patients, as well as in C9orf72 repeat transgenic mice. These findings demonstrate the application of CRISPR/Cas13d in targeting RNA with intricate higher-order structures and suggest a potential therapeutic approach for ALS and FTD.}, }
@article {pmid39287680, year = {2024}, author = {Castelnovo, V and Canu, E and Aiello, EN and Curti, B and Sibilla, E and Torre, S and Freri, F and Tripodi, C and Lumaca, L and Spinelli, EG and Schito, P and Russo, T and Falzone, Y and Verde, F and Silani, V and Ticozzi, N and Sturm, VE and Rankin, KP and Gorno-Tempini, ML and Poletti, B and Filippi, M and Agosta, F}, title = {How to detect affect recognition alterations in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7208-7221}, pmid = {39287680}, issn = {1432-1459}, support = {StG-2016_714388_NeuroTRACK//FP7 Ideas: European Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Male ; Female ; Middle Aged ; Aged ; *Neuropsychological Tests ; Recognition, Psychology/physiology ; Cognitive Dysfunction/diagnosis/etiology/physiopathology ; Reproducibility of Results ; }, abstract = {OBJECTIVE: To define the clinical usability of an affect recognition (AR) battery-the Comprehensive Affect Testing System (CATS)-in an Italian sample of patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (&#x2265;&#x2009;.70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models.<br><br>RESULTS: CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range&#x2009;=&#x2009;.79-.83). ARQ showed to be the best diagnostic measure (sensitivity&#x2009;=&#x2009;.80; specificity&#x2009;=&#x2009;.75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions.<br><br>CONCLUSIONS: The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients.}, }
@article {pmid39287519, year = {2024}, author = {Wendebourg, MJ and Kesenheimer, E and Sander, L and Weigel, M and Weidensteiner, C and Haas, T and Madoerin, P and Diebold, M and Deigendesch, N and Neuhaus, D and Naumann, N and Neuwirth, C and Braun, N and Weber, M and Granziera, C and Scheurer, E and Lenz, C and Schweikert, K and Sinnreich, M and Lieb, J and Bieri, O and Schlaeger, R}, title = {The Lateral Corticospinal Tract Sign: An MRI Marker for Amyotrophic Lateral Sclerosis.}, journal = {Radiology}, volume = {312}, number = {3}, pages = {e231630}, doi = {10.1148/radiol.231630}, pmid = {39287519}, issn = {1527-1315}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Prospective Studies ; *Pyramidal Tracts/diagnostic imaging/pathology ; Sensitivity and Specificity ; }, abstract = {Background Radially sampled averaged magnetization inversion-recovery acquisition (rAMIRA) imaging shows hyperintensity in the lateral corticospinal tract (CST) in patients with motor neuron diseases. Purpose To systematically determine the accuracy of the lateral corticospinal tract sign for detecting patients with amyotrophic lateral sclerosis (ALS) at rAMIRA MRI. Materials and Methods This study included prospectively acquired data from participants in ALS and other motor neuron disease imaging studies at the University Hospital Basel, Switzerland. All participants underwent 3-T axial two-dimensional rAMIRA imaging at four cervical intervertebral disk levels. The lateral CST sign was defined as spinal cord white matter hyperintensity dorsolateral to the anterior horns, with higher signal intensity than in the dorsal columns on axial rAMIRA images. Marker accuracy was assessed in a study data set and in an independent validation data set. Postmortem rAMIRA imaging and histopathologic analysis were performed in one participant who died during the study. Results Participants with ALS (study data set: 38 participants [mean age, 61 years; IQR, 15 years], 22 male participants; validation data set: 10 participants [mean age, 61 years; IQR, 21 years], seven male participants), post-polio syndrome (study data set: 25 participants [mean age, 68 years; IQR, 8 years], 12 male participants), spinal muscular atrophy (study data set: 10 participants [mean age, 43 years; IQR, 14 years], eight male participants; validation data set: five participants [mean age, 38 years; IQR, 19 years], two male participants), and healthy control participants (study data set: 60 participants [mean age, 57 years; IQR, 20 years], 36 male participants; validation data set: 10 participants [mean age, 44 years; IQR, 17 years], seven male participants) were included. The sensitivity and specificity of rAMIRA for ALS were 60% (23 of 38) and 97% (91 of 94) in the study data set and 100% (10 of 10) and 93% (14 of 15) in the validation data set, respectively. Histopathologic analysis showed distinct loss of myelinated axons in the localization of the hyperintensities observed at rAMIRA imaging performed in situ and after organ extraction. Conclusion The recently defined marker at rAMIRA MRI may be a promising tool for assessing upper motor neuron degeneration in the lateral CST in patients with ALS. Clinical trials registration no. NCT03561623, NCT05764434, NCT06137612 © RSNA, 2024 Supplemental material is available for this article.}, }
@article {pmid39287472, year = {2024}, author = {Kasperkiewicz, M}, title = {Letter to the Editor: Comment on Bocanegra-Oyola et al's "Clinical Characteristics of Ocular Mucous Membrane Pemphigoid: A Systematic Review and Meta-Analysis".}, journal = {Ocular immunology and inflammation}, volume = {32}, number = {10}, pages = {2622-2623}, doi = {10.1080/09273948.2024.2404105}, pmid = {39287472}, issn = {1744-5078}, mesh = {Humans ; Diagnosis, Differential ; *Pemphigoid, Benign Mucous Membrane/diagnosis ; Meta-Analysis as Topic ; }, abstract = {The work by Bocanegra-Oyola et al. provides a qualitative analysis and meta-analysis of ocular pemphigoid characteristics. This correspondence discusses the need for diagnostic process optimization to better differentiate between ocular pemphigoid and its mimicker pseudopemphigoid.}, }
@article {pmid39286440, year = {2024}, author = {Kew, SYN and Mok, SY and Goh, CH}, title = {Machine learning and brain-computer interface approaches in prognosis and individualized care strategies for individuals with amyotrophic lateral sclerosis: A systematic review.}, journal = {MethodsX}, volume = {13}, number = {}, pages = {102765}, pmid = {39286440}, issn = {2215-0161}, abstract = {Amyotrophic lateral sclerosis (ALS) characterized by progressive degeneration of motor neurons is a debilitating disease, posing substantial challenges in both prognosis and daily life assistance. However, with the advancement of machine learning (ML) which is renowned for tackling many real-world settings, it can offer unprecedented opportunities in prognostic studies and facilitate individuals with ALS in motor-imagery tasks. ML models, such as random forests (RF), have emerged as the most common and effective algorithms for predicting disease progression and survival time in ALS. The findings revealed that RF models had an excellent predictive performance for ALS, with a testing R2 of 0.524 and minimal treatment effects of 0.0717 for patient survival time. Despite significant limitations in sample size, with a maximum of 18 participants, which may not adequately reflect the population diversity being studied, ML approaches have been effectively applied to ALS datasets, and numerous prognostic models have been tested using neuroimaging data, longitudinal datasets, and core clinical variables. In many literatures, the constraints of ML models are seldom explicitly enunciated. Therefore, the main objective of this research is to provide a review of the most significant studies on the usage of ML models for analyzing ALS. This review covers a variation of ML algorithms involved in applications in ALS prognosis besides, leveraging ML to improve the efficacy of brain-computer interfaces (BCIs) for ALS individuals in later stages with restricted voluntary muscular control. The key future advances in individualized care and ALS prognosis may include the advancement of more personalized care aids that enable real-time input and ongoing validation of ML in diverse healthcare contexts.}, }
@article {pmid39286389, year = {2024}, author = {Willman, M and Patel, G and Lucke-Wold, B}, title = {T lymphocyte proportion in Alzheimer's disease prognosis.}, journal = {World journal of clinical cases}, volume = {12}, number = {26}, pages = {6001-6003}, pmid = {39286389}, issn = {2307-8960}, abstract = {Bai et al investigate the predictive value of T lymphocyte proportion in Alzheimer's disease (AD) prognosis. Through a retrospective study involving 62 AD patients, they found that a decrease in T lymphocyte proportion correlated with a poorer prognosis, as indicated by higher modified Rankin scale scores. While the study highlights the potential of T lymphocyte proportion as a prognostic marker, it suggests the need for larger, multicenter studies to enhance generalizability and validity. Additionally, future research could use cognitive exams when evaluating prognosis and delve into immune mechanisms underlying AD progression. Despite limitations inherent in retrospective designs, Bai et al's work contributes to understanding the immune system's role in AD prognosis, paving the way for further exploration in this under-researched area.}, }
@article {pmid39283513, year = {2024}, author = {Koopmann, A and Hoffmann, S and Riegler, A and Cordes, J and Kiefer, F}, title = {[Factors influencing hospital readmission rates in alcohol use disorder].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, pmid = {39283513}, issn = {1433-0407}, abstract = {BACKGROUND: According to data from the Federal Statistical Office, the diagnosis of alcohol use disorder (AUD) (F 10) is the second most common main diagnosis for hospital treatment. Those affected by this disorder are often repeatedly hospitalized at short intervals due to relapses; however, little is known about the factors that influence readmission rates after initial treatment.<br><br>AIM OF THE STUDY: The aim of this retrospective analysis is to analyze the effects of treatment type (qualified withdrawal treatment&#xa0;(QE) versus physical detoxification) and discharge mode on the probability of readmission in alcohol-dependent patients after inpatient treatment.<br><br>MATERIAL AND METHODS: Data from 981 male and female alcohol-dependent patients who completed either qualified withdrawal treatment (QE) (68% men; mean age&#xa0;47.6 years) or inpatient detoxification (74% men; mean age&#xa0;48.0 years) were analyzed. Predictors of regular discharge were determined separately for both types of treatment using stepwise logistic regression.<br><br>RESULTS: Patients who had completed a&#xa0;qualified withdrawal treatment were significantly more likely to be regularly discharged. Regular completion of the qualified withdrawal treatment (QE) led to a&#xa0;relative reduction in the readmission rate of 25.64% within 1 year compared to a&#xa0;physical detoxification.<br><br>CONCLUSION: In order to prevent readmission and chronic courses of alcohol use disorder (AUD), qualified withdrawal treatment should always be recommended to affected patients instead of physical detoxification. Aktuelle Daten des Statistischen Bundesamtes f&#xfc;r das Jahr 2022 zeigen, dass die Diagnose "Psychische und Verhaltensst&#xf6;rungen durch Alkohol (F&#xa0;10.X)" die zweith&#xe4;ufigste Hauptdiagnose bei Krankenhausbehandlungen darstellt [13]. Im Gesundheitssystem entstehen durch dieses Erkrankungsbild und seine somatischen und psychischen Folgeerkrankungen j&#xe4;hrlich ca.&#xa0;10&#x202f;Mrd. &#x20ac; direkte Kosten [13]. Dieser Sachverhalt wird dadurch kontrastiert, dass die Krankenkassen die qualifizierte Entzugsbehandlung (QE) als leitliniengerechte Goldstandardtherapie [4] wiederholt infrage stellen [10].}, }
@article {pmid39283487, year = {2024}, author = {Zufiría, M and Pikatza-Menoio, O and Garciandia-Arcelus, M and Bengoetxea, X and Jiménez, A and Elicegui, A and Levchuk, M and Arnold-García, O and Ondaro, J and Iruzubieta, P and Rodríguez-Gómez, L and Fernández-Pelayo, U and Muñoz-Oreja, M and Aiastui, A and García-Verdugo, JM and Herranz-Pérez, V and Zulaica, M and Poza, JJ and Ruiz-Onandi, R and Fernández-Torrón, R and Espinal, JB and Bonilla, M and Lersundi, A and Fernández-Eulate, G and Riancho, J and Vallejo-Illarramendi, A and Holt, IJ and Sáenz, A and Malfatti, E and Duguez, S and Blázquez, L and López de Munain, A and Gerenu, G and Gil-Bea, F and Alonso-Martín, S}, title = {Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {43}, pmid = {39283487}, issn = {1432-0533}, support = {CB06/05/1126//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; PI2020/08-1//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red sobre Enfermedades Neurodegenerativas/ ; P18/01066//Instituto de Salud Carlos III/ ; PI19/00175//Instituto de Salud Carlos III/ ; PI21/00153//Instituto de Salud Carlos III/ ; PI22/00433//Instituto de Salud Carlos III/ ; IJC2019-039965-I//Instituto de Salud Carlos III/ ; 2020-CIEN-000057-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; 2021-CIEN-000020-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; 2019-FELL-000010-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; 2020-FELL-000016-02-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; 2021-FELL-000013-02-01//Diputaci&#xf3;n Foral de Gipuzkoa/ ; BIO17/ND/023/BD//EiTB Maratoia/ ; 2015111122//Osasun Saila, Eusko Jaurlaritzako/ ; 2017222027//Osasun Saila, Eusko Jaurlaritzako/ ; 2018111042//Osasun Saila, Eusko Jaurlaritzako/ ; 2019222020//Osasun Saila, Eusko Jaurlaritzako/ ; 2020111032//Osasun Saila, Eusko Jaurlaritzako/ ; 2020333043//Osasun Saila, Eusko Jaurlaritzako/ ; 2021333050//Osasun Saila, Eusko Jaurlaritzako/ ; PRE_2015_1_0023//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2019_1_0339//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0122//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0191//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2020_1_0119//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0095//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2021_1_0125//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PRE_2018_1_0253//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; NEURODEGENPROT//Hezkuntza, Hizkuntza Politika Eta Kultura Saila, Eusko Jaurlaritza/ ; PIF18/317//Euskal Herriko Unibertsitatea/ ; RYC2018-024397-I//Spanish National Plan for Scientific and Technical Research and Innovation/ ; RF/2019/001//Ikerbasque, Basque Foundation for Science/ ; RF/2023/010//Ikerbasque, Basque Foundation for Science/ ; PP/2022/003//Ikerbasque, Basque Foundation for Science/ ; BIO19/ROCHE/017/BD//Roche Espa&#xf1;a/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Humans ; Animals ; *Muscle, Skeletal/metabolism/pathology ; *Forkhead Box Protein O1/metabolism/genetics ; DNA-Binding Proteins/genetics/metabolism ; Male ; RNA-Binding Protein FUS/genetics/metabolism ; Female ; Drosophila ; Muscle Development/physiology ; Middle Aged ; Aged ; Motor Neurons/metabolism/pathology ; Myoblasts/metabolism ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.}, }
@article {pmid39282230, year = {2024}, author = {Tsai, YC and Brown, KA and Bernardi, MT and Harting, J and Clelland, CD}, title = {Single-Molecule Sequencing of the C9orf72 Repeat Expansion in Patient iPSCs.}, journal = {Bio-protocol}, volume = {14}, number = {17}, pages = {e5060}, pmid = {39282230}, issn = {2331-8325}, abstract = {A hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). C9orf72 repeat expansions are currently identified with long-range PCR or Southern blot for clinical and research purposes, but these methods lack accuracy and sensitivity. The GC-rich and repetitive content of the region cannot be amplified by PCR, which leads traditional sequencing approaches to fail. We turned instead to PacBio single-molecule sequencing to detect and size the C9orf72 repeat expansion without amplification. We isolated high molecular weight genomic DNA from patient-derived iPSCs of varying repeat lengths and then excised the region containing the C9orf72 repeat expansion from naked DNA with a CRISPR/Cas9 system. We added adapters to the cut ends, capturing the target region for sequencing on PacBio's Sequel, Sequel II, or Sequel IIe. This approach enriches the C9orf72 repeat region without amplification and allows the repeat expansion to be consistently and accurately sized, even for repeats in the thousands. Key features • This protocol is adapted from PacBio's previous "no-amp targeted sequencing utilizing the CRISPR-Cas9 system." • Optimized for sizing C9orf72 repeat expansions in patient-derived iPSCs and applicable to DNA from any cell type, blood, or tissue. • Requires high molecular weight naked DNA. • Compatible with Sequel I and II but not Revio.}, }
@article {pmid39281855, year = {2024}, author = {Jones, VM and Thompson, LDR and Pettus, JR and Green, DC and Lefferts, JA and Shah, PS and Tsongalis, GJ and Sajed, DP and Guilmette, JM and Lewis, JS and Fisch, AS and Tafe, LJ and Kerr, DA}, title = {Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39281855}, issn = {2693-5015}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head &amp; Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored.<br><br>METHODS: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing.<br><br>RESULTS: Fifteen lesions (3 to 42 mm) were identified predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AMLs contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four ALs contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included surface ulceration, vascular thrombosis, chronic inflammation, and myxoid change; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin and/or desmin) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2.<br><br>CONCLUSION: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AMLs. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.}, }
@article {pmid39280885, year = {2024}, author = {Robinson, SE and Findlay, AR and Li, S and Wang, F and Schiava, M and Daw, J and Diaz-Manera, J and Chou, TF and Weihl, CC}, title = {Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200191}, pmid = {39280885}, issn = {2376-7839}, support = {K24 AR073317/AR/NIAMS NIH HHS/United States ; R01 AG031867/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity.<br><br>METHODS: Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein.<br><br>RESULTS: Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15&#xa0;&#xb1;&#xa0;9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = -0.94, p = 0.01).<br><br>DISCUSSION: Previous studies have reported that VCP pathogenic variants are "hyperactive." Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.}, }
@article {pmid39280794, year = {2024}, author = {Ren, K and Wang, Q and Jiang, D and Liu, E and Alsmaan, J and Jiang, R and Rutkove, SB and Tian, F}, title = {A comprehensive review of electrophysiological techniques in amyotrophic lateral sclerosis research.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1435619}, pmid = {39280794}, issn = {1662-5102}, support = {R01 NS055099/NS/NINDS NIH HHS/United States ; }, abstract = {Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is characterized by progressive motor neuron degeneration, leading to widespread weakness and respiratory failure. While a variety of mechanisms have been proposed as causes of this disease, a full understanding remains elusive. Electrophysiological alterations, including increased motor axon excitability, likely play an important role in disease progression. There remains a critical need for non-animal disease models that can integrate electrophysiological tools to better understand underlying mechanisms, track disease progression, and evaluate potential therapeutic interventions. This review explores the integration of electrophysiological technologies with ALS disease models. It covers cellular and clinical electrophysiological tools and their applications in ALS research. Additionally, we examine conventional animal models and highlight advancements in humanized models and 3D organoid technologies. By bridging the gap between these models, we aim to enhance our understanding of ALS pathogenesis and facilitate the development of new therapeutic strategies.}, }
@article {pmid39280372, year = {2024}, author = {Nishiwaki, T and Oya, A and Fujie, A and Kanaji, A}, title = {Higher Incidence of Venous Thromboembolism in Anterolateral Approach in Lateral Position Compared to Anterolateral Supine and Direct Anterior Approaches in Minimally Invasive Total Hip Arthroplasty.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66831}, pmid = {39280372}, issn = {2168-8184}, abstract = {INTRODUCTION: Venous thromboembolism (VTE) remains a major complication after total hip arthroplasty (THA), irrespective of the surgical approach. This study investigated the incidence of VTE in patients undergoing THA through intermuscular minimally invasive surgical techniques, which included a direct anterior approach (DAA), an anterolateral approach (AL), and an anterolateral supine approach (ALS), at a single institution.<br><br>METHODS: A hundred consecutive patients treated with each surgical approach were evaluated. Plasma D-dimer levels one month preoperatively and one day postoperatively, operative time, and intraoperative blood loss were recorded, and the presence of VTE was evaluated based on multidetector-row computed tomography performed the day after surgery. Student's t-test and Pearson's chi-square test or one-way analysis of variance were used in statistical analysis.<br><br>RESULTS: No differences among the groups in terms of age, height, weight, operative time, intraoperative bleeding, and preoperative and postoperative D-dimer levels were observed. The overall incidence of VTE was 21%. The incidences of VTE were 30% in AL, 17% in ALS, and 16% in DAA, representing a significantly higher rate in AL than in ALS and DAA (P=0.025). The incidences of VTE on the operated side were 19% in AL, 13% in ALS, and 12% in DAA, with no statistically significant differences. The incidences of VTE on the non-operated side were 22% in AL, 9% in ALS, and 8% in DAA; these differences were statistically significant (P=0.0045).<br><br>DISCUSSION: Results showed that the incidence of VTE was significantly higher in AL than in ALS and DAA, especially for the non-operated side.}, }
@article {pmid39280119, year = {2024}, author = {Banack, SA and Dunlop, RA and Mehta, P and Mitsumoto, H and Wood, SP and Han, M and Cox, PA}, title = {A microRNA diagnostic biomarker for amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae268}, pmid = {39280119}, issn = {2632-1297}, abstract = {Blood-based diagnostic biomarkers for amyotrophic lateral sclerosis will improve patient outcomes and positively impact novel drug development. Critical to the development of such biomarkers is robust method validation, optimization and replication with adequate sample sizes and neurological disease comparative blood samples. We sought to test an amyotrophic lateral sclerosis biomarker derived from diverse samples to determine if it is disease specific. Extracellular vesicles were extracted from blood plasma obtained from individuals diagnosed with amyotrophic lateral sclerosis, primary lateral sclerosis, Parkinson's disease and healthy controls. Immunoaffinity purification was used to create a neural-enriched extracellular vesicle fraction. MicroRNAs were measured across sample cohorts using real-time polymerase chain reaction. A Kruskal-Wallis test was used to assess differences in plasma microRNAs followed by post hoc Mann-Whitney tests to compare disease groups. Diagnostic accuracy was determined using a machine learning algorithm and a logistic regression model. We identified an eight-microRNA diagnostic signature for blood samples from amyotrophic lateral sclerosis patients with high sensitivity and specificity and an area under the curve calculation of 98% with clear statistical separation from neurological controls. The eight identified microRNAs represent disease-related biological processes consistent with amyotrophic lateral sclerosis. The direction and magnitude of gene fold regulation are consistent across four separate patient cohorts with real-time polymerase chain reaction analyses conducted in two laboratories from diverse samples and sample collection procedures. We propose that this diagnostic signature could be an aid to neurologists to supplement current clinical metrics used to diagnose amyotrophic lateral sclerosis.}, }
@article {pmid39279312, year = {2024}, author = {Banaszak-Ziemska, M and Rojek, A and Niedziela, M}, title = {Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.}, journal = {Endokrynologia Polska}, volume = {75}, number = {4}, pages = {428-437}, doi = {10.5603/ep.100030}, pmid = {39279312}, issn = {2299-8306}, mesh = {Humans ; *Pregnancy-Associated Plasma Protein-A/genetics/metabolism/analysis ; Female ; *Insulin-Like Growth Factor I/genetics/analysis/metabolism ; Male ; Child ; Adolescent ; *Insulin-Like Growth Factor Binding Protein 5/genetics ; Carrier Proteins/genetics ; Glycoproteins/genetics/blood ; Growth Disorders/genetics/blood ; Mutation ; Child, Preschool ; }, abstract = {INTRODUCTION: Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs).<br><br>MATERIAL AND METHODS: The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA).<br><br>RESULTS: The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found.<br><br>CONCLUSIONS: Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.}, }
@article {pmid39279053, year = {2024}, author = {Lin, PH and Yao, HY and Huang, L and Fu, CC and Yao, XL and Lian, C and Zhang, SF and Lai, WD and Lin, GY and Liao, S and Yang, J and Mao, ZF and Liu, D and Long, BY and Yue, JJ and Gao, C and Long, YM}, title = {Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {30}, number = {9}, pages = {e70042}, pmid = {39279053}, issn = {1755-5949}, support = {2022A1515110143//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010225//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022-LCYJ-YYDZX-04//Multi-center Project of The Second Affiliated Hospital of Guangzhou Medical University/ ; }, mesh = {Humans ; *Glial Fibrillary Acidic Protein/cerebrospinal fluid/immunology ; Female ; Male ; *Aquaporin 4/immunology ; Middle Aged ; *Astrocytes/immunology/metabolism/pathology ; Retrospective Studies ; Adult ; *Biomarkers/cerebrospinal fluid/blood ; Aged ; *Immunoglobulin G/cerebrospinal fluid/blood ; Neurofilament Proteins/cerebrospinal fluid/blood ; Autoantibodies/cerebrospinal fluid/blood ; Young Adult ; Adolescent ; }, abstract = {OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies.<br><br>METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA).<br><br>RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p&#x2009;<&#x2009;0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p&#x2009;=&#x2009;0.002). GFAP levels decreased in DNAP (n&#x2009;=&#x2009;5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p&#x2009;=&#x2009;0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p&#x2009;=&#x2009;0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient.<br><br>DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.}, }
@article {pmid39278909, year = {2024}, author = {Reis, ALG and Maximino, JR and Lage, LAPC and Gomes, HR and Pereira, J and Brofman, PRS and Senegaglia, AC and Rebelatto, CLK and Daga, DR and Paiva, WS and Chadi, G}, title = {Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.}, journal = {Stem cell research &amp; therapy}, volume = {15}, number = {1}, pages = {301}, pmid = {39278909}, issn = {1757-6512}, support = {401922/2014-6//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 836458/2016//Minist&#xe9;rio da Sa&#xfa;de/ ; 1701/22//Financiadora de Estudos e Projetos/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/therapy/metabolism ; Apolipoprotein A-I/cerebrospinal fluid/metabolism ; Apolipoproteins E/metabolism/genetics/cerebrospinal fluid ; Bone Marrow Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/metabolism ; Protein Interaction Maps ; *Proteomics/methods ; *Transplantation, Autologous ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS.<br><br>METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1&#x2009;&#xd7;&#x2009;10[6] cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129.<br><br>RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects.<br><br>CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.<br><br>TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.}, }
@article {pmid39277385, year = {2024}, author = {Porri, A and Panozzo, S and Tekeste Sisay, M and Scarabel, L and Lerchl, J and Milani, A}, title = {3D structure of acetolactate synthase explains why the Asp-376-Glu point mutation does not give the same resistance level to different imidazolinone herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106070}, doi = {10.1016/j.pestbp.2024.106070}, pmid = {39277385}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism/chemistry ; *Herbicides/pharmacology/chemistry ; *Herbicide Resistance/genetics ; *Imidazoles/pharmacology/chemistry ; *Amaranthus/drug effects/genetics ; *Point Mutation ; Sorghum/genetics/drug effects ; Molecular Docking Simulation ; Plant Proteins/genetics/metabolism/chemistry ; Nicotinic Acids/pharmacology ; Niacin/analogs &amp; derivatives ; }, abstract = {Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.}, }
@article {pmid39277366, year = {2024}, author = {Weng, WF and Yao, X and Zhao, M and Fang, Z and Yang, S and Ruan, JJ}, title = {Novel mutations in acetolactate synthase confer high levels of resistance to tribenuron-methyl in Fagopyrum tataricum.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106039}, doi = {10.1016/j.pestbp.2024.106039}, pmid = {39277366}, issn = {1095-9939}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Fagopyrum/genetics/drug effects ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Arylsulfonates/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; }, abstract = {Tartary buckwheat (Fagopyrum tataricum) field weeds are rich in species, with many weeds causing reduced quality, yield, and crop failure. The selection of herbicide-resistant Tartary buckwheat varieties, while applying low-toxicity and efficient herbicides as a complementary weed control system, is one way to improve Tartary buckwheat yield and quality. Therefore, the development of herbicide-resistant varieties is important for the breeding of Tartary buckwheat. In this experiment, 50 mM ethyl methyl sulfonate solution was used to treat Tartary buckwheat seeds (M1) and then planted in the field. Harvested seeds (M2) were planted in the experiment field of Guizhou University, and when seedlings had 5-7 leaves, the seedlings were sprayed with 166 mg/L tribenuron-methyl (TBM). A total of 15 resistant plants were obtained, of which three were highly resistant. Using the homologous cloning method, an acetolactate synthase (ALS) gene encoding 547 amino acids was identified in Tartary buckwheat. A GTG (valine) to GGA (glycine) mutation (V409G) occurred at position 409 of the ALS gene in the high tribenuron-methyl resistant mutant sm113. The dm36 mutant harbored a double mutation, a deletion mutation at position 405, and a GTG (valine) to GGA (glycine) mutation (V411G) at position 411. The dm110 mutant underwent a double mutation: an ATG (methionine) to AGG (arginine) mutation (M333R) at position 333 and an insertion mutation at position 372. The synthesis of Chl a, Chl b, total Chl, and Car was significantly inhibited by TBM treatment. TBM was more efficient at suppressing the growth of wild-type plants than that of mutant plants. Antioxidant enzyme activities such as ascorbate peroxidase, peroxidase, and superoxide dismutase were significantly higher in resistant plants than in wild-type after spraying with TBM; malondialdehyde content was significantly lower than in wild-type plants after spraying with TBM. Plants with a single-site mutation in the ALS gene could survive, but their growth was affected by herbicide application. In contrast, plants with dual-site mutations in the ALS gene were not affected, indicating that plants with dual-site mutations in the ALS gene showed higher levels of resistance than plants with a single-site mutation in the ALS gene.}, }
@article {pmid39277365, year = {2024}, author = {Guan, Y and Liu, L and Zou, Y and Yang, C and Ji, M}, title = {Involvement of P450s in the metabolic resistance of Digitaria sanguinalis (L.) Scop. To ALS-inhibiting herbicides.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106038}, doi = {10.1016/j.pestbp.2024.106038}, pmid = {39277365}, issn = {1095-9939}, mesh = {*Herbicides/pharmacology/toxicity ; *Acetolactate Synthase/metabolism/genetics/antagonists &amp; inhibitors ; *Herbicide Resistance/genetics ; *Cytochrome P-450 Enzyme System/metabolism/genetics ; *Digitaria/drug effects ; Sulfonylurea Compounds/pharmacology ; Plant Weeds/drug effects/metabolism ; Plant Proteins/genetics/metabolism ; Pyridines ; }, abstract = {Weed resistance to a range of herbicides has rapidly evolved, often with different mechanisms of action. The resulting uninhibited growth of weeds poses demonstrable threats to crop production and sustainable agriculture. Digitaria sanguinalis (L.) Scop., a troublesome weed in corn and other agricultural fields, has developed resistance to herbicides that inhibiting ALS (Acetolactate Synthase), such as nicosulfuron. Understanding the weed's resistance patterns and mechanisms is crucial. However, little is known of the non-target site resistance (NTSR) mechanisms of D. sanguinalis owing to a lack of relevant genome sequences and other materials. Therefore, in this study, a population of D.sanguinalis presenting multiple resistance was tested and found that its high level of resistance to ALS-inhibiting herbicides was not associated with target-related alterations.Administration of P450 inhibitors reversed the resistance to ALS-inhibiting herbicides. Following the application of ALS-inhibiting herbicides, the activities of NADPH-P450 reductase and p-nitroanisole O-demethylase (PNOD) were notably greater in the resistant population of D. sanguinalis than those in the susceptible population. The results suggested P450 enzyme familyplays a major role in the metabolic resistance mechanism, that increased P450 enzyme activity promote cross-resistance in D. sanguinalis to ALS-inhibiting herbicides. RNA-seq analysis showed that five genes from the P450 family (CYP709B2, CYP714C2, CYP71A1, CYP76C2, and CYP81E8) were upregulated in resistant D. sanguinalis. In conclusion, the upregulation of several P450 genes is responsible for establishing resistance to ALS-inhibiting herbicides in D. sanguinalis.}, }
@article {pmid39277361, year = {2024}, author = {Liu, L and Zou, Y and Guan, Y and Yang, C and Ji, M}, title = {Diverse mechanisms confer bensulfuron-methyl resistance in Schoenoplectiella juncoides (Roxb.) lye.}, journal = {Pesticide biochemistry and physiology}, volume = {204}, number = {}, pages = {106034}, doi = {10.1016/j.pestbp.2024.106034}, pmid = {39277361}, issn = {1095-9939}, mesh = {*Sulfonylurea Compounds/pharmacology ; Herbicide Resistance/genetics ; Herbicides/pharmacology ; Mutation ; Glutathione Transferase/metabolism/genetics ; }, abstract = {The effectiveness of bensulfuron-methyl in controlling Schoenoplectiella juncoides (Roxb.) Lye has significantly decreased in rice fields in China. Hence, a bensulfuron-methyl-resistant S. juncoides population (W15) was collected from Dandong City, Liaoning Province, China, to investigate the underlying resistance mechanisms. Whole-plant dose-response experiments and ALS activity assay confirmed that W15 has evolved high-level resistance to bensulfuron-methyl compared with the susceptible S. juncoides population (W4). Molecular analysis revealed a Pro-197-Ser mutation in ALS1, while there was no significant difference in the relative ALS gene expression between W15 and W4. LC-MS/MS analysis showed W15 metabolized bensulfuron-methyl more rapidly than W4. Furthermore, bensulfuron-methyl resistance in W15 was significantly alleviated by malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl). Glutathione S-transferase activity was higher in W15 than in W4. Meanwhile, W15 displayed cross-resistance to halosulfuron-methyl and multi-resistance to MCPA-Na. In summary, these findings demonstrated for the first time that both target- and non-target-site resistance are relevant in the resistance of S. juncoides to bensulfuron-methyl.}, }
@article {pmid39268612, year = {2025}, author = {Meyer, T and Schumann, P and Grehl, T and Weyen, U and Petri, S and Rödiger, A and Steinbach, R and Grosskreutz, J and Bernsen, S and Weydt, P and Wolf, J and Günther, R and Vidovic, M and Baum, P and Metelmann, M and Weishaupt, JH and Streubel, B and Kasper, DC and Koc, Y and Kettemann, D and Norden, J and Schmitt, P and Walter, B and Münch, C and Spittel, S and Maier, A and Körtvélyessy, P}, title = {SOD1 gene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {162-171}, doi = {10.1080/21678421.2024.2401131}, pmid = {39268612}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; *Genetic Testing/methods ; Middle Aged ; *Mutation/genetics ; Aged ; Adult ; C9orf72 Protein/genetics ; Germany ; RNA-Binding Protein FUS/genetics ; DNA-Binding Proteins ; }, abstract = {OBJECTIVE: To report the frequency of pathogenic SOD1 gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment.<br><br>METHODS: From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for SOD1, FUS, TARDBP, and C9orf72 was performed. Patients were offered to opt for notification either about all genetic variants or SOD1 variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed.<br><br>RESULTS: 1935 patients were screened (94.7% sporadic ALS). 48.8% (n&#x2009;=&#x2009;928) opted for notification of treatment-relevant information. Genetic variants were found as follows: SOD1 (likely) pathogenic variants (class 4/5) 1.8% (n&#x2009;=&#x2009;34), variants of unknown significance (class 3) 0.8% (n&#x2009;=&#x2009;16), FUS (class 4/5) 0.9% (n&#x2009;=&#x2009;17), TARDBP (class 4/5) 1.3% (n&#x2009;=&#x2009;25), C9orf72 hexanucleotide repeat expansion 7.0% (n&#x2009;=&#x2009;135). In SOD1-ALS (encompassing class 3-5 variants, n&#x2009;=&#x2009;50), 68.0% (n&#x2009;=&#x2009;34) reported a negative family history. 74.0% (n&#x2009;=&#x2009;37) of SOD1-ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy.<br><br>CONCLUSION: The finding of SOD1 variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In SOD1-ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a SOD1-ALS management program.}, }
@article {pmid39276073, year = {2025}, author = {Raymond, J and Berry, JD and Larson, T and Horton, DK and Mehta, P}, title = {Effects of COVID-19 on motor neuron disease mortality in the United States: a population-based cross-sectional study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {149-156}, doi = {10.1080/21678421.2024.2401621}, pmid = {39276073}, issn = {2167-9223}, mesh = {Humans ; *COVID-19/mortality/epidemiology ; United States/epidemiology ; Male ; *Motor Neuron Disease/mortality/epidemiology ; Female ; Aged ; Middle Aged ; Cross-Sectional Studies ; Adult ; Aged, 80 and over ; Young Adult ; SARS-CoV-2 ; }, abstract = {BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) to be a pandemic, stating that those with underlying health conditions are most susceptible, including motor neuron disease (MND).<br><br>OBJECTIVE: To examine the effect the COVID-19 pandemic had on deaths from MND in the United States.<br><br>METHODS: Death certificate data for all MND deaths aged 20 years and older were analyzed from 2017 to 2019 (pre-COVID), then expanded to include 2020 and 2021 (COVID) deaths to evaluate if COVID-19 impacted MND deaths.<br><br>RESULTS: The average number of MND deaths documented during the COVID-19 years was 8009, up from 7485 MND deaths pre-COVID. The age-adjusted mortality rate among the non-Hispanic population increased during COVID to 2.78 per 100,000 persons (95% CI = 2.73-2.82) from 1.81 (95% CI = 1.78-1.84). The Hispanic population also saw an increase in mortality rate during COVID (1.61, 95% CI = 1.51-1.71) compared with pre-COVID (1.10, 95% CI = 1.03-1.17). Decedent's home as a place of death also saw a mortality rate increase during COVID (1.51, 95% CI = 1.48-1.54) compared with pre-COVID (1.30, 95% CI = 1.27-1.32). For the Hispanic population, the rate peaked at 80-84 years pre-COVID, but for the COVID years, the rate peaked earlier, at 75-79 years.<br><br>CONCLUSION: The total number of MND deaths was greater during COVID than in the preceding years. The analysis suggests there might have been a consequence of circumstances surrounding the global pandemic and the associated restrictions.}, }
@article {pmid39275316, year = {2024}, author = {Hamm, JD and Laferrère, B and Albu, JB and Kini, S and Pi-Sunyer, X and Kissileff, HR}, title = {Responsiveness and Reliability of a Sipping Device to Measure Motivation in Normal-Weight Individuals and Bariatric Surgery Patients.}, journal = {Nutrients}, volume = {16}, number = {17}, pages = {}, pmid = {39275316}, issn = {2072-6643}, support = {R01 DK108643/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Motivation ; *Bariatric Surgery ; Female ; Male ; Adult ; Reproducibility of Results ; Middle Aged ; Obesity/surgery/psychology ; Taste ; Beverages ; Sweetening Agents ; Feeding Behavior/psychology ; }, abstract = {There is an urgent need to measure the motivation to taste a sweet fluid in order to determine the influence of sweet tastes on the potential choices and consumption of beverages in patients with obesity. Current methods utilize either survey instruments or arbitrary operant tasks. The sipometer enables the participant to utilize an actual ingestive behavioral response to measure motivation during access to beverages on either ad libitum (AL) or progressive time ratio (PR) schedules. We determined the sipometer's responsiveness and reliability as a test of change in motivation for sweet tastes after bariatric surgery. Participants (58 patients and 28 controls, BMI: 18.5-24.9 kg/m[2]) sham-consumed an aspartame-sweetened (S) and non-sweetened (N) beverage under AL and PR schedules at a pre-surgery/baseline and a 3-month and 24-month visit (patients only). Cumulative pressure (CumPres), a measure of effort, was the sum of the pressures exerted during sipping under each condition. Baseline CumPres for PRS was higher than ALS and ALN in patients (p < 0.03) and higher than PRN in controls (p = 0.009). At 3 months, CumPres did not differ amongst conditions in patients, but CumPres for PRS was higher than all other conditions in controls (p < 0.0005). There were no baseline group differences; however, patients' CumPres for PRS was lower than controls' at 3 months (p = 0.002). Patients' CumPres for PRS decreased non-significantly between the baseline and 3 months but increased at 24 months compared to 3 months (p = 0.025) and was no different from baseline. Controls' CumPres for PRS increased at 3 months (p = 0.0359), but CumPres for all conditions was correlated between visits (p's < 0.038). The sipometer is a reliable and sensitive measure of motivation to consume sweet beverages and may reflect changes in post-operative energy intake.}, }
@article {pmid39273978, year = {2024}, author = {Wu, Z and Liu, S and Zhang, X and Qian, X and Chen, Z and Zhao, H and Wan, H and Yin, N and Li, J and Qu, C and Du, H}, title = {Genome-Wide Characterization of Alfin-like Genes in Brassica napus and Functional Analyses of BnaAL02 and BnaAL28 in Response to Nitrogen and Phosphorus Deficiency.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {17}, pages = {}, pmid = {39273978}, issn = {2223-7747}, support = {32072094//National Key Research and Development Program of China/ ; 2023NSCQ-MSX3166//Natural Science Foundation of Chongqing/ ; }, abstract = {Alfin-like proteins (ALs) form a plant-specific transcription factor (TF) gene family involved in the regulation of plant growth and development, and abiotic stress response. In this study, 30 ALs were identified in Brassica napus ecotype 'Zhongshuang 11' genome (BnaALs), and unevenly distributed on 15 chromosomes. Structural characteristic analysis showed that all of the BnaALs contained two highly conserved domains: the N terminal DUF3594 domain and the C-terminal PHD-finger domain. The BnaALs were classified into four groups (Group I-IV), supported by conserved intron-exon and protein motif structures in each group. The allopolyploid event between B. oleracea and B. rapa ancestors and the small-scale duplication events in B. napus both contributed to the large BnaALs expansion. The promoter regions of BnaALs contained multiple abiotic stress cis-elements. The BnaALs in I-IV groups were mainly expressed in cotyledon, petal, root, silique, and seed tissues, and the duplicated gene pairs shared highly similar expression patterns. RNA-seq and RT-qPCR analysis showed that BnaALs were obviously induced by low nitrogen (LN) and low phosphorus (LP) treatments in roots. Overexpressing BnaAL02 and BnaAL28 in Arabidopsis demonstrated their functions in response to LN and LP stresses. BnaAL28 enhanced primary roots' (PRs) length and lateral roots' (LRs) number under LP and LN conditions, where BnaAL02 can inhibit LR numbers under the two conditions. They can promote root hair (RH) elongation under LP conditions; however, they suppressed RH elongation under LN conditions. Our result provides new insight into the functional dissection of this family in response to nutrient stresses in plants.}, }
@article {pmid39273694, year = {2024}, author = {Evangelisti, C and Ramadan, S and Orlacchio, A and Panza, E}, title = {Experimental Cell Models for Investigating Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273694}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/pathology/metabolism ; Animals ; *Induced Pluripotent Stem Cells/cytology/metabolism ; *Organoids/pathology ; Models, Biological ; }, abstract = {Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease, which present complex challenges for research and therapy development. In this work, we review the recent literature about experimental models and motor neuron disease. We identified three main categories of models that are highly studied by scientists. In fact, experimental models for investigating these diseases encompass a variety of approaches, including modeling the patient's cell culture, patient-derived induced pluripotent stem cells, and organoids. Each model offers unique advantages and limitations, providing researchers with a range of tools to address complex biological questions. Here, we discuss the characteristics, applications, and recent advancements in terms of each model system, highlighting their contributions to advancing biomedical knowledge and translational research.}, }
@article {pmid39273435, year = {2024}, author = {Di Chiano, M and Sallustio, F and Fiocco, D and Rocchetti, MT and Spano, G and Pontrelli, P and Moschetta, A and Gesualdo, L and Gadaleta, RM and Gallone, A}, title = {Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {25}, number = {17}, pages = {}, pmid = {39273435}, issn = {1422-0067}, support = {1062//PON "RICERCA E INNOVAZIONE" 2014-2020-Innovazione/ ; Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - Next Generation EU//National Recovery and Resilience Plan (NRRP)/ ; Concession Decree No. 1550 of 11 October 2022 adopted by the Italian Ministry of University and Research, CUP D93C22000890001//Italian Ministry of University and Research, CUP D93C22000890001/ ; Codice progetto n. 2022H9MPZ5//MIUR- PRIN Progetti di Ricerca di Rilevante Interesse Nazionale 2022/ ; Id. 23239//AIRC IG 2019/ ; Call for tender No. 3138 of 16/12/2021 of Italian Ministry of University and Research funded by the European Union//National Recovery and Resilience Plan (NRRP)/ ; Project code: CN00000041, CUP H93C22000430007//NextGenerationEU/ ; PNRR-MR1-2022-12376395//European Union - Next Generation EU - PNRR M6C2/ ; "POFACS" - ARS01_00640 -", D.D. 1211/2020 and 1104/2021//Italian Ministry of University and Research (MIUR)/ ; PRA-HE 2021//University of Foggia/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism ; *Gastrointestinal Microbiome ; *Probiotics/therapeutic use ; Dysbiosis/microbiology ; Brain-Gut Axis ; Animals ; }, abstract = {Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.}, }
@article {pmid39273079, year = {2024}, author = {Lundt, S and Ding, S}, title = {Potential Therapeutic Interventions Targeting NAD[+] Metabolism for ALS.}, journal = {Cells}, volume = {13}, number = {17}, pages = {}, pmid = {39273079}, issn = {2073-4409}, support = {R01NS069726/NS/NINDS NIH HHS/United States ; R01 NS123023/NS/NINDS NIH HHS/United States ; R21 AG080715/AG/NIA NIH HHS/United States ; R01 NS069726/NS/NINDS NIH HHS/United States ; R21AG080715/AG/NIA NIH HHS/United States ; R01NS123023/NS/NINDS NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *NAD/metabolism ; Humans ; Animals ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD[+]) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD[+] can be synthesized from three different intracellular pathways, but it is the NAD[+] salvage pathway that generates the largest proportion of NAD[+]. Impaired NAD[+] homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD[+] homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD[+] metabolism, either by administering NAD[+] precursor metabolites or small molecules that alter NAD[+]-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD[+] metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models.}, }
@article {pmid39271939, year = {2024}, author = {Yu, Y and Pang, D and Huang, J and Li, C and Cui, Y and Shang, H}, title = {Downregulation of Lnc-ABCA12-3 modulates UBQLN1 expression and protein homeostasis pathways in amyotrophic lateral sclerosis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {21383}, pmid = {39271939}, issn = {2045-2322}, support = {2022NSFSC0750//The Sichuan Science and Technology Program/ ; 81871000//National Natural Science Foundation of China/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; *Autophagy-Related Proteins/genetics/metabolism ; *Down-Regulation ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; *Apoptosis/genetics ; Female ; Proteostasis ; Male ; Middle Aged ; Autophagy/genetics ; Oxidative Stress ; Gene Expression Regulation ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.}, }
@article {pmid39271680, year = {2024}, author = {Shan, Y and Zhang, M and Tao, E and Wang, J and Wei, N and Lu, Y and Liu, Q and Hao, K and Zhou, F and Wang, G}, title = {Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges.}, journal = {Signal transduction and targeted therapy}, volume = {9}, number = {1}, pages = {242}, pmid = {39271680}, issn = {2059-3635}, support = {82104184//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82373949//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073928//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation ; Graft vs Host Disease/therapy ; Translational Research, Biomedical ; Amyotrophic Lateral Sclerosis/therapy ; }, abstract = {Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.}, }
@article {pmid39271636, year = {2025}, author = {Wang, Y and Ju, R and Jiang, J and Mao, L and Li, X and Deng, M}, title = {Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {1}, pages = {195-205}, pmid = {39271636}, issn = {1590-3478}, support = {No. 82273915//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; China ; *DNA Copy Number Variations/genetics ; East Asian People/genetics ; *Frontotemporal Dementia/genetics ; Pedigree ; Profilins/genetics ; Whole Genome Sequencing ; *Phosphoproteins/genetics ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.}, }
@article {pmid39270726, year = {2024}, author = {Roos, AK and Stenvall, E and Kockum, ES and Grönlund, K&#xc5; and Alstermark, H and Wuolikainen, A and Andersen, PM and Nordin, A and Forsberg, KME}, title = {Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions.}, journal = {Human molecular genetics}, volume = {33}, number = {22}, pages = {1966-1974}, pmid = {39270726}, issn = {1460-2083}, support = {//Umea University/ ; Nos.FO 2022-0309//Swedish Brain Foundation/ ; 2012-3167//Swedish Research Council/ ; //Research and Development Unit/ ; JLL-980693//Region J&#xe4;mtland H&#xe4;rjedalen/ ; 2012.0091//Knut and Alice Wallenberg Foundation/ ; //Neurof&#xf6;rbundet patient organization/ ; 2023.16//Ulla-Carin Lindquist Foundation/ ; RV-993493//V&#xe4;sterbotten County Council/ ; //King Gustaf V:s and Queen Victoria's Freemason's Foundation/ ; //B&#xf6;rje Salming ALS Foundation/ ; }, mesh = {Humans ; *Huntingtin Protein/genetics/metabolism ; *Penetrance ; Male ; Female ; *Motor Neuron Disease/genetics/pathology/metabolism ; Middle Aged ; Aged ; *C9orf72 Protein/genetics/metabolism ; *DNA Repeat Expansion/genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Inclusion Bodies/metabolism/genetics/pathology ; Alleles ; Adult ; Huntington Disease/genetics/pathology/metabolism ; Cohort Studies ; Corpus Striatum/metabolism/pathology ; }, abstract = {Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington's disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36-39 CAG repeats), or alleles with intermediate penetrance, (27-35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%-6.61%) and reduced penetrance (range 0.57%-0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.}, }
@article {pmid39270623, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J and , }, title = {Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105323}, pmid = {39270623}, issn = {2352-3964}, support = {R35 NS097273/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/blood/diagnosis/mortality ; *Biomarkers/blood ; *Clinical Trials as Topic ; *Disease Progression ; Neurofilament Proteins/blood ; Prognosis ; Research Design ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.<br><br>METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.<br><br>FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40&#xa0;pg/mL and >100&#xa0;pg/mL correspond to future ALSFRS-R slopes of &#x223c;0.5 and &#x223c;1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields &#x223c;25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.<br><br>INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.<br><br>FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, }
@article {pmid39270519, year = {2024}, author = {Nishiyama, M and Koreki, A and Isose, S and Takeda, T and Ishikawa, A and Kokubun, S and Saito, Y and Ito, K and Arai, K and Takahashi, N and Motoda, Y and Kuwabara, S and Honda, K}, title = {Factors associated with psychological distress in patients with amyotrophic lateral sclerosis: A retrospective medical records study.}, journal = {Journal of psychosomatic research}, volume = {187}, number = {}, pages = {111915}, doi = {10.1016/j.jpsychores.2024.111915}, pmid = {39270519}, issn = {1879-1360}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Male ; Female ; Middle Aged ; *Psychological Distress ; Aged ; Retrospective Studies ; Adult ; Depression/psychology ; Stress, Psychological/psychology ; Surveys and Questionnaires ; Risk Factors ; Sex Factors ; }, abstract = {OBJECTIVE: Although psychological distress is a prevalent issue among patients with amyotrophic lateral sclerosis (ALS) and can impact survival, the risk factors contributing to this distress remain insufficiently understood.<br><br>METHODS: Patients with ALS who completed the Profile of Mood States (POMS) between June 2017 and March 2022 were included. Participants with moderate to severe cognitive decline were excluded, resulting in the recruitment of 121 patients. The associations between POMS profiles and clinical characteristics were analyzed. Physical motor symptoms were evaluated using the Revised ALS Functional Rating Scale (ALSFRS-R) for objective measurement and the 40-item ALS Assessment Questionnaire (ALSAQ-40) for subjective assessment.<br><br>RESULTS: Our model, employing the ALSFRS-R, revealed significant factors associated with overall psychological distress, as assessed by the POMS, including upper limb symptoms, the presence of sleep apnea syndrome, older age at onset, and male sex, with an inverse association with tracheostomy. The POMS subscale scores revealed that anger and depression were significantly associated with upper limb symptoms. The second model, which employed subjective scales, yielded similar results, reinforcing the robustness of our findings. Moreover, subjective bulbar symptoms on the ALSAQ-40 were significantly associated with psychological distress, particularly in female patients.<br><br>CONCLUSION: This study identified the main clinical characteristics significantly associated with psychological distress in patients with ALS. Our findings may be useful in developing individualized psychological management strategies for these patients.}, }
@article {pmid39269505, year = {2024}, author = {Denis, PA and Laranjeira, JAS and Martins, NF and Sambrano, JR}, title = {Codoped germanene with 3p and 4p elements elements.}, journal = {Journal of molecular modeling}, volume = {30}, number = {10}, pages = {331}, pmid = {39269505}, issn = {0948-5023}, abstract = {CONTEXT: The relentless need for new materials to be used in electronic devices has opened new research directions in materials science. One of them involves using two-dimensional materials, among which there is current interest in using germanene. The heteroatom doping of germanene has been proposed as a possible approach to fine-tuning its electronic properties. However, this procedure is complicated because locating the dopants with a specific arrangement is challenging, thus achieving reproducibility. To avoid this problem, we propose the codoping of germanene to understand if dopants prefer to be agglomerated as observed for graphene or if they prefer to adopt a random disposition. Herein, we employed first-principles calculations to study 21 codoped germanene systems with one 3p (Al, Si, P, and S) and one 4p (Ga, As, and Se) element. Our results indicate that in the cases of AlP, AlS, GaP, GaS, GaAs, and GaSe codoped germanene, the dopants show a tendency to be located in specific lattice positions. The ortho disposition of dopants is preferred for AlP, AlS, GaP and GaS codoped germanene and their 4p counterparts GaAs and GaSe codoped germanene, and the materials showed interesting electronic properties making them suitable to develop germanene-based electronic materials.<br><br>METHODS: We utilized the M06-L, HSE06 methods accompanied by the 6-31G* basis sets to perform periodic boundary conditions calculations as implemented in Gaussian 09. The unit cells were sampled employing 100&#xa0;k-points for geometry optimizations and 2000&#xa0;k-points for electronic properties The ultrafine grid was employed. Results were visualized employing Gaussview 5.0.1. In addition to this, we performed B3LYP-D3 periodic calculations as implemented in CRYSTAL17.}, }
@article {pmid39268841, year = {2024}, author = {Xing, C and Luo, M and Sheng, Q and Zhu, Z and Yu, D and Huang, J and He, D and Zhang, M and Fan, W and Chen, D}, title = {Silk Fabric Functionalized by Nanosilver Enabling the Wearable Sensing for Biomechanics and Biomolecules.}, journal = {ACS applied materials &amp; interfaces}, volume = {16}, number = {38}, pages = {51669-51678}, doi = {10.1021/acsami.4c10253}, pmid = {39268841}, issn = {1944-8252}, mesh = {*Wearable Electronic Devices ; *Silver/chemistry ; *Silk/chemistry ; Humans ; *Metal Nanoparticles/chemistry ; Biomechanical Phenomena ; Textiles ; Biosensing Techniques/instrumentation/methods ; Spectrum Analysis, Raman ; }, abstract = {Integrating biomechanical and biomolecular sensing mechanisms into wearable devices is a formidable challenge and key to acquiring personalized health management. To address this, we have developed an innovative multifunctional sensor enabled by plasma functionalized silk fabric, which possesses multimodal sensing capabilities for biomechanics and biomolecules. A seed-mediated in situ growth method was employed to coat silver nanoparticles (AgNPs) onto silk fibers, resulting in silk fibers functionalized with AgNPs (SFs@Ag) that exhibit both piezoresistive response and localized surface plasmon resonance effects. The SFs@Ag membrane enables accurate detection of mechanical pressure and specific biomolecules during wearable sensing, offering a versatile solution for comprehensive personalized health monitoring. Additionally, a machine learning algorithm has been established to specifically recognize muscle strain signals, potentially extending to the diagnosis and monitoring of neuromuscular disorders such as amyotrophic lateral sclerosis (ALS). Unlike electromyography, which detects large muscles in clinical medicine, sensing data for tiny muscles enhance our understanding of muscle coordination using the SFs@Ag sensor. This detection model provides feasibility for the early detection and prevention of neuromuscular diseases. Beyond muscle stress and strain sensing, biomolecular detection is a critical addition to achieving effective health management. In this study, we developed highly sensitive surface-enhanced Raman scattering (SERS) detection for wearable health monitoring. Finite-difference time-domain numerical simulations ware utilized to analyze the efficacy of the SFs@Ag sensor for wearable SERS sensing of biomolecules. Based on the specific SERS spectra, automatic extraction of signals of sweat molecules was also achieved. In summary, the SFs@Ag sensor bridges the gap between biomechanical and biomolecular sensing in wearable applications, providing significant value for personalized health management.}, }
@article {pmid39268298, year = {2024}, author = {Contractor, RN and Shah, M and Manwell, W and Dempsey, KJ and Simhadri, P}, title = {Jean-Martin Charcot: Pioneer of Neurology.}, journal = {Cureus}, volume = {16}, number = {8}, pages = {e66762}, pmid = {39268298}, issn = {2168-8184}, abstract = {Jean-Martin Charcot, born on November 29, 1825, in Paris, France, is known as the father of neurology. During a time when neurology was not yet a recognized medical specialty, Charcot's pioneering contributions significantly advanced the field. Charcot's use of the anatomo-clinical method, which correlates clinical symptoms with anatomical findings, led to the discovery and characterization of numerous neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Charcot's joint, and Charcot-Marie-Tooth (CMT) disease. His methodical approach to documenting clinical signs and conducting post-mortem examinations revolutionized neurological research and diagnosis, laying the groundwork for modern neurology. The anatomo-clinical methods continue to be a vital tool in neurological research and practice today. Charcot's work extended beyond clinical practice, influencing the study of neurology through his role as an educator and mentor to many, including Sigmund Freud. Despite some controversies and a reputation for being difficult to work with, Charcot's legacy endures, with his initial discoveries fostering greater awareness and the development of therapies for various neurological disorders.}, }
@article {pmid39267142, year = {2024}, author = {Wang, YM and Yan, J and Williams, SK and Fairless, R and Bading, H}, title = {TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {149}, pmid = {39267142}, issn = {2051-5960}, support = {BA 1007/7-1//Deutsche Forschungsgemeinschaft/ ; FOR 2289//Deutsche Forschungsgemeinschaft/ ; Advanced Grant 233024//HORIZON EUROPE European Research Council/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/metabolism/drug therapy ; *Retinal Ganglion Cells/drug effects/pathology/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; Mice ; Electroretinography ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Humans ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; }, abstract = {Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1[G93A], we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1[G93A] mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.}, }
@article {pmid39266192, year = {2024}, author = {Chiappini, FA and Pinto, L and Alcaraz, MR and Omidikia, N and Goicoechea, HC and Olivieri, AC}, title = {Multivariate curve resolution-alternating least-squares and second-order advantage in first-order calibration. A systematic characterisation for three-component analytical systems.}, journal = {Analytica chimica acta}, volume = {1328}, number = {}, pages = {343159}, doi = {10.1016/j.aca.2024.343159}, pmid = {39266192}, issn = {1873-4324}, abstract = {BACKGROUND: Recent interest has been focused on the application of multivariate curve resolution-alternating least-squares (MCR-ALS) to systems involving the measurement of first-order and non-bilinear second-order data. The latter pose important challenges to bilinear decomposition models, due to the phenomenon of rotational ambiguity in the solutions, even under the application of the full set of chemical constraints that is usually employed in MCR-ALS calibration.<br><br>RESULTS: After the analysis of several simulated and experimental datasets, important conclusions regarding the role of the selectivity patterns in the constituent spectra have been drawn concerning the achievement of the second-order advantage. Theoretical considerations based on the calculation of the areas of feasible solutions helped to support the observations regarding the predictive ability of MCR- ALS in the various datasets.<br><br>SIGNIFICANCE: The understanding of the impact of rotational ambiguity in obtaining the second-order advantage with both first-order and non-bilinear second-order data is of paramount importance in the future development of analytical protocols of complex samples.}, }
@article {pmid39264833, year = {2024}, author = {Su, B and He, Z and Liu, J and Li, M and Huang, X}, title = {Mangiferin activates the nuclear factor erythroid 2-related factor pathway to protect SOD1-G93A induced NSC-34 motor neurons from oxidative stress and apoptosis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23849}, doi = {10.1002/jbt.23849}, pmid = {39264833}, issn = {1099-0461}, mesh = {*Xanthones/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Mice ; Animals ; *Motor Neurons/metabolism/drug effects/pathology ; *Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Line ; Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; Humans ; NAD(P)H Dehydrogenase (Quinone)/metabolism/genetics ; }, abstract = {One of the main factors in the pathophysiology of amyotrophic lateral sclerosis is oxidative stress. Mangiferin (MF), a natural plant polyphenol, has anti-inflammatory and antioxidant effects. The aim of our study was to investigate the protective effects and mechanisms of MF in the hSOD1-G93A ALS cell model. Our result revealed that MF treatment reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreased oxidative damage, and reduced apoptosis. Additionally, it was observed that MF significantly increased the synthesis of the antioxidant genes hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase 1, which are downstream of the Nrf2 signaling pathway, and increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 knockdown greatly promoted apoptosis, which was reversed by MF treatment. To summarize, MF promoted the Nrf2 pathway and scavenged MDA and ROS to protect the ALS cell model.}, }
@article {pmid39264557, year = {2024}, author = {Grigoryev, PN and Gaptrakhmanova, GA and Plotnikova, AA and Zefirov, AL and Mukhamedyarov, MA}, title = {Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.}, journal = {Bulletin of experimental biology and medicine}, volume = {177}, number = {4}, pages = {449-453}, pmid = {39264557}, issn = {1573-8221}, mesh = {Animals ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism/physiopathology ; Diaphragm/innervation/metabolism/physiopathology ; *Disease Models, Animal ; *Endocytosis/physiology ; Fluorescent Dyes/metabolism ; Imidazoles/pharmacology ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; Nerve Endings/metabolism ; Pyridinium Compounds/metabolism ; Quaternary Ammonium Compounds/metabolism ; RNA-Binding Protein FUS/genetics/metabolism ; Synaptic Transmission/physiology/genetics ; *Synaptic Vesicles/metabolism ; }, abstract = {In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice. However, at the time of stimulation, during which an equal number of quanta are released in wild-type and FUS mice, no differences in the intensity of dye loading were found. Thus, endocytosis is not the key factor in the mechanism of synaptic dysfunction in FUS mice at the pre-symptomatic stage.}, }
@article {pmid39263607, year = {2024}, author = {He, D and He, X and Shen, D and Liu, L and Yang, X and Hao, M and Wang, Y and Li, Y and Liu, Q and Liu, M and Wang, J and Zhang, X and Cui, L}, title = {Loss-of-function variants in RNA binding motif protein X-linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis.}, journal = {MedComm}, volume = {5}, number = {9}, pages = {e712}, pmid = {39263607}, issn = {2688-2663}, abstract = {Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43[Q331K] results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.}, }
@article {pmid39262980, year = {2024}, author = {Joshi, R and Goswami, D and Saha, P and Hole, A and Mandhare, P and Wadke, R and Murthy, PR and Borgohain, S and C, MK and Kapoor, S}, title = {Serum Raman spectroscopy: Unearthing the snapshot of distinct metabolic profile in patients with congenital heart defects (CHDs).}, journal = {Heliyon}, volume = {10}, number = {16}, pages = {e34575}, pmid = {39262980}, issn = {2405-8440}, abstract = {In the present study, efficacy of minimally-invasive serum Raman spectroscopy (SRS) in stratification of congenital heart diseases was explored. Blood was collected from 62 subjects [42 congenital heart defect (CHD) patients (19 with atrial septal defect, 13 with ventricular septal defect and 10 with tetralogy of fallot) and 20 controls], and serum separated. Raman spectra of sera were recorded, pre-processed and subjected to spectral and multivariate analyses. Multivariate curve resolution-alternating least squares (MCR-ALS) analyses indicated alterations in lipid and protein levels between the study groups. Principal Component Analysis (PCA) and Principal Component based Linear Discriminant Analysis (PC-LDA), cross-validated with Leave-one-out cross validation (LOOCV), were employed to study stratification between the different groups. CHD could be classified from controls with 76 % efficiency. The different CHD subtypes could be distinguished with efficiencies as high as ∼90 %. To the best of our knowledge, differentiation between controls and CHDs as well as the stratification between controls and CHDs subtypes was for the first time successfully accomplished by serum-based Raman spectroscopy.}, }
@article {pmid39261725, year = {2024}, author = {Abe, P and Lavalley, A and Morassut, I and Santinha, AJ and Roig-Puiggros, S and Javed, A and Klingler, E and Baumann, N and Prados, J and Platt, RJ and Jabaudon, D}, title = {Molecular programs guiding arealization of descending cortical pathways.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {644-651}, pmid = {39261725}, issn = {1476-4687}, mesh = {Animals ; Female ; Male ; Mice ; Axons/metabolism ; Gene Expression Regulation, Developmental ; Motor Cortex/cytology/metabolism ; *Neocortex/anatomy &amp; histology/cytology/metabolism ; *Neural Pathways ; *Neurons/metabolism/cytology ; Single-Cell Gene Expression Analysis ; Transcription Factors/metabolism ; }, abstract = {Layer 5 extratelencephalic (ET) neurons are present across neocortical areas and send axons to multiple subcortical targets[1-6]. Two cardinal subtypes exist[7,8]: (1) Slco2a1-expressing neurons (ETdist), which predominate in the motor cortex and project distally to the pons, medulla and spinal cord; and (2) Nprs1- or Hpgd-expressing neurons (ETprox), which predominate in the visual cortex and project more proximally to the pons and thalamus. An understanding of how area-specific ETdist and ETprox emerge during development is important because they are critical for fine motor skills and are susceptible to spinal cord injury and amyotrophic lateral sclerosis[9-12]. Here, using cross-areal mapping of axonal projections in the mouse neocortex, we identify the subtype-specific developmental dynamics of ET neurons. Whereas subsets of ETprox emerge by pruning of ETdist axons, others emerge de novo. We outline corresponding subtype-specific developmental transcriptional programs using single-nucleus sequencing. Leveraging these findings, we use postnatal in vivo knockdown of subtype-specific transcription factors to reprogram ET neuron connectivity towards more proximal targets. Together, these results show the functional transcriptional programs driving ET neuron diversity and uncover cell subtype-specific gene regulatory networks that can be manipulated to direct target specificity in motor corticofugal pathways.}, }
@article {pmid39260590, year = {2024}, author = {Petel Légaré, V and Harji, ZA and Rampal, CJ and Antonicka, H and Gurberg, TJN and Persia, O and Rodríguez, EC and Shoubridge, EA and Armstrong, GAB}, title = {CHCHD10[P80L] knock-in zebrafish display a mild ALS-like phenotype.}, journal = {Experimental neurology}, volume = {382}, number = {}, pages = {114945}, doi = {10.1016/j.expneurol.2024.114945}, pmid = {39260590}, issn = {1090-2430}, mesh = {Animals ; *Zebrafish ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *Phenotype ; *Mitochondrial Proteins/genetics ; Zebrafish Proteins/genetics ; Motor Neurons/metabolism/pathology ; Gene Knock-In Techniques ; Animals, Genetically Modified ; Disease Models, Animal ; Neuromuscular Junction/pathology/genetics/metabolism ; }, abstract = {Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10[P80L] variant (zebrafish: Chchd10[P83L]). Larval chchd10[P83L/P83L] fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10[-/-]). Adult, 11-month old chchd10[P83L/P83L] zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10[P83L/P83L] zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2[-/-] adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10[P83L/P83L] model. The findings presented here, suggest that the CHCHD10[P80L] variant confers an ALS-like phenotype when expressed in zebrafish.}, }
@article {pmid39260416, year = {2024}, author = {Arseni, D and Nonaka, T and Jacobsen, MH and Murzin, AG and Cracco, L and Peak-Chew, SY and Garringer, HJ and Kawakami, I and Suzuki, H and Onaya, M and Saito, Y and Murayama, S and Geula, C and Vidal, R and Newell, KL and Mesulam, M and Ghetti, B and Hasegawa, M and Ryskeldi-Falcon, B}, title = {Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.}, journal = {Nature}, volume = {634}, number = {8034}, pages = {662-668}, pmid = {39260416}, issn = {1476-4687}, support = {R01 AG077444/AG/NIA NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01 NS110437/NS/NINDS NIH HHS/United States ; R01 NS085770/NS/NINDS NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; RF1 NS110437/NS/NINDS NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG080001/AG/NIA NIH HHS/United States ; R01 AG071177/AG/NIA NIH HHS/United States ; R01 NS137469/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Amyloid/chemistry/metabolism/ultrastructure ; *Annexins/chemistry/metabolism/ultrastructure ; Aphasia/complications/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Cryoelectron Microscopy ; *DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; *Frontotemporal Dementia/classification/complications/metabolism ; Models, Molecular ; Protein Multimerization ; }, abstract = {Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system[1]. Human genetic studies have established a causal role for protein assembly in neurodegeneration[2]. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients[1]. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B[3,4]. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.}, }
@article {pmid39260140, year = {2024}, author = {Emori, S and Kume, K and Nakayama, Y and Ito, H and Kawakami, H}, title = {C9orf72 repeat expansions in Wakayama: One potential cause of amyotrophic lateral sclerosis in the Kii Peninsula, Japan.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123209}, doi = {10.1016/j.jns.2024.123209}, pmid = {39260140}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *C9orf72 Protein/genetics ; Japan/epidemiology ; Male ; Female ; *DNA Repeat Expansion/genetics ; Middle Aged ; Aged ; Proteins/genetics ; Adult ; Aged, 80 and over ; Genetic Predisposition to Disease/genetics ; Haplotypes ; }, abstract = {A cluster of cases of amyotrophic lateral sclerosis (ALS) exists in the southern part of the Kii Peninsula in Japan. Although both genetic and environmental factors are thought to be causative, the critical cause of this cluster has not been identified. C9orf72 is the most common genetic factor in both familial and sporadic C9orf72-related ALS in people of European ancestry, but it is rare among Japanese populations. However, a previous report revealed that the frequency of C9orf72-related ALS was significantly higher in the cluster area. We evaluated the proportion of C9orf72 hexanucleotide repeat expansions in 99 cases of ALS diagnosed in Wakayama Prefecture, including the cluster area, by using repeat-primed polymerase chain reaction and fluorescence fragment length analysis. We found that 2 of the 99 patients (0 % of those with familial ALS and 2.4 % of those with sporadic ALS) had hexanucleotide repeat expansions in C9orf72, and long-read sequencing revealed that these expansions were causative. No expansions were observed among 90 patients with Parkinson's disease or among 90 healthy controls. Haplotype analysis with long-read sequencing data revealed that the two patients with repeat expansions shared the common haplotype with that previously reported in Finnish patients with C9orf72-related ALS, which suggests a founder effect. C9orf72 was thought to be a rare causative gene in Japan, but this study revealed that it may be relatively common in Wakayama Prefecture.}, }
@article {pmid39259763, year = {2024}, author = {Caredio, D and Koderman, M and Frontzek, KJ and Sorce, S and Nuvolone, M and Bremer, J and Mariutti, G and Schwarz, P and Madrigal, L and Mitrovic, M and Sellitto, S and Streichenberger, N and Scheckel, C and Aguzzi, A}, title = {Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle.}, journal = {PLoS pathogens}, volume = {20}, number = {9}, pages = {e1012552}, pmid = {39259763}, issn = {1553-7374}, mesh = {Animals ; *Muscle, Skeletal/metabolism/pathology ; *Glutamine/metabolism ; *Glutamic Acid/metabolism ; Mice ; *Prion Diseases/metabolism/genetics ; Humans ; Glutamate-Ammonia Ligase/metabolism ; Creutzfeldt-Jakob Syndrome/metabolism/pathology/genetics ; Female ; Mice, Inbred C57BL ; }, abstract = {In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer's disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.}, }
@article {pmid39258797, year = {2024}, author = {Coppedè, F}, title = {DNA methylation in amyotrophic lateral sclerosis: where do we stand and what is next?.}, journal = {Epigenomics}, volume = {16}, number = {17}, pages = {1185-1196}, pmid = {39258797}, issn = {1750-192X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *DNA Methylation ; Epigenesis, Genetic ; }, abstract = {Genes involved in immune response, inflammation and metabolism are among those most likely affected by changes in DNA methylation (DNAm) and expression levels in amyotrophic lateral sclerosis (ALS) tissues. Unfortunately, it is still largely unclear whether any of these changes precede the onset of disease symptoms or whether most of them are the result of the muscular and metabolic changes that follow symptoms onset. In this article the author discusses the strengths and limitations of the available studies of DNAm in ALS and provides some suggestions on what, in his opinion, could be done in the near future for a better understanding of the DNAm changes occurring in ALS, their link with environmental exposures and their potential clinical utility.}, }
@article {pmid39258740, year = {2025}, author = {O'Connell, C and Kavanaugh, MS and Cummings, C and Genge, A}, title = {How to break the news in amyotrophic lateral sclerosis/motor neuron disease: practical guidelines from experts.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {5-14}, doi = {10.1080/21678421.2024.2397517}, pmid = {39258740}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Motor Neuron Disease/psychology/therapy ; Communication ; Quality of Life/psychology ; Practice Guidelines as Topic/standards ; }, abstract = {In amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), it is necessary to communicate difficult news during the initial diagnosis and throughout the disease trajectory as the condition progresses. However, delivering difficult news to people with ALS/MND is an emotionally demanding task for healthcare and allied health professionals-one for which many feel ill-prepared because of limited training in this area. Ineffective communication of difficult news damages the patient-provider relationship and negatively impacts patient quality of life (QoL). To address this issue, we developed the A-L S-PIKES protocol based on available literature and our extensive clinical experience. It provides easy-to-follow, stepwise guidelines to effectively deliver difficult news to people with ALS/MND (PALS) that includes: Advance Preparation (preparing for the discussion logistically and emotionally); Location &amp; Setting (creating a comfortable setting that fosters rapport); Patient's Perceptions (assessing PALS' understanding and perception of their condition); Invitation (seeking PALS' permission to share information); Knowledge (sharing information in a clear, understandable manner); Emotion/Empathy (addressing emotions with empathy and providing emotional support); and Strategy &amp; Summary (summarizing the discussion and collaboratively developing a plan of action). A-L S-PIKES provides practical guidelines on how to prepare for and conduct these challenging conversations. It emphasizes effective communication tailored to the individual needs of PALS and their families, empathy, sensitivity, and support for PALS' emotional well-being and autonomy. The aim of A-L S-PIKES is to both enhance skills and confidence in delivering difficult news and to improve the QoL of PALS and their families. Future studies should systematically evaluate the feasibility and effectiveness of A-L S-PIKES to establish its utility in clinical practice.}, }
@article {pmid39258714, year = {2024}, author = {Winroth, I and Börjesson, A and Andersen, PM and Karlsson, T}, title = {Cognitive deficits in ALS patients with SOD1 mutations.}, journal = {Journal of clinical and experimental neuropsychology}, volume = {46}, number = {7}, pages = {669-682}, doi = {10.1080/13803395.2024.2393366}, pmid = {39258714}, issn = {1744-411X}, mesh = {Humans ; Female ; Male ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Mutation ; Aged ; *Neuropsychological Tests ; Cognitive Dysfunction/physiopathology/genetics/etiology ; Adult ; Memory, Short-Term/physiology ; C9orf72 Protein/genetics ; Bayes Theorem ; }, abstract = {OBJECTIVE: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE. However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (mSOD1) gene.<br><br>METHODS: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls.<br><br>RESULTS: Carriers of SOD1-mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE. All groups had deficits in working memory, although mSOD1-carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A-SOD1 mutation overall performed as well as or better than carriers of other SOD1-mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, mSOD1 and sporadic ALS.<br><br>CONCLUSION: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.}, }
@article {pmid39258588, year = {2025}, author = {Walsh, S and Simmons, Z and Miyamoto, S and Geronimo, A}, title = {A nurse coaching intervention to improve support to individuals living with ALS.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {22-28}, doi = {10.1080/21678421.2024.2399154}, pmid = {39258588}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; Male ; Female ; Middle Aged ; *Quality of Life/psychology ; *Mentoring/methods ; Aged ; *Self Efficacy ; Motivational Interviewing/methods ; Adult ; }, abstract = {OBJECTIVE: Health coaching may supplement the multidisciplinary ALS clinic model to facilitate patient-centered health behavior change. The aim of this study was to determine the effects of nurse health coaching (NHC) on the quality of life and self-efficacy of individuals living with ALS.<br><br>METHODS: Twenty-nine participants were randomized at 1:1 to the standard of care and coaching arms. All participants attended multidisciplinary ALS clinic visits quarterly, at which times they completed assessments of quality of life and self-efficacy. Those in the coaching arm participated in monthly coaching with a nurse coach over 12 months. The coaching sessions utilized motivational interviewing to identify personal goals along with barriers and solutions to achieve them. Linear mixed-effect models were used to quantify the effect of coaching on quality of life and self-efficacy outcomes. Thematic analysis was performed to summarize the participants' experiences with coaching.<br><br>RESULTS: Adherence to the coaching intervention was good. No effects of coaching were observed on the primary outcomes of quality of life and self-efficacy, although debriefed participants reported that they would recommend it to others. Patients and caregivers reflected on the impacts of coaching that extended beyond the pre-defined study outcomes and measures put in place to gauge effectiveness.<br><br>CONCLUSIONS: The elicited qualitative themes illustrating patient experience of coaching demonstrate the utility of nurse coaching as an important adjunct support to complement the multidisciplinary ALS clinic model.}, }
@article {pmid39258586, year = {2025}, author = {Sommers-Spijkerman, M and Zwarts-Engelbert, A and Kruitwagen-Van Reenen, E and Van Eijk, RPA and Visser-Meily, JMA and Heijmans, E and Austin, J and Drossaert, C and Bohlmeijer, E and Beelen, A}, title = {Acceptability and potential benefit of a self-compassion intervention for people living with amyotrophic lateral sclerosis: a mixed methods pilot study.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {29-39}, doi = {10.1080/21678421.2024.2400516}, pmid = {39258586}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/rehabilitation ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Empathy ; *Caregivers/psychology ; Adaptation, Psychological/physiology ; Adult ; Surveys and Questionnaires ; Self Concept ; Patient Acceptance of Health Care/psychology/statistics &amp; numerical data ; Psychological Distress ; }, abstract = {OBJECTIVE: This proof-of-concept study aimed to explore the acceptability and potential benefit of a self-guided online self-compassion intervention to aid resilient coping and reduce emotional distress among patients and caregivers living with ALS.<br><br>METHODS: A single-arm pilot study was conducted in 20 adults living with ALS either as a patient or as a caregiver. Acceptability was examined using questionnaires (n&#x2009;=&#x2009;20) and semi-structured interviews (n&#x2009;=&#x2009;9). Potential benefit was assessed as changes in self-compassion, self-criticism and emotional distress, determined using psychological questionnaires at 3 and 6 weeks. Questionnaires were analyzed using linear mixed-effects models and interview data using inductive thematic analysis.<br><br>RESULTS: Out of 20 participants who started the intervention, 16 completed the study (80%). The majority of study completers (12/16) were satisfied with the intervention, but the data suggest room for improvement in terms of personalization. Qualitative data revealed multiple psychological benefits of using the intervention, including self-kindness, emotional self-awareness and savoring. Although not statistically significant, quantitative data showed positive trends with increased self-compassion (mean difference: 2.07; 95% CI: -.5.76&#x2009;-&#x2009;1.63) and reduced self-criticism (mean difference: -2.62; 95% CI: -.1.97&#x2009;-&#x2009;7.23) and emotional distress (mean difference: -2.49; 95% CI: -.51&#x2009;-&#x2009;5.50) at week 6 compared to baseline.<br><br>CONCLUSIONS: The findings suggest that a self-compassion intervention is acceptable to people living with ALS, but its beneficial effects and the mechanisms involved have yet to be established in larger and more diverse samples, using controlled designs.}, }
@article {pmid39257530, year = {2024}, author = {Baird, MC and Likhite, SB and Vetter, TA and Caporale, JR and Girard, HB and Roussel, FS and Howard, AE and Schwartz, MK and Reed, AR and Kaleem, A and Zhang, X and Meyer, KC}, title = {Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {32}, number = {3}, pages = {101312}, pmid = {39257530}, issn = {2329-0501}, abstract = {Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 [G93A] microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 [G93A] mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.}, }
@article {pmid39255192, year = {2024}, author = {Hwang, RD and Lu, Y and Tang, Q and Periz, G and Park, G and Li, X and Xiang, Q and Liu, Y and Zhang, T and Wang, J}, title = {DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {39255192}, issn = {2050-084X}, support = {R01 NS128494/NS/NINDS NIH HHS/United States ; I01 BX002466/BX/BLRD VA/United States ; R01 NS074324/NS/NINDS NIH HHS/United States ; R01 NS110098/NS/NINDS NIH HHS/United States ; R01 NS089616/NS/NINDS NIH HHS/United States ; NS074324/NH/NIH HHS/United States ; NS089616/NH/NIH HHS/United States ; NS128494/NH/NIH HHS/United States ; NS110098/NH/NIH HHS/United States ; }, mesh = {Animals ; *Proteasome Endopeptidase Complex/metabolism ; *Proteostasis ; Humans ; Drosophila/metabolism ; Autophagy ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Neurons/metabolism ; Drosophila melanogaster/metabolism/genetics ; }, abstract = {Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.}, }
@article {pmid39255062, year = {2024}, author = {Germeys, C and Vandoorne, T and Davie, K and Poovathingal, S and Heeren, K and Vermeire, W and Nami, F and Moisse, M and Quaegebeur, A and Sierksma, A and Rué, L and Sicart, A and Eykens, C and De Cock, L and De Strooper, B and Carmeliet, P and Van Damme, P and De Bock, K and Van Den Bosch, L}, title = {Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114719}, doi = {10.1016/j.celrep.2024.114719}, pmid = {39255062}, issn = {2211-1247}, support = {/ERC_/European Research Council/International ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/metabolism/pathology ; *Astrocytes/metabolism ; Disease Models, Animal ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists &amp; inhibitors/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Interferons/metabolism ; *Motor Neurons/metabolism ; *Zebrafish/metabolism ; }, abstract = {Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.}, }
@article {pmid39254699, year = {2024}, author = {Maccabeo, A and Pateri, MI and Pili, F and Pilotto, S and Pierri, V and Muroni, A and Ercoli, T and Montisci, R and Marchetti, MF and Martis, A and Fazzini, L and Defazio, G and Puligheddu, M and Borghero, G}, title = {Takotsubo syndrome in a Sardinian amyotrophic lateral sclerosis cohort.}, journal = {Journal of neurology}, volume = {271}, number = {12}, pages = {7489-7493}, pmid = {39254699}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/complications/physiopathology ; *Takotsubo Cardiomyopathy/physiopathology/epidemiology/etiology ; Female ; Italy/epidemiology ; Aged ; Middle Aged ; Retrospective Studies ; Cohort Studies ; Male ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is known to be associated with varying degrees of autonomic and cardiovascular dysfunction. Recent case reports showed that ALS may be linked to Takotsubo syndrome (TTS). We assessed the frequency of TTS in an incident ALS cohort from Sardinia, Italy, and investigated the relationship of TTS with ALS course.<br><br>METHODS: We retrospectively examined a 10-year (2010-2019) incident cohort of ALS patients of Sardinian ancestry, reported TTS frequency and patients' clinical characteristics. Following, we checked for TTS among patients with ALS onset after 2019 and focused on the same features as for the incident cohort.<br><br>RESULTS: Our incident cohort included 344 ALS patients and 5 of them (1.45%) developed TTS. All were female and their median onset age was 71.5&#xa0;years (IQR 62.75-77). Two patients had spinal and three bulbar onset, though all patients had bulbar involvement and were at an advanced stage of disease (ALSFRS&#x2009;&#x2264;&#x2009;25, King's&#x2009;&#x2265;&#x2009;3) at TTS diagnosis. We identified a potential TTS trigger in three patients (hospitalization for PEG placement, pneumonia). Among patients who had ALS onset after 2019, we identified a further TTS case and described it.<br><br>CONCLUSION: TTS is not a rare condition in ALS. Female sex, bulbar involvement, and later age of disease onset may be important risk factors for developing this cardiac condition and a physical or psychological trigger is often observed. Despite autonomic dysfunction in ALS has been already demonstrated, the precise physiopathological mechanism underlying TTS needs to be further clarified.}, }
@article {pmid39254548, year = {2025}, author = {Zhang, M and Xiang, C and Niu, R and He, X and Luo, W and Liu, W and Gu, R}, title = {Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety.}, journal = {Neural regeneration research}, volume = {20}, number = {7}, pages = {1883-1899}, pmid = {39254548}, issn = {1673-5374}, abstract = {Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood-brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood-brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research.}, }
@article {pmid39254482, year = {2025}, author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P}, title = {A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {48-57}, doi = {10.1080/21678421.2024.2400522}, pmid = {39254482}, issn = {2167-9223}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Muscular Atrophy, Spinal/drug therapy ; }, abstract = {INTRODUCTION: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS.<br><br>METHODS: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH).<br><br>RESULTS: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH.<br><br>CONCLUSION: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.}, }
@article {pmid39253877, year = {2024}, author = {Thornburg-Suresh, EJC and Summers, DW}, title = {Microtubules, Membranes, and Movement: New Roles for Stathmin-2 in Axon Integrity.}, journal = {Journal of neuroscience research}, volume = {102}, number = {9}, pages = {e25382}, pmid = {39253877}, issn = {1097-4547}, support = {R01 NS126191/NS/NINDS NIH HHS/United States ; R01NS126191/NH/NIH HHS/United States ; }, mesh = {*Stathmin/metabolism ; *Microtubules/metabolism ; Humans ; *Axons/metabolism/physiology ; Animals ; Cell Membrane/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology ; }, abstract = {Neurons establish functional connections responsible for how we perceive and react to the world around us. Communication from a neuron to its target cell occurs through a long projection called an axon. Axon distances can exceed 1 m in length in humans and require a dynamic microtubule cytoskeleton for growth during development and maintenance in adulthood. Stathmins are microtubule-associated proteins that function as relays between kinase signaling and microtubule polymerization. In this review, we describe the prolific role of Stathmins in microtubule homeostasis with an emphasis on emerging roles for Stathmin-2 (Stmn2) in axon integrity and neurodegeneration. Stmn2 levels are altered in Amyotrophic Lateral Sclerosis and loss of Stmn2 provokes motor and sensory neuropathies. There is growing potential for employing Stmn2 as a disease biomarker or even a therapeutic target. Meeting this potential requires a mechanistic understanding of emerging complexity in Stmn2 function. In particular, Stmn2 palmitoylation has a surprising contribution to axon maintenance through undefined mechanisms linking membrane association, tubulin interaction, and axon transport. Exploring these connections will reveal new insight on neuronal cell biology and novel opportunities for disease intervention.}, }
@article {pmid39253499, year = {2024}, author = {Thompson, EG and Spead, O and Akerman, SC and Curcio, C and Zaepfel, BL and Kent, ER and Philips, T and Vijayakumar, BG and Zacco, A and Zhou, W and Nagappan, G and Rothstein, JD}, title = {A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66 mouse model.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39253499}, issn = {2692-8205}, support = {F32 NS120940/NS/NINDS NIH HHS/United States ; R35 NS132179/NS/NINDS NIH HHS/United States ; }, abstract = {The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.}, }
@article {pmid39252332, year = {2024}, author = {Li, LS and Tong, Y and Yuan, C and Zhang, W}, title = {Evaluation of diagnostic value and Mendelian randomization study of appendicitis hub genes obtained by WGCNA analysis.}, journal = {Medicine}, volume = {103}, number = {36}, pages = {e39307}, doi = {10.1097/MD.0000000000039307}, pmid = {39252332}, issn = {1536-5964}, mesh = {Humans ; *Appendicitis/genetics/diagnosis ; *Mendelian Randomization Analysis ; Gene Expression Profiling/methods ; ROC Curve ; Gene Regulatory Networks ; Nomograms ; Gastrointestinal Microbiome/genetics ; }, abstract = {The timely and precise diagnosis of appendicitis was deemed essential. This study sought to examine the diagnostic significance of hub genes linked to appendicitis and to delve deeper into the pathophysiology of the condition. Differential gene expression analysis revealed distinct genes in the appendicitis group compared to other abdominal pain group, while weighted gene co-expression network analysis identified appendicitis-associated modules. Further analysis of common genes was conducted using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis. The diagnostic efficiency of hub genes was explored through the use of nomograms and receiver operator characteristic curves. Additionally, immunoinfiltration analysis was performed to investigate the immune cell infiltration in both groups. The causal relationship between hub genes and appendicitis, as well as gut microbiota and appendicitis, was ultimately examined through Mendelian randomization. By conducting differential expression analysis and weighted gene co-expression network analysis, a total of 757 common genes were identified. Subsequent Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses revealed that these common genes were primarily associated with positive regulation of cell adhesion, focal adhesion, protein serine kinase activity, and amyotrophic lateral sclerosis. Utilizing Cytoscape software, the top 10 genes with the highest degree of interaction were identified as RPS3A, RPSA, RPL5, RPL37A, RPS27L, FLT3LG, ARL6IP1, RPL32, MRPL3, and GSPT1. Evaluation using nomograms and receiver operator characteristic curves demonstrated the diagnostic value of these hub genes. Ultimately, a causal relationship between hub genes and appendicitis was not identified in our study. Nevertheless, our findings indicate that appendicitis is correlated with 9 gut microbiota. This study identified 5 hub genes, specifically HSP90AA1, RPL5, MYC, CD44, and RPS3A, which exhibit diagnostic significance of appendicitis. Furthermore, the elucidation of these hub genes aids in enhancing our comprehension of the molecular pathways implicated in the development of appendicitis.}, }
@article {pmid39251386, year = {2024}, author = {Liddell, JR and Hilton, JBW and Wang, YJ and Billings, JL and Nikseresht, S and Kysenius, K and Fuller-Jackson, JP and Hare, DJ and Crouch, PJ}, title = {Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.}, journal = {Metallomics : integrated biometal science}, volume = {16}, number = {9}, pages = {}, pmid = {39251386}, issn = {1756-591X}, support = {//National Health and Medical Research Council/ ; }, mesh = {Animals ; *Copper/metabolism ; *Motor Neurons/metabolism/pathology ; *Spinal Cord/metabolism/pathology ; Mice ; *Copper Transporter 1/metabolism ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Central Nervous System/metabolism ; Mice, Transgenic ; Superoxide Dismutase-1/genetics/metabolism ; Disease Models, Animal ; }, abstract = {Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.}, }
@article {pmid39251203, year = {2025}, author = {Rolf, O and Blana, A and Hagedorn, P}, title = {Implantation of Reverse Shoulder Endoprothesis Using Navigation.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {176-180}, doi = {10.1055/a-2346-9916}, pmid = {39251203}, issn = {1864-6743}, mesh = {Humans ; *Surgery, Computer-Assisted/methods ; Imaging, Three-Dimensional ; Arthroplasty, Replacement, Shoulder/methods ; Shoulder Prosthesis ; Augmented Reality ; Prosthesis Design ; Tomography, X-Ray Computed ; Shoulder Joint/surgery/diagnostic imaging ; }, abstract = {Die Implantation einer inversen Schulterendoprothese (TEP) stellt eine bewährte Methode zur Schmerzlinderung und Schulterfunktionsverbesserung dar. Die Ergebnisse variieren je nach Patientenalter, Krankheitsgrad und Erfahrung des Operateurs. Indikationen für eine inverse TEP sind vielfältig, von der Defektarthropathie bis hin zu Frakturen. Aktuelle Studien zeigen verbesserte Überlebensraten und reduzierte Komplikationen nach primärer Implantation. Die präoperative Planung mittels 3-D-CT oder MRT gilt als Goldstandard. Patientenspezifische Instrumente (PSI) wurden eingeführt, sind jedoch mit Kosten und Wartezeit verbunden. Die Navigation mit "Augmented Reality" (AR) bietet eine effizientere Alternative. Die intraoperative Übertragung der Planung auf den Patienten erfolgt über AR-Brillen und ermöglicht Echtzeitinformationen, wodurch der Chirurg den Blick vom Situs nicht abwenden muss. Dies optimiert den Workflow und bietet potenziell präzisere Implantationsresultate. Zusammenfassend bietet die Kombination von 3-D-Planung, Navigation und AR eine vielversprechende Methode für präzise und effiziente Implantationen von inversen Schulterendoprothesen. Allerdings steht der Nachweis verbesserter Standzeiten und Funktionsscores noch aus.}, }
@article {pmid39251159, year = {2024}, author = {Liu, Y and Chen, H and Zhang, Z and Wang, J}, title = {Development of an integrated framework for dissecting source-oriented ecological and health risks of heavy metals in soils.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143299}, doi = {10.1016/j.chemosphere.2024.143299}, pmid = {39251159}, issn = {1879-1298}, mesh = {*Metals, Heavy/analysis ; *Soil Pollutants/analysis ; Environmental Exposure/statistics &amp; numerical data ; Risk Assessment ; Soil/chemistry ; }, abstract = {Heavy metals (HMs) in soils pose significant risks on ecosystem and human health. To design targeted regulatory measures for mitigating and controlling the risk, it is necessary to accurately identify the pollution sources and environmental risks of soil HMs, as well as to reveal the linkages between them. To date, yet systematic investigation aimed at deciphering the links between source apportionment of soil HMs and their associated environmental risks is still lacking. To fill the gap, an integrated framework has been developed in this study and applied for dissecting the source-sink relationship and source-oriented ecological and health risks of soil HMs in Shanxi, a province with rich coal resource, in which long-term coal mining activities in history has resulted in soil HMs pollution and unavoidably posed environmental risks. Two advanced receptor models, multivariate curve resolution alternating least squares based on maximum likelihood principal component analysis (MCR-ALS/MLPCA) and multilinear engine 2 (ME2), have been employed for apportioning the potential sources, and their apportionment results are jointly incorporated into a modified ecological risk index and a probabilistic health risk assessment model for identifying the source-oriented ecological and health risks posed by soil metals. The results show that the soils in study area have been polluted by HMs (i.e., Cd, Cr, Hg and As) to varying degrees. Industrial activities (35%-35.8%), agricultural activities (11.1%-20.5%), atmospheric deposition (10.5%-13%) and mix source (31.5%-42.6%) are apportioned as the main contributors of soil HMs in the area. The source-oriented ecological risk assessment suggests Hg has presented significant ecological risk and largely contributed by the sources from atmospheric deposition and industrial activities. The source-oriented health risk assessment shows the non-carcinogenic hazard level and carcinogenic risk posed by soil HMs in the study area are acceptable. Relatively, industrial activities and mix source have contributed more on the health risks.}, }
@article {pmid39251025, year = {2025}, author = {Del Rosso, JQ and Zaenglein, A and Callender, V and Schlosser, B and Graber, E and Keri, J and Weiss, J}, title = {Response to Reynolds et al's "Guidelines of care for the management of acne vulgaris".}, journal = {Journal of the American Academy of Dermatology}, volume = {92}, number = {1}, pages = {e15}, doi = {10.1016/j.jaad.2024.07.1528}, pmid = {39251025}, issn = {1097-6787}, }
@article {pmid39250425, year = {2025}, author = {Neuhaus, D and Rost, T and Haas, T and Wendebourg, MJ and Schulze, K and Schlaeger, R and Scheurer, E and Lenz, C}, title = {Comparative analysis of in situ and ex situ postmortem brain MRI: Evaluating volumetry, DTI, and relaxometry.}, journal = {Magnetic resonance in medicine}, volume = {93}, number = {1}, pages = {213-227}, doi = {10.1002/mrm.30264}, pmid = {39250425}, issn = {1522-2594}, support = {//Stiftung zur Foerderung der gastroenterologischen und der allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; //Neuromuscular Research Association Basel/ ; }, mesh = {*Postmortem Imaging/methods ; *Brain/diagnostic imaging/drug effects/pathology ; *Diffusion Tensor Imaging/instrumentation/methods ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/pathology ; Organ Size ; Tissue Fixation/methods ; *Formaldehyde/chemistry ; Anisotropy ; Humans ; Male ; Middle Aged ; Aged ; *Magnetic Resonance Imaging/instrumentation/methods ; }, abstract = {PURPOSE: To compare postmortem in situ with ex situ MRI parameters, including volumetry, diffusion tensor imaging (DTI), and relaxometry for assessing methodology-induced alterations, which is a crucial prerequisite when performing MRI biomarker validation.<br><br>METHODS: MRI whole-brain scans of five deceased patients with amyotrophic lateral sclerosis were performed at 3 T. In situ scans were conducted within 32&#x2009;h after death (SD 18&#x2009;h), and ex situ scans after brain extraction and 3&#x2009;months of formalin fixation. The imaging protocol included MP2RAGE, DTI, and multi-contrast spin-echo and multi-echo gradient-echo sequences. Volumetry, fractional anisotropy, mean diffusivity, T1, T2, and T 2 * $$ {T}_2^{\ast } $$ have been assessed for specific brain regions.<br><br>RESULTS: When comparing ex situ to in situ values, the following results were obtained. Deep gray matter as well as the thalamus and the hippocampus showed a reduced volume. Fractional anisotropy was reduced in the cortex and the whole brain. Mean diffusivity was decreased in white matter and deep gray matter. T1 and T2 were reduced in all investigated structures, whereas T 2 * $$ {T}_2^{\ast } $$ was increased in the cortex.<br><br>CONCLUSION: The results of this study show that the volumes and MRI parameters of several brain regions are potentially affected by tissue extraction and subsequent formalin fixation, suggesting that methodological alterations are present in ex situ MRI. To avoid overlap of indistinguishable methodological and disease-related changes, we recommend performing in situ postmortem MRI as an additional intermediate step for in vivo MRI biomarker validation.}, }
@article {pmid39249108, year = {2024}, author = {Jin, W and Boss, J and Bakulski, KM and Goutman, SA and Feldman, EL and Fritsche, LG and Mukherjee, B}, title = {Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6923-6934}, pmid = {39249108}, issn = {1432-1459}, support = {R01TS000344/CC/CDC HHS/United States ; 20-IIA-532//ALS Association/ ; K23 ES027221/ES/NIEHS NIH HHS/United States ; K23ES027221/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01 NS127188/NS/NINDS NIH HHS/United States ; R01 TS000344/TS/ATSDR CDC HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/epidemiology/diagnosis ; Humans ; United Kingdom/epidemiology ; *Multifactorial Inheritance ; Male ; Female ; Middle Aged ; *Biological Specimen Banks ; Aged ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Adult ; Phenotype ; UK Biobank ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential.<br><br>METHODS: Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates.<br><br>RESULTS: Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC]&#x2009;=&#x2009;0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1&#xa0;year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC&#x2009;=&#x2009;0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC&#x2009;=&#x2009;0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range.<br><br>DISCUSSION: By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.}, }
@article {pmid39249104, year = {2024}, author = {Hafsteinsdóttir, B and Farman, H and Lagerström, N and Zetterberg, H and Andersen, O and Novakova, L and Nellgård, B and Rosén, H and Malmeström, C and Rosenstein, I and Lycke, J and Axelsson, M}, title = {Neurofilament light chain as a diagnostic and prognostic biomarker in Guillain-Barré syndrome.}, journal = {Journal of neurology}, volume = {271}, number = {11}, pages = {7282-7293}, pmid = {39249104}, issn = {1432-1459}, support = {ALFGBG-722081//Swedish State Support for Clinical Research/ ; }, mesh = {Humans ; *Guillain-Barre Syndrome/blood/diagnosis/cerebrospinal fluid ; *Neurofilament Proteins/blood/cerebrospinal fluid ; Female ; Male ; Middle Aged ; *Biomarkers/blood/cerebrospinal fluid ; Adult ; Prognosis ; Aged ; Amyotrophic Lateral Sclerosis/blood/diagnosis/cerebrospinal fluid ; }, abstract = {BACKGROUND: Elevated neurofilament light chain (NfL) levels are associated with worse prognosis in Guillain-Barré syndrome (GBS). Our objectives were to determine the utility of serum NfL (sNfL), cerebrospinal fluid (CSF)/serum NfL ratio and NfL index as prognostic and diagnostic biomarkers for GBS.<br><br>METHODS: We measured NfL in serum and/or CSF obtained from 96 GBS patients between 1989 and 2014 in western Sweden. The sNfL Z-scores, NfL ratios and NfL indices were calculated. Outcome was determined with the GBS disability scale (GBSDS) at 3 and 12&#xa0;months. NfL parameters in GBS were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).<br><br>RESULTS: The sNfL Z-score was higher for GBSDS&#x2009;>&#x2009;2 at 3&#xa0;months (median [IQR], 3.5&#xa0;ng/L [3.2-4.0], vs 2.6 [1.7-3.4], p&#x2009;=&#x2009;0.008) and at 12&#xa0;months (3.6&#xa0;ng/L [3.5-3.8] vs 2.6 [1.8-3.5], p&#x2009;=&#x2009;0.049). NfL ratio and index were not associated with outcome. The area under the curve (AUC) for sNfL Z-score was 0.76 (95% CI 0.58-0.93, p&#x2009;<&#x2009;0.0001) for GBSDS&#x2009;>&#x2009;2 at 3&#xa0;months. NfL ratio and index were lower in GBS than HC, MS, and ALS. The AUC for the NfL ratio was 0.66 (95% CI 0.55-0.78, p&#x2009;=&#x2009;0.0018) and for the NfL index 0.86 (95% CI 0.78-0.93, p&#x2009;<&#x2009;0.0001).<br><br>DISCUSSION: Our results confirm sNfL as prognostic biomarker for GBS and the precision was improved using the age-adjusted sNfL Z score. NfL index and Qalb are potential diagnostic biomarkers for GBS.}, }
@article {pmid39246739, year = {2024}, author = {Li, S and Gui, J and Passarelli, MN and Andrew, AS and Sullivan, KM and Cornell, KA and Traynor, BJ and Stark, A and Chia, R and Kuenzler, RM and Pioro, EP and Bradley, WG and Stommel, EW}, title = {Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts.}, journal = {Neurology. Genetics}, volume = {10}, number = {5}, pages = {e200188}, pmid = {39246739}, issn = {2376-7839}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown.<br><br>METHODS: We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk.<br><br>RESULTS: GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk.<br><br>DISCUSSION: Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.}, }
@article {pmid39246712, year = {2024}, author = {Calderón-Garcidueñas, L and Cejudo-Ruiz, FR and Stommel, EW and González-Maciel, A and Reynoso-Robles, R and Torres-Jardón, R and Tehuacanero-Cuapa, S and Rodríguez-Gómez, A and Bautista, F and Goguitchaichvili, A and Pérez-Guille, BE and Soriano-Rosales, RE and Koseoglu, E and Mukherjee, PS}, title = {Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1411849}, pmid = {39246712}, issn = {1662-5161}, abstract = {Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC ≤ 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 μT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves.}, }
@article {pmid39246264, year = {2024}, author = {Iseli, LM and Poppe, C and Wangmo, T}, title = {Receiving and adjusting to a diagnosis of ALS: A qualitative study with informal caregivers.}, journal = {Palliative &amp; supportive care}, volume = {}, number = {}, pages = {1-7}, doi = {10.1017/S1478951524001044}, pmid = {39246264}, issn = {1478-9523}, abstract = {OBJECTIVES: Diagnosis of amyotrophic lateral sclerosis (ALS) takes more than 1year from detection of first symptoms. The paper seeks to understand the ALS diagnostic process and adjustment from the perspective of informal caregivers.<br><br>METHODS: The data stems from an interview study with 9 current and 13 bereaved informal caregivers of people with ALS in Switzerland. The interviews were analyzed using thematic analysis.<br><br>RESULTS: We identified 3 key themes pertaining to ALS diagnosis. In the first theme, we present the close involvement of informal caregivers in the "diagnosis journey." Highlighted within this theme is the important role they play, which ultimately leads to diagnosis of ALS avoiding further delays. Second, we relay their perceptions on "diagnosis communication pitfalls" where they underlined empathy and planning from the part of medical professional, while communicating the terminal diagnosis of ALS. Participants' reactions and adjustments post-ALS diagnosis are described in "the aftermath of diagnosis." In this third theme, we highlight participants' shock and their need to rethink overall life plans and roles in their family.<br><br>SIGNIFICANCE OF THE RESULTS: Diagnosis communication that is clear, empathetic, and adjusted to the needs of the patients as well as their caregivers is critical. More work is needed to improve diagnosis communication for ALS patients. Receiving the diagnosis of ALS leads to complete changes in life of caregivers. It is therefore necessary that medical professionals provide adequate support that allows them to plan for their future.}, }
@article {pmid39244645, year = {2025}, author = {Tang, IW and Hansen, J and Dickerson, AS and Weisskopf, MG}, title = {Occupational lead exposure and amyotrophic lateral sclerosis survival in the Danish National Patient Registry.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {26}, number = {1-2}, pages = {124-131}, pmid = {39244645}, issn = {2167-9223}, support = {P30 ES000002/ES/NIEHS NIH HHS/United States ; R01 ES019188/ES/NIEHS NIH HHS/United States ; T32 ES007069/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/epidemiology ; Male ; *Occupational Exposure/adverse effects/statistics &amp; numerical data ; Female ; Middle Aged ; Denmark/epidemiology ; *Registries ; *Lead/adverse effects ; Aged ; Adult ; Proportional Hazards Models ; }, abstract = {OBJECTIVES: We investigated the relationship between occupational lead exposure and amyotrophic lateral sclerosis (ALS) survival in Denmark.<br><br>METHODS: We identified 2,161 ALS cases diagnosed from 1982 to 2013 with at least 5 years of employment history before ALS diagnosis, via the Danish National Patient Registry. Cases were followed until March 2017. We defined lead exposure as never employed in a lead job, ever employed in a lead job, and ever employed in a lead job by exposure probability (<50% vs. &#x2265;50%), excluding jobs held in the 5 years before diagnosis in main analyses. Survival was evaluated using Cox proportional hazards models and stratified by sex and age of diagnosis.<br><br>RESULTS: Median age of diagnosis was 63.5 years, and individuals in lead-exposed jobs were diagnosed at a younger age. Adjusted hazard ratios (aHR) were slightly decreased for men ever lead-exposed (aHR:0.92, 95%CI: 0.80, 1.05) and more so among those diagnosed at age 60-69 (lead &#x2265; 50% aHR: 0.66, 95%CI: 0.45, 0.98), but reversed for men diagnosed at age 70 and later (aHR: 2.03, 95%CI: 1.13, 3.64). No apparent pattern was observed among women.<br><br>CONCLUSIONS: Occupational lead exposure contributed to shorter survival among men diagnosed at older ages. The inverse associations observed for men diagnosed earlier could relate to possible healthy worker hire effect or health advantages of working in lead-exposed jobs. Our results are consistent with an adverse impact of lead exposure on ALS survival at older ages, with the age at which lead's effects on survival worsen later on among those in lead-exposed jobs.}, }
@article {pmid39243983, year = {2025}, author = {Mohan, M and Mannan, A and Nauriyal, A and Singh, TG}, title = {Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115242}, doi = {10.1016/j.bbr.2024.115242}, pmid = {39243983}, issn = {1872-7549}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Humans ; Animals ; *ATP-Binding Cassette Transporters/metabolism ; Signal Transduction/physiology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.}, }
@article {pmid39243146, year = {2024}, author = {Jimenez, JV and Tang, MJ and Wilson, MW and Morrison, AH and Ackrivo, J and Choi, PJ}, title = {Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {5}, pages = {1099-1103}, doi = {10.1002/mus.28250}, pmid = {39243146}, issn = {1097-4598}, support = {NIH NHLBI K23 HL-151879//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/complications ; *Noninvasive Ventilation/methods ; Female ; Male ; Middle Aged ; Aged ; Retrospective Studies ; *Respiratory Insufficiency/therapy/etiology/physiopathology ; Vital Capacity/physiology ; Hypercapnia/therapy/etiology/physiopathology ; Cohort Studies ; }, abstract = {INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure.<br><br>METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45&#x2009;mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60&#x2009;cmH2O or forced vital capacity (FVC) <50% predicted normal.<br><br>RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64&#x2009;years &#xb1;11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64%&#x2009;&#xb1;&#x2009;19%, the mean MIP; 41 cmH2O&#x2009;&#xb1;&#x2009;17, and diurnal TcCO2; 40&#x2009;&#xb1;&#x2009;6&#x2009;mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1&#x2009;year of NIV initiation, 126 (37%) patients were deceased.<br><br>DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.}, }
@article {pmid39242803, year = {2024}, author = {Monselise, EB and Vyazmensky, M and Scherf, T and Batushansky, A and Fishov, I}, title = {Author Correction: D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20873}, doi = {10.1038/s41598-024-71813-5}, pmid = {39242803}, issn = {2045-2322}, }
@article {pmid39242576, year = {2024}, author = {Phillips, MCL and Picard, M}, title = {Neurodegenerative disorders, metabolic icebergs, and mitohormesis.}, journal = {Translational neurodegeneration}, volume = {13}, number = {1}, pages = {46}, pmid = {39242576}, issn = {2047-9158}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Mitochondria/metabolism ; Hormesis/physiology ; Animals ; }, abstract = {Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.}, }
@article {pmid39242281, year = {2025}, author = {Amalia, R and Prasetya Wibawa, A and Surya Aditya, R and Andana Pohan, R and Tetteng, B and Zuhroh, L and Ainy Sadijah, N}, title = {Enhancing caregiver well being by integrating mindfulness and technology in amyotrophic lateral sclerosis care.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {131}, number = {}, pages = {110819}, doi = {10.1016/j.jocn.2024.110819}, pmid = {39242281}, issn = {1532-2653}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/psychology ; Humans ; *Mindfulness/methods ; *Caregivers/psychology ; *Quality of Life ; Mobile Applications ; Stress, Psychological/therapy/psychology ; }, abstract = {This letter discusses the pressing issue of caregiver burden in Amyotrophic Lateral Sclerosis (ALS) care, emphasizing the potential of mindfulness practices to alleviate stress and improve quality of life for caregivers. The integration of digital platforms, such as mindfulness apps, offers an accessible and effective solution, particularly in resource-limited settings. By adopting these strategies, we can enhance caregiver well-being and overall patient care, making it a crucial consideration for global health interventions.}, }
@article {pmid39242252, year = {2024}, author = {Benmoussa, A and Assernannas, I and Maatoui-Belabbes, H and Dahmaoui, N and Qachouh, M and Cherkaoui, S and Lamchaheb, M and Rachid, M and Madani, A and Khoubila, N}, title = {[Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca].}, journal = {Bulletin du cancer}, volume = {111}, number = {10}, pages = {944-954}, doi = {10.1016/j.bulcan.2024.06.010}, pmid = {39242252}, issn = {1769-6917}, mesh = {Humans ; Male ; Female ; Infant ; Child, Preschool ; Child ; Adolescent ; Adult ; *Anemia, Aplastic/mortality/therapy ; Morocco/epidemiology ; Retrospective Studies ; Prognosis ; Time-to-Treatment ; *Cyclosporine/therapeutic use ; *Antilymphocyte Serum/therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Treatment Outcome ; Delayed Diagnosis ; }, abstract = {Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.}, }
@article {pmid39242198, year = {2024}, author = {Grassano, M and Canosa, A and D'Alfonso, S and Corrado, L and Brodini, G and Koumantakis, E and Cugnasco, P and Manera, U and Vasta, R and Palumbo, F and Mazzini, L and Gallone, S and Moglia, C and Dewan, R and Chia, R and Ding, J and Dalgard, C and Gibbs, RJ and Scholz, S and Calvo, A and Traynor, B and Chio, A}, title = {Intermediate HTT CAG repeats worsen disease severity in amyotrophic lateral sclerosis.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {1}, pages = {100-102}, pmid = {39242198}, issn = {1468-330X}, }
@article {pmid39241508, year = {2024}, author = {Zheng, X and Liu, J and Wang, S and Xiao, Y and Jiang, Q and Li, C and Shang, H}, title = {Total physical activity, plant-based diet and neurodegenerative diseases: A prospective cohort study of the UK biobank.}, journal = {Parkinsonism &amp; related disorders}, volume = {128}, number = {}, pages = {107125}, doi = {10.1016/j.parkreldis.2024.107125}, pmid = {39241508}, issn = {1873-5126}, mesh = {Humans ; Male ; Female ; *Exercise/physiology ; Middle Aged ; United Kingdom/epidemiology ; Aged ; *Diet, Vegetarian ; *Neurodegenerative Diseases/epidemiology ; *Biological Specimen Banks ; Prospective Studies ; Alzheimer Disease/epidemiology ; Parkinson Disease/epidemiology ; Amyotrophic Lateral Sclerosis/epidemiology ; Adult ; Cohort Studies ; Diet, Plant-Based ; UK Biobank ; }, abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) result from a complex interplay of genetic, environmental and aging factors. A balanced diet and adequate physical activity (PA) are recognized as pivotal components among modifiable environmental factors. The independent impact on NDD incidence has been previously debated. This investigation seeks to delineate the association between PA and NDDs across various levels of adherence to a plant-based diet.<br><br>METHODS: In this study, a cohort of 368,934 participants from the UK Biobank was analyzed. Total physical activity (TPA) levels and healthful plant-based diet index (hPDI) were calculated and categorized. A multiple adjusted Cox model was utilized to evaluate the influence of TPA and hPDI on common NDDs, respectively.<br><br>RESULTS: Finally, 4602 identified cases diagnosed as Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). We found that higher TPA was significantly associated with a reduced risk of developing AD (Q3: HR 0.87; Q4: HR 0.78) and PD (Q3: HR 0.86; Q4: HR 0.81). The protective effect was further accentuated with adherence to a plant-based diet. However, these connections were not observed in the analysis of ALS regardless of dietary patterns.<br><br>CONCLUSION: Our findings underscore a significant association between higher TPA and reduced risks of AD and PD, with an enhanced effect observed in conjunction with a plant-based diet. This study contributes to addressing the knowledge gap regarding the combined impact of TPA and a plant-based diet on NDDs occurrence, providing insights into potential underlying mechanisms.}, }
@article {pmid39241471, year = {2024}, author = {Casiraghi, V and Milone, I and Brusati, A and Peverelli, S and Doretti, A and Poletti, B and Maderna, L and Morelli, C and Ticozzi, N and Silani, V and Verde, F and Ratti, A}, title = {Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype.}, journal = {Journal of the neurological sciences}, volume = {466}, number = {}, pages = {123210}, doi = {10.1016/j.jns.2024.123210}, pmid = {39241471}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/blood/diagnosis ; Female ; Male ; *Neurofilament Proteins/blood/genetics ; Middle Aged ; Aged ; *Polymorphism, Single Nucleotide ; *DNA-Binding Proteins/genetics/blood ; *Genotype ; Biomarkers/blood ; Cohort Studies ; Adult ; Nerve Tissue Proteins ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition affecting upper and/or lower motor neurons and characterized neuropathologically by TDP-43 proteinopathy. Given its role in ALS pathobiology, it is currently under debate whether TDP-43 might represent a suitable ALS biomarker to be measured in patients' biofluids. The rs12608932 A > C single nucleotide polymorphism in the UNC13A gene is a risk factor for ALS and patients homozygous for the high-risk C allele display a higher burden of TDP-43 neuropathology than homozygotes for the low-risk A allele, although the association with TDP-43 levels in biofluids has never been evaluated. In this study, we measured serum levels of TDP-43 and neurofilament light chain (NFL) by Simoa technology in a cohort of 69 ALS patients stratified according to the UNC13A rs12608932 genotype compared to 43 neurologically healthy controls. By multiple linear regression analysis, serum TDP-43 was significantly elevated in ALS patients compared to controls, with UNC13A AA and AC, but not CC, ALS patients showing higher serum TDP-43 levels than controls. We also confirmed that serum NFL concentration was increased in ALS patients, without any correlation with the UNC13A genotype. Our results indicate that serum TDP-43 is higher in ALS patients compared to controls and that, in contrast to NFL, this increase is specifically associated with the UNC13A rs12608932 AA and AC genotypes, but not with the high-risk CC genotype. Studies in larger cohorts will be needed to confirm these findings and to elucidate the biological link between serum TDP-43 levels and UNC13A genotype.}, }
@article {pmid39241118, year = {2024}, author = {Sharkey, RJ and Cortese, F and Goodyear, BG and Korngut, LW and Jacob, SM and Sharkey, KA and Kalra, S and Nguyen, MD and Frayne, R and Pfeffer, G}, title = {Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {147}, number = {12}, pages = {4026-4032}, pmid = {39241118}, issn = {1460-2156}, support = {//ALS Society of Canada/ ; //Barry Barrett Foundation/ ; //Rose Family Foundation/ ; //Hotchkiss Brain Institute/ ; /CAPMC/CIHR/Canada ; //Brain Canada Foundation/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnostic imaging/pathology ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; *Glymphatic System/diagnostic imaging ; *Diffusion Tensor Imaging ; Disease Progression ; White Matter/diagnostic imaging/pathology ; Adult ; Motor Neuron Disease/physiopathology/diagnostic imaging/pathology ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central to the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we performed a longitudinal analysis of glymphatic function in ALS and compared it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analysed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate) and white matter hyperintensity burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared with PLS and control participants across all three time points. There was no association with clinical factors; however, the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.}, }
@article {pmid39240038, year = {2024}, author = {García-Casanova, PH and Pérez-Martínez, P and Sevilla, T and Doménech, R and León, M and Vázquez-Costa, JF}, title = {Impact of SARS-CoV-2 infection and COVID-19 pandemic on the morbidity and mortality of amyotrophic lateral sclerosis patients in Valencia, Spain.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16465}, pmid = {39240038}, issn = {1468-1331}, support = {JR19/00030//Instituto de Salud Carlos III/ ; PI 21/00737//Instituto de Salud Carlos III/ ; }, mesh = {Humans ; *COVID-19/mortality/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/mortality ; Spain/epidemiology ; Female ; Male ; Middle Aged ; Aged ; *Hospitalization/statistics &amp; numerical data ; Risk Factors ; Noninvasive Ventilation/statistics &amp; numerical data ; Pandemics ; SARS-CoV-2 ; }, abstract = {BACKGROUND AND PURPOSE: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared.<br><br>RESULTS: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR]&#x2009;=&#x2009;7.96, p&#x2009;=&#x2009;0.003) and COVID-19 vaccination as a protective factor (OR&#x2009;=&#x2009;0.093, p&#x2009;=&#x2009;0.025) independent of age, sex and gastrostomy. Within 30&#x2009;days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p&#x2009;=&#x2009;0.89).<br><br>CONCLUSIONS: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources.}, }
@article {pmid39239358, year = {2024}, author = {Segerstrom, SC and Kasarskis, EJ}, title = {The Seattle Amyotrophic Lateral Sclerosis (ALS) Patient Project Database: observational, longitudinal, dyadic characterization of people with ALS and their partners.}, journal = {Health psychology and behavioral medicine}, volume = {12}, number = {1}, pages = {2396137}, pmid = {39239358}, issn = {2164-2850}, support = {R03 NS128748/NS/NINDS NIH HHS/United States ; R16 NS129748/NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: The median survival time in ALS is approximately 3 years, but survival times range from less than a year to more than 10 years and much variance in disease course remains to be explained. As is true for physical outcomes, there is considerable variance in QOL, which is influenced by psychological health, coping, and social support, among other psychosocial factors. The Seattle ALS Patient Project Database (SALSPPD) provides a unique opportunity for researchers to address established and novel hypotheses about disease progression and QOL in ALS.<br><br>METHODS: The SALSPPD is a longitudinal dataset of people with ALS (n&#x2009;=&#x2009;143) and their partners (spouses, significant others, or caregivers; n&#x2009;=&#x2009;123) from clinics and community-based ALS support groups. Participants were interviewed in their homes every 3 months for up to 18 months between March 1987 and August 1989. Follow-up phone calls were completed in 1990, 1994, and 2008, primarily to ascertain disease outcomes.<br><br>RESULTS: The provided data dictionary includes details of the over 500 variables measured in the study, which have been subsetted into domain datasets. Domains address physical, psychological, social, and behavioral status on the person with ALS and their partners. Missing data were coded according to their mechanism. Data are available in two formats: The person-level (wide) databases and the time-level (long) databases.<br><br>DISCUSSION: The SALSPPD will provide a rich resource to scientists interested in the natural history of ALS, psychosocial effects on ALS outcomes and vice versa, and psychosocial and disease outcomes of treatments.}, }
@article {pmid39239150, year = {2024}, author = {Vidovic, M and Lapp, HS and Weber, C and Plitzko, L and Seifert, M and Steinacker, P and Otto, M and Hermann, A and Günther, R}, title = {Comparative analysis of neurofilaments and biomarkers of muscular damage in amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae288}, pmid = {39239150}, issn = {2632-1297}, abstract = {Diagnosis of the fatal neurodegenerative disease amyotrophic lateral sclerosis is challenging. Neurofilaments, indicative of neuronal damage, along with creatine kinase, creatinine, myoglobin, and troponin T, representing muscular damage, have been identified as promising fluid biomarkers. This study aims to comprehensively assess and compare their diagnostic and prognostic potential in a 'real-world' cohort of patients with amyotrophic lateral sclerosis. About 77 patients with amyotrophic lateral sclerosis and its clinical variants, and 26 age- and sex-matched controls with various neuromuscular and neurodegenerative diseases, were retrospectively included in this monocentric, cross-sectional study. Neurofilaments in cerebrospinal fluid and biomarkers of muscular damage in serum were measured and correlated with demographic features, motor function, survival time, clinical phenotypes, and the extent of upper and lower motor neuron involvement. Neurofilament, myoglobin, and troponin T concentrations were higher in patients with amyotrophic lateral sclerosis compared to disease controls. Higher neurofilament levels correlated with lower motor function and faster disease progression rate, while higher creatine kinase and creatinine concentrations were linked to preserved motor function. In contrast, troponin T elevation indicated poorer fine and gross motor functions. Increased neurofilament levels were associated with shorter survival, whereas biomarkers of muscular damage lacked survival correlation. Neurofilament concentrations were higher in classical amyotrophic lateral sclerosis than in progressive muscular atrophy, while myoglobin and troponin T levels were elevated in progressive muscular atrophy compared to primary lateral sclerosis. Neurofilaments were predominantly linked to upper motor neuron involvement. Our findings confirmed the robust diagnostic and prognostic value of neurofilaments in amyotrophic lateral sclerosis. Elevated neurofilament concentrations were associated with higher disease severity, faster disease progression, shorter survival, and predominant upper motor neuron degeneration. Biomarkers of muscular damage were inferior in distinguishing amyotrophic lateral sclerosis from other neuromuscular and neurodegenerative diseases. However, they may serve as complementary biomarkers and support in discriminating clinical variants of amyotrophic lateral sclerosis.}, }
@article {pmid39239063, year = {2024}, author = {Pezeshgi, S and Ghaderi, S and Mohammadi, S and Karimi, N and Ziaadini, B and Mohammadi, M and Fatehi, F}, title = {Diffusion tensor imaging biomarkers and clinical assessments in amyotrophic lateral sclerosis (ALS) patients: an exploratory study.}, journal = {Annals of medicine and surgery (2012)}, volume = {86}, number = {9}, pages = {5080-5090}, pmid = {39239063}, issn = {2049-0801}, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Biomarkers are needed to improve diagnosis, gauge progression, and evaluate treatment. Diffusion tensor imaging (DTI) is a promising biomarker for detecting microstructural alterations in the white matter tracts. This study aimed to assess DTI metrics as biomarkers and to examine their relationship with clinical assessments in patients with ALS. Eleven patients with ALS and 21 healthy controls (HCs) underwent 3T MRI with DTI. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were compared between key motor and extra-motor tract groups. Group comparisons and correlations between DTI metrics also correlated with clinical scores of disability (ALSFRS-R), muscle strength (dynamometry), and motor unit loss (MUNIX). Widespread differences were found between patients with ALS and HCs in DTI metrics, including decreased FA and increased diffusivity metrics. However, MD and RD are more sensitive metrics for detecting white matter changes in patients with ALS. Significant interhemispheric correlations between the tract DTI metrics were also observed. DTI metrics showed symmetry between the hemispheres and correlated with the clinical assessments. MD, RD, and AD increases significantly correlated with lower ALSFRS-R and MUNIX scores and weaker dynamometry results. DTI reveals microstructural damage along the motor and extra-motor regions in ALS patients. DTI metrics can serve as quantitative neuroimaging biomarkers for diagnosis, prognosis, monitoring of progression, and treatment. Combined analysis of imaging, electrodiagnostic, and functional biomarkers shows potential for characterizing disease pathophysiology and progression.}, }
@article {pmid39236857, year = {2024}, author = {Reiter, RJ and Sharma, RN and Manucha, W and Rosales-Corral, S and Almieda Chuffa, LG and Loh, D and Luchetti, F and Balduini, W and Govitrapong, P}, title = {Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102480}, doi = {10.1016/j.arr.2024.102480}, pmid = {39236857}, issn = {1872-9649}, mesh = {*Melatonin/metabolism/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; *Mitochondria/metabolism/drug effects ; *Aging/metabolism/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.}, }
@article {pmid39236792, year = {2024}, author = {Hattori, H and Osumi, K and Tanaka, M and Arai, T and Nishimura, K and Yamamoto, N and Sakamoto, K and Goto, Y and Sugawara, Y}, title = {Discovery of 5-phenyl-3-ureidothiophene-2-carboxamides as protective agents for ALS patient iPSC-derived motor neurons.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {113}, number = {}, pages = {129935}, doi = {10.1016/j.bmcl.2024.129935}, pmid = {39236792}, issn = {1464-3405}, mesh = {Humans ; *Induced Pluripotent Stem Cells/drug effects/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Motor Neurons/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Drug Discovery ; Structure-Activity Relationship ; Molecular Structure ; Thiophenes/chemistry/pharmacology/chemical synthesis ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology/chemistry/chemical synthesis ; Dose-Response Relationship, Drug ; Superoxide Dismutase-1/metabolism/genetics ; Intracellular Signaling Peptides and Proteins ; }, abstract = {We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.}, }
@article {pmid39236307, year = {2024}, author = {Doneddu, PE and Gallo, C and Gentile, L and Cocito, D and Falzone, Y and Di Stefano, V and Inghilleri, M and Cosentino, G and Matà, S and Mazzeo, A and Filosto, M and Peci, E and Sorrenti, B and Brighina, F and Moret, F and Vegezzi, E and Sperti, M and Risi, B and Nobile-Orazio, E and , }, title = {Comparison of the diagnostic accuracy of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society and American Association of Electrodiagnostic Medicine diagnostic criteria for multifocal motor neuropathy.}, journal = {European journal of neurology}, volume = {31}, number = {12}, pages = {e16444}, pmid = {39236307}, issn = {1468-1331}, support = {IIR-ITA-BXLT-001955/ IISR-2017-104226//Takeda Italia SPA/ ; //Fondazione Humanitas per la Ricerca/ ; }, mesh = {Humans ; Male ; Middle Aged ; Female ; *Electrodiagnosis/standards/methods ; *Sensitivity and Specificity ; Retrospective Studies ; Aged ; *Neural Conduction/physiology ; *Societies, Medical/standards ; *Polyneuropathies/diagnosis/physiopathology ; Adult ; Europe ; Motor Neuron Disease/diagnosis/physiopathology ; United States ; Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; }, abstract = {BACKGROUND AND PURPOSE: This study was undertaken to compare the sensitivity and specificity of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for multifocal motor neuropathy (MMN) with those of the American Association of Electrodiagnostic Medicine (AAEM).<br><br>METHODS: Sensitivity and specificity of the two sets of criteria were retrospectively evaluated in 53 patients with MMN and 280 controls with axonal peripheral neuropathy, inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis. Comparison of the utility of nerve conduction studies with different numbers of nerves examined was also assessed.<br><br>RESULTS: The 2010 EFNS/PNS criteria had a sensitivity of 47% for definite MMN and 57% for probable/definite MMN, whereas the AAEM criteria had a sensitivity of 28% for definite MMN and 53% for probable/definite MMN. The sensitivity of the AAEM criteria was higher when utilizing area compared to amplitude reduction to define conduction block. Using supportive criteria, the sensitivity of the 2010 EFNS/PNS criteria for probable/definite MMN increased to 64%, and an additional 36% patients fulfilled the criteria (possible MMN). Specificity values for definite and probable/definite MMN were slightly higher with the AAEM criteria (100%) compared to the EFNS/PNS criteria (98.5% and 97%). Extended nerve conduction studies yielded slightly increased diagnostic sensitivity for both sets of criteria without significantly affecting specificity.<br><br>CONCLUSIONS: In our patient populations, the 2010 EFNS/PNS criteria demonstrated higher sensitivity but slightly lower specificity compared to the AAEM criteria. Extended nerve conduction studies are advised to achieve slightly higher sensitivity while maintaining very high specificity.}, }
@article {pmid39235524, year = {2024}, author = {Poletti, B and Aiello, EN and Consonni, M and Iazzolino, B and Torre, S and Solca, F and Faltracco, V and Telesca, A and Palumbo, F and Dalla Bella, E and Bersano, E and Riva, N and Verde, F and Messina, S and Doretti, A and Maranzano, A and Morelli, C and Calvo, A and Silani, V and Lauria, G and Chiò, A and Ticozzi, N}, title = {Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6944-6955}, pmid = {39235524}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/physiopathology/complications ; Male ; Female ; Middle Aged ; Aged ; Prevalence ; Frontotemporal Dementia/physiopathology/epidemiology ; Cohort Studies ; Neuropsychological Tests ; Disease Progression ; Adult ; }, abstract = {BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates.<br><br>METHODS: N&#x2009;=&#x2009;808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (&#x394;FS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi).<br><br>RESULTS: Defective ECAS-Total performances were detected in&#x2009;~&#x2009;29% of patients, with the ECAS-Executive being failed by the highest number of patients (~&#x2009;30%), followed by the ECAS-Language, -Fluency, and -Memory (~&#x2009;15-17%) and -Visuospatial (~&#x2009;%8). Apathy was the most frequent behavioural change (~&#x2009;28%), followed by loss of sympathy/empathy (~&#x2009;13%); remaining symptoms were reported in&#x2009;<&#x2009;4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p&#x2009;&#x2264;&#x2009;.008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p&#x2009;&#x2264;&#x2009;.031).<br><br>CONCLUSIONS: FTSDs affect&#x2009;~&#x2009;50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.}, }
@article {pmid39234934, year = {2024}, author = {Mao, M and Zeng, W and Zheng, Y and Fan, W and Yao, Y}, title = {Fasudil attenuates syncytin-1-mediated activation of microglia and impairments of motor neurons and motor function in mice.}, journal = {Drug development research}, volume = {85}, number = {6}, pages = {e22254}, doi = {10.1002/ddr.22254}, pmid = {39234934}, issn = {1098-2299}, support = {81860245//National Natural Science Foundation of China/ ; [2019]5664//Department of Science and Technology of Guizhou Province/ ; GZSYBS[2017]01//Doctor Fund of Guizhou Provincial People's Hospital/ ; GZSYQN[2018]09//Youth Fund of Guizhou Provincial People's Hospital/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Motor Neurons/drug effects/metabolism ; Mice ; *Mice, Inbred C57BL ; *1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs &amp; derivatives/pharmacology ; Gene Products, env ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Pregnancy Proteins/metabolism ; Male ; Cytokines/metabolism ; Disease Models, Animal ; Motor Activity/drug effects ; Spinal Cord/metabolism/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin-1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus-W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno-associated virus-overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin-eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial- and motor neurons-related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule-associated protein 2, HB9, neuronal nuclei and neuron-specific enolase in Syn-induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn-activated microglia plays a pivotal role during the progression of ALS.}, }
@article {pmid39233852, year = {2024}, author = {Gilbert, JW and Kennedy, Z and Godinho, BMDC and Summers, A and Weiss, A and Echeverria, D and Bramato, B and McHugh, N and Cooper, D and Yamada, K and Hassler, M and Tran, H and Gao, FB and Brown, RH and Khvorova, A}, title = {Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102291}, pmid = {39233852}, issn = {2162-2531}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; }, abstract = {A hexanucleotide (G4C2) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm.}, }
@article {pmid39233624, year = {2024}, author = {Garnier, M and Camdessanché, JP and Cassereau, J and Codron, P}, title = {From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2398199}, pmid = {39233624}, issn = {1365-2060}, mesh = {*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Humans ; Diagnosis, Differential ; Electromyography/methods ; }, abstract = {The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.}, }
@article {pmid39233146, year = {2024}, author = {Wang, H and Liu, S and Sun, Y and Chen, C and Hu, Z and Li, Q and Long, J and Yan, Q and Liang, J and Lin, Y and Yang, S and Lin, M and Liu, X and Wang, H and Yu, J and Yi, F and Tan, Y and Yang, Y and Chen, N and Ai, Q}, title = {Target modulation of glycolytic pathways as a new strategy for the treatment of neuroinflammatory diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102472}, doi = {10.1016/j.arr.2024.102472}, pmid = {39233146}, issn = {1872-9649}, mesh = {Humans ; *Glycolysis/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Aging/metabolism ; }, abstract = {Neuroinflammation is an innate and adaptive immune response initiated by the release of inflammatory mediators from various immune cells in response to harmful stimuli. While initially beneficial and protective, prolonged or excessive neuroinflammation has been identified in clinical and experimental studies as a key pathological driver of numerous neurological diseases and an accelerant of the aging process. Glycolysis, the metabolic process that converts glucose to pyruvate or lactate to produce adenosine 5'-triphosphate (ATP), is often dysregulated in many neuroinflammatory disorders and in the affected nerve cells. Enhancing glucose availability and uptake, as well as increasing glycolytic flux through pharmacological or genetic manipulation of glycolytic enzymes, has shown potential protective effects in several animal models of neuroinflammatory diseases. Modulating the glycolytic pathway to improve glucose metabolism and ATP production may help alleviate energy deficiencies associated with these conditions. In this review, we examine six neuroinflammatory diseases-stroke, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and depression-and provide evidence supporting the role of glycolysis in their treatment. We also explore the potential link between inflammation-induced aging and glycolysis. Additionally, we briefly discuss the critical role of glycolysis in three types of neuronal cells-neurons, microglia, and astrocytes-within physiological processes. This review highlights the significance of glycolysis in the pathology of neuroinflammatory diseases and its relevance to the aging process.}, }
@article {pmid39232594, year = {2024}, author = {Martínez-Payá, JJ and Ríos-Díaz, J and Del Baño-Aledo, ME and Hervás, D and Tembl-Ferrairó, JI and Sevilla-Mantecón, T and Vázquez-Costa, JF}, title = {The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.}, journal = {Neurologia}, volume = {39}, number = {7}, pages = {564-572}, doi = {10.1016/j.nrleng.2024.07.003}, pmid = {39232594}, issn = {2173-5808}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis ; Male ; Middle Aged ; Female ; *Median Nerve/diagnostic imaging ; Prognosis ; *Biomarkers ; Aged ; *Ultrasonography ; Disease Progression ; Cohort Studies ; }, abstract = {INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS).<br><br>METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed.<br><br>RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay.<br><br>CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.}, }
@article {pmid39232248, year = {2024}, author = {Borchert, GA and Shanks, ME and Whitfield, J and Clouston, P and Raji, S and Sperring, S and Thompson, JA and Xue, K and De Silva, SR and Downes, SM and MacLaren, RE and Cehajic-Kapetanovic, J}, title = {Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.}, journal = {Ophthalmic genetics}, volume = {45}, number = {6}, pages = {633-639}, pmid = {39232248}, issn = {1744-5094}, mesh = {Humans ; Female ; Adult ; *Ciliopathies/genetics ; *Pedigree ; *Phenotype ; Retrospective Studies ; Genotype ; Cone Dystrophy/genetics/diagnosis ; Consanguinity ; Visual Acuity/physiology ; Tomography, Optical Coherence ; Mutation ; Homozygote ; }, abstract = {BACKGROUND: CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 have been described in association with cone rod dystrophy, retinitis pigmentosa, with or without macular staphyloma, or with systemic abnormalities such as skeletal dysplasia and amyotrophic lateral sclerosis. Herein, we report a consanguineous family with a novel homozygous CFAP410 c.335_346del variant with cone only degeneration and no systemic features.<br><br>METHODS: A retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry was performed as well as genetic testing with in silico pathogenicity predictions and a literature review.<br><br>RESULTS: A systemically well 28-year-old female of Pakistani ethnicity with parental consanguinity and no relevant family history, presented with childhood-onset poor central vision and photophobia. Best-corrected visual acuity and colour vision were reduced (0.5 LogMAR, 6/17 Ishihara plates (right) and 0.6 LogMAR, 3/17 Ishihara plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Optical coherence tomography showed subtle signs of intermittent disruption of the ellipsoid zone. Microperimetry demonstrated a reduction in central retinal sensitivity. Electrodiagnostic testing confirmed a reduction in cone-driven responses. Whole-genome sequencing identified an in-frame homozygous deletion of 12 base pairs at c.335_346del in CFAP410.<br><br>CONCLUSIONS: The non-syndromic cone dystrophy phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for light of potential future genetic therapies.}, }
@article {pmid39231585, year = {2025}, author = {Kato, C and Morimoto, S and Takahashi, S and Namba, S and Wang, QS and Okada, Y and Okano, H}, title = {Spinal cord motor neuron phenotypes and polygenic risk scores in sporadic amyotrophic lateral sclerosis: deciphering the disease pathology and therapeutic potential of ropinirole hydrochloride.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {96}, number = {2}, pages = {199-201}, pmid = {39231585}, issn = {1468-330X}, }
@article {pmid39231554, year = {2024}, author = {Gong, Z and Deng, W and Li, Z and Tang, J and Zhang, M}, title = {Association between apathy and caregiver burden in patients with amyotrophic lateral sclerosis: a cross-sectional study.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e080803}, pmid = {39231554}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology ; Male ; Female ; Cross-Sectional Studies ; *Apathy ; Middle Aged ; *Anxiety/psychology/etiology ; *Depression/psychology/etiology ; China/epidemiology ; *Caregiver Burden/psychology ; Aged ; Caregivers/psychology ; Adult ; Cognitive Dysfunction/etiology/psychology ; Psychiatric Status Rating Scales ; Logistic Models ; Cost of Illness ; }, abstract = {OBJECTIVES: To investigate the relationship among patients' apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).<br><br>DESIGN: A cross-sectional study design was used.<br><br>SETTING: The study was conducted at a tertiary hospital in Wuhan, Hubei, China.<br><br>PARTICIPANTS: A total of 109 patients with ALS and their caregivers were included.<br><br>OUTCOME MEASURES: Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients' apathy on the relationship between depression/anxiety and caregiver burden.<br><br>RESULTS: Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=-0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95%&#x2009;CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (&#x3b2;=0.35, 95%&#x2009;CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (&#x3b2;=0.34, 95%&#x2009;CI 0.16 to 0.52, p<0.05).<br><br>CONCLUSIONS: Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.}, }
@article {pmid39231437, year = {2024}, author = {Chu, HS and Oh, J}, title = {Family Caregivers' Experiences of People With Amyotrophic Lateral Sclerosis Undergoing Gastrostomy Tube Feeding.}, journal = {The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses}, volume = {56}, number = {6}, pages = {224-228}, pmid = {39231437}, issn = {1945-2810}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/nursing/psychology ; *Caregivers/psychology ; *Enteral Nutrition ; *Gastrostomy ; Female ; Male ; Middle Aged ; Republic of Korea ; *Qualitative Research ; Adult ; Aged ; Stress, Psychological ; Interviews as Topic ; }, abstract = {INTRODUCTION: In amyotrophic lateral sclerosis (ALS) patients with impaired swallowing function, gastrostomy tube (G-tube) placement is recommended, but significantly increases the caregiving burden on families. This study aimed to describe the experiences of family caregivers of patients with ALS receiving home enteral nutrition through a G-tube. METHOD: Using purposive sampling, 8 family caregivers participated in the study. Data collection was conducted between February 2021 and October 2022 at a university hospital in Seoul, Korea. Semistructured face-to-face interviews were used to collect data until saturation. Data were analyzed using Krippendorff's content analysis approach. RESULTS: Qualitative analysis of the data revealed 3 main themes regarding caregiving. The emerging themes included psychological distress, unmet practical needs, and the struggle to provide care. CONCLUSION: After a G-tube placement, family caregivers experience various emotional stresses and have numerous unmet practical needs. Healthcare professionals caring for people with ALS receiving enteral nutrition should provide a tailored support program that addresses the specific needs of these family caregivers.}, }
@article {pmid39231048, year = {2024}, author = {Trescato, I and Tavazzi, E and Vettoretti, M and Gatta, R and Vasta, R and Chio, A and Camillo, BD}, title = {DYNAMITE: Integrating Archetypal Analysis and Process Mining for Interpretable Disease Progression Modelling.}, journal = {IEEE journal of biomedical and health informatics}, volume = {28}, number = {12}, pages = {7553-7564}, doi = {10.1109/JBHI.2024.3453602}, pmid = {39231048}, issn = {2168-2208}, mesh = {Humans ; *Disease Progression ; *Data Mining/methods ; *Amyotrophic Lateral Sclerosis/physiopathology ; Electronic Health Records ; Algorithms ; }, abstract = {DYNAMITE, an acronym for DYNamic Archetypal analysis for MIning disease TrajEctories, is a new methodology developed specifically to model disease progression by exploiting information available in longitudinal clinical datasets. First, archetypal analysis is applied to data organised in matrix form, with the aim of finding extreme and representative disease states (archetypes) linked to the original data through convex coefficients. Then, each original observation is associated with a single archetype based on their similarity; finally, an event log is created encoding the progression of disease states for each patient in terms of archetype states. In the last stage of the procedure, archetypal analysis is coupled with process mining, which allows the event log archetypes to be visualised graphically as sequences of disease states, allowing the clinical trajectories of patients to be extracted and examined. As a proof of concept, we applied the proposed method to data from a cohort of amyotrophic lateral sclerosis patients whose progression was monitored using the 12-item ALSFRS-R questionnaire. Without any a priori knowledge, DYNAMITE identified six archetypes clearly describing different types and severity of impairment and provided reliable clinical trajectories consistent with the prognosis of amyotrophic lateral sclerosis patients. DYNAMITE offers high interpretability at every stage of the analysis, which makes it particularly suitable for use in healthcare where explainability is paramount, and enables analysis of clinical trajectories at both individual and population levels.}, }
@article {pmid39230722, year = {2024}, author = {Chalitsios, CV and Ley, H and Gao, J and Turner, MR and Thompson, AG}, title = {Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6956-6969}, pmid = {39230722}, issn = {1432-1459}, support = {MR/T006927/1/MRC_/Medical Research Council/United Kingdom ; Thompson/Apr23/896-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/epidemiology ; *Apolipoproteins/antagonists &amp; inhibitors/blood/genetics ; *Frontotemporal Dementia/blood/genetics/epidemiology ; Hypolipidemic Agents/pharmacology/therapeutic use ; Lipids/blood ; Mendelian Randomization Analysis ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS.<br><br>METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications.<br><br>RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L&#x2009;=&#x2009;1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L&#x2009;=&#x2009;0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW&#x2009;=&#x2009;1.085, 95%:CI 1.008-1.168, pFDR&#x2009;=&#x2009;0.0406), total cholesterol (ORIVW&#x2009;=&#x2009;1.081, 95%:CI 1.013-1.154, pFDR&#x2009;=&#x2009;0.0458) and apolipoprotein B (ORIVW&#x2009;=&#x2009;1.104, 95%:CI 1.041-1.171, pFDR&#x2009;=&#x2009;0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW&#x2009;=&#x2009;1.424, 95%CI 1.072-1.829, pFDR&#x2009;=&#x2009;0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW&#x2009;=&#x2009;0.84, 95%CI 0.759-0.929, pFDR&#x2009;=&#x2009;0.00275) and FTD risk (ORIVW&#x2009;=&#x2009;0.581, 95%CI 0.387-0.874, pFDR&#x2009;=&#x2009;0.0362).<br><br>CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.}, }
@article {pmid39229489, year = {2024}, author = {Feng, F and Feng, G and Liu, J and Hao, W and Huang, W and Bi, X and Li, M and Wang, H and Yang, F and He, Z and Bai, J and Wang, H and Ma, G and Xu, B and Shu, N and Huang, X}, title = {Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae222}, pmid = {39229489}, issn = {2632-1297}, abstract = {The structural network damages in amyotrophic lateral sclerosis patients are evident but contradictory due to the high heterogeneity of the disease. We hypothesized that patterns of structural network impairments would be different in amyotrophic lateral sclerosis subtypes by a data-driven method using [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging. The data of positron emission tomography, structural MRI and diffusion tensor imaging in fifty patients with amyotrophic lateral sclerosis and 23 healthy controls were collected by a [18]F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid. Two amyotrophic lateral sclerosis subtypes were identified as the optimal cluster based on grey matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural networks in the identified subtypes. Compared with healthy controls, the two amyotrophic lateral sclerosis subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two amyotrophic lateral sclerosis subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every amyotrophic lateral sclerosis patient and demonstrated a positive correlation with disease severity. We clustered two amyotrophic lateral sclerosis subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that amyotrophic lateral sclerosis may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research.}, }
@article {pmid39229486, year = {2024}, author = {Rivers-Auty, J and Hoyle, C and Pointer, A and Lawrence, C and Pickering-Brown, S and Brough, D and Ryan, S}, title = {C9orf72 dipeptides activate the NLRP3 inflammasome.}, journal = {Brain communications}, volume = {6}, number = {5}, pages = {fcae282}, pmid = {39229486}, issn = {2632-1297}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases with considerable clinical, genetic and pathological overlap. The most common cause of both diseases is a hexanucleotide repeat expansion in C9orf72. The expansion is translated to produce five toxic dipeptides, which aggregate in patient brain. Neuroinflammation is a feature of frontotemporal dementia and amyotrophic lateral sclerosis; however, its causes are unknown. The nod-like receptor family, pyrin domain-containing 3 inflammasome is implicated in several other neurodegenerative diseases as a driver of damaging inflammation. The inflammasome is a multi-protein complex which forms in immune cells in response to tissue damage, pathogens or aggregating proteins. Inflammasome activation is observed in models of other neurodegenerative diseases such as Alzheimer's disease, and inflammasome inhibition rescues cognitive decline in rodent models of Alzheimer's disease. Here, we show that a dipeptide arising from the C9orf72 expansion, poly-glycine-arginine, activated the inflammasome in microglia and macrophages, leading to secretion of the pro-inflammatory cytokine, interleukin-1β. Poly-glycine-arginine also activated the inflammasome in organotypic hippocampal slice cultures, and immunofluorescence imaging demonstrated formation of inflammasome specks in response to poly-glycine-arginine. Several clinically available anti-inflammatory drugs rescued poly-glycine-arginine-induced inflammasome activation. These data suggest that C9orf72 dipeptides contribute to the neuroinflammation observed in patients, and highlight the inflammasome as a potential therapeutic target for frontotemporal dementia and amyotrophic lateral sclerosis.}, }
@article {pmid39229047, year = {2024}, author = {Wairagkar, M and Card, NS and Singer-Clark, T and Hou, X and Iacobacci, C and Hochberg, LR and Brandman, DM and Stavisky, SD}, title = {An instantaneous voice synthesis neuroprosthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229047}, issn = {2692-8205}, support = {DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, abstract = {Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text[1-3]. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one's own voice. Here, we demonstrate a "brain-to-voice" neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.}, }
@article {pmid39229019, year = {2024}, author = {Erwin, AL and Chang, ML and Fernandez, MG and Attili, D and Russ, JE and Sutanto, R and Pinarbasi, ES and Bekier, M and Brant, TS and Hahn, T and Dykstra, M and Thomas, D and Li, X and Baldridge, RD and Tank, EMH and Barmada, SJ and Mosalaganti, S}, title = {Molecular Visualization of Neuronal TDP43 Pathology In Situ.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39229019}, issn = {2692-8205}, support = {DP2 GM150019/GM/NIGMS NIH HHS/United States ; S10 OD030275/OD/NIH HHS/United States ; T32 GM007544/GM/NIGMS NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; T32 GM141840/GM/NIGMS NIH HHS/United States ; R01 NS113943/NS/NINDS NIH HHS/United States ; R01 NS097542/NS/NINDS NIH HHS/United States ; R56 NS128110/NS/NINDS NIH HHS/United States ; F31 NS134123/NS/NINDS NIH HHS/United States ; R35 GM128592/GM/NIGMS NIH HHS/United States ; }, abstract = {Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, enhancing RNA misprocessing due to loss of nuclear TDP43 and engendering a cycle that ends in cell death. Here, we show that adding small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation in iPSC-derived neurons (iNeurons). By employing a multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine how RNA influences the localization and aggregation of TDP43 in near-native conditions. We find that mislocalized TDP43 forms ordered fibrils within lysosomes and autophagosomes in iNeurons as well as in patient tissue, and provide the first high-resolution snapshots of TDP43 aggregates in situ. In so doing, we provide a cellular model for studying initial pathogenic events underlying ALS, FTLD, and related TDP43-proteinopathies.}, }
@article {pmid39227882, year = {2024}, author = {Zelina, P and de Ruiter, AA and Kolsteeg, C and van Ginneken, I and Vos, HR and Supiot, LF and Burgering, BMT and Meye, FJ and Veldink, JH and van den Berg, LH and Pasterkamp, RJ}, title = {ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.}, journal = {Acta neuropathologica communications}, volume = {12}, number = {1}, pages = {144}, pmid = {39227882}, issn = {2051-5960}, support = {TOTALS//Stichting ALS Nederland/ ; GoALS//Stichting ALS Nederland/ ; MAXOMOD//E-Rare/ ; TRIAGE//JPND/ ; X-omics initiative//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; EScORIAL//H2020 European Research Council/ ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; DNA Damage ; DNA Repair/genetics ; *Induced Pluripotent Stem Cells/metabolism ; *Mitochondria/metabolism/pathology ; *Motor Neurons/metabolism/pathology ; Mutation ; *NIMA-Related Kinase 1/genetics/metabolism ; *Zebrafish ; Cytoskeletal Proteins/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.}, }
@article {pmid39227337, year = {2024}, author = {Choi, SJ and Yoo, SH and Lee, SY and Sung, JJ}, title = {Withdrawal of Life-Sustaining Mechanical Ventilation for a Patient With Amyotrophic Lateral Sclerosis in Locked-In Syndrome.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {20}, number = {5}, pages = {537-538}, pmid = {39227337}, issn = {1738-6586}, support = {NRF-2018R1A5A2025964/NRF/National Research Foundation of Korea/Korea ; }, }
@article {pmid39226927, year = {2024}, author = {Cossu, L and Cappon, G and Facchinetti, A}, title = {Adaptive and self-learning Bayesian filtering algorithm to statistically characterize and improve signal-to-noise ratio of heart-rate data in wearable devices.}, journal = {Journal of the Royal Society, Interface}, volume = {21}, number = {218}, pages = {20240222}, pmid = {39226927}, issn = {1742-5662}, support = {//Horizon 2020 Framework Programme/ ; }, mesh = {Humans ; *Bayes Theorem ; *Wearable Electronic Devices ; *Heart Rate/physiology ; *Algorithms ; *Signal-To-Noise Ratio ; Male ; Female ; Signal Processing, Computer-Assisted ; }, abstract = {The use of wearable sensors to monitor vital signs is increasingly important in assessing individual health. However, their accuracy often falls short of that of dedicated medical devices, limiting their usefulness in a clinical setting. This study introduces a new Bayesian filtering (BF) algorithm that is designed to learn the statistical characteristics of signal and noise, allowing for optimal smoothing. The algorithm is able to adapt to changes in the signal-to-noise ratio (SNR) over time, improving performance through windowed analysis and Bayesian criterion-based smoothing. By evaluating the algorithm on heart-rate (HR) data collected from Garmin Vivoactive 4 smartwatches worn by individuals with amyotrophic lateral sclerosis and multiple sclerosis, it is demonstrated that BF provides superior SNR tracking and smoothing compared with non-adaptive methods. The results show that BF accurately captures SNR variability, reducing the root mean square error from 2.84 bpm to 1.21 bpm and the mean absolute relative error from 3.46% to 1.36%. These findings highlight the potential of BF as a preprocessing tool to enhance signal quality from wearable sensors, particularly in HR data, thereby expanding their applications in clinical and research settings.}, }
@article {pmid39226712, year = {2024}, author = {Santos Silva, C and Gormicho, M and Simão, S and Pronto-Laborinho, AC and Alves, I and Pinto, S and Oliveira Santos, M and de Carvalho, M}, title = {C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.}, journal = {Journal of the neurological sciences}, volume = {465}, number = {}, pages = {123208}, doi = {10.1016/j.jns.2024.123208}, pmid = {39226712}, issn = {1878-5883}, mesh = {Humans ; Male ; Portugal/epidemiology ; Female ; Middle Aged ; *C9orf72 Protein/genetics ; *Motor Neuron Disease/genetics/epidemiology ; Aged ; *Phenotype ; *DNA Repeat Expansion/genetics ; Cohort Studies ; Amyotrophic Lateral Sclerosis/genetics/diagnosis ; }, abstract = {BACKGROUND: C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort.<br><br>METHODS: Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model.<br><br>RESULTS: We included 761 patients of whom 61 (8.0&#xa0;%) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4&#xa0;%, p&#xa0;=&#xa0;0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7&#xa0;%, p&#xa0;=&#xa0;0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6&#xa0;years, p&#xa0;=&#xa0;0.003) and more frequent MND family history (65.5 vs 11.4&#xa0;%, p&#xa0;<&#xa0;0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (&#x394;F), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p&#xa0;=&#xa0;0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR&#xa0;=&#xa0;0.96, 95&#xa0;%CI 0.92-0.99, p&#xa0;=&#xa0;0.008) and &#x394;F (HR&#xa0;=&#xa0;1.93, 95&#xa0;%CI 1.26-2.96, p&#xa0;=&#xa0;0.002).<br><br>CONCLUSION: Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology.}, }
@article {pmid39226692, year = {2024}, author = {Kwon, S and Kim, B and Han, KD and Jung, W and Cho, EB and Shin, DW and Min, JH}, title = {Risk of depression in amyotrophic lateral sclerosis: A nationwide cohort study in South Korea.}, journal = {Journal of psychiatric research}, volume = {178}, number = {}, pages = {414-420}, doi = {10.1016/j.jpsychires.2024.08.030}, pmid = {39226692}, issn = {1879-1379}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology ; Republic of Korea/epidemiology ; Male ; Female ; Middle Aged ; Aged ; *Depression/epidemiology ; Adult ; Cohort Studies ; Proportional Hazards Models ; }, abstract = {Depression is frequently reported in amyotrophic lateral sclerosis (ALS) due to the disastrous prognosis of progressive motor impairment, but the risk of depression in ALS is still unclear. Therefore, we investigated the risk of depression in ALS and analyzed the effect of ALS-related physical disability on the risk of developing depression using the Korean National Health Insurance Service (KNHIS) database. A total of 2241 ALS patients, as defined by the International Classification Diseases (ICD, G12.21) and Rare Intractable Disease codes (V123), and 1:10 sex- and age-matched controls were selected from the KNHIS. After applying exclusion criteria (non-participation in national health screening, history of depression, or having missing data), 595 ALS patients and 9896 non-ALS individuals were finally selected. Primary outcome is newly diagnosed depression during follow-up duration defined by ICD code (F32 or F33). A Cox regression model was used to examine the hazard ratios (HRs) after adjustment for potential confounders. During the follow-up period, 283 cases of depression in the ALS group and 1547 in the controls were recorded. The adjusted HR for depression in ALS was 9.1 (95% confidence interval [CI] 7.87-10.60). The risk of depression was slightly higher in the disabled ALS group (aHR 10.1, 95% CI 7.98-12.67) than in the non-disabled ALS group (aHR 8.78, 95% CI 7.42-10.39). The relative risk of depression was higher in younger patients than in older patients, and in obese patients than in non-obese patients. Our study showed that ALS patients have an increased risk of depression compared to non-ALS individuals.}, }
@article {pmid39225243, year = {2024}, author = {Liang, J and Zhu, Y and Liu, S and Kuang, B and Tian, Z and Zhang, L and Yang, S and Lin, M and Chen, N and Liu, X and Ai, Q and Yang, Y}, title = {Progress of Exosomal MicroRNAs and Traditional Chinese Medicine Monomers in Neurodegenerative Diseases.}, journal = {Phytotherapy research : PTR}, volume = {38}, number = {11}, pages = {5323-5349}, doi = {10.1002/ptr.8322}, pmid = {39225243}, issn = {1099-1573}, support = {//The Key Discipline of Biological Engineering of Hunan University of Chinese Medicine [2018] No. 3/ ; 22JBZ052//Hunan University of Chinese Medicine Discipline Construction Project/ ; 202329-2//Key Project of Changsha Hospital for Maternal &amp; Child Health Care Affiliated to Hunan Normal University/ ; 2021JJ30512//Hunan Natural Science Foundation/ ; 2022JJ40313//Hunan Natural Science Foundation/ ; 2022JJ40456//Hunan Natural Science Foundation/ ; 2023JJ60126//Hunan Natural Science Foundation/ ; 2023JJ60471//Hunan Natural Science Foundation/ ; 21B0354//Outstanding Youth Project of Hunan Education Department/ ; B2023061//Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine/ ; //Hunan University of Chinese Medicine First-class Disciple Construction Project of Chinese Material Medica/ ; kq2014091//Changsha Natural Science Foundation/ ; kq2202269//Changsha Natural Science Foundation/ ; //The First-class Discipline Construction Project of Chemical Engineering and Technology of Hunan University of Traditional Chinese Medicine/ ; 212010//Special Scientific and Technological Project for Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd/ ; 2019xjjj001//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; 2021XJJJ028//Key Project of Hunan University of Chinese Medicine School level Scientific Research Fund/ ; U2202214//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *MicroRNAs/genetics ; *Neurodegenerative Diseases/drug therapy ; *Medicine, Chinese Traditional/methods ; Drugs, Chinese Herbal/pharmacology ; Animals ; }, abstract = {Exosomes, extracellular vesicles secreted by various cells, actively participate in intercellular communication by facilitating the exchange of crucial molecular information such as DNA, RNA, and lipids. Within this intricate network, microRNAs, endogenous non-coding small RNAs, emerge as pivotal regulators of post-transcriptional gene expression, significantly influencing the development of neurodegenerative diseases. The historical prominence of traditional Chinese medicine (TCM) in clinical practice in China underscores its enduring significance. Notably, TCM monomers, serving as active constituents within herbal medicine, assume a critical role in the treatment of neurodegenerative diseases, particularly in mitigating oxidative stress, inhibiting apoptosis, and reducing inflammation. This comprehensive review aims to delineate the specific involvement of exosomal microRNAs in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. Furthermore, the exploration extends to the application of TCM monomers, elucidating their efficacy as therapeutic agents in these conditions. Additionally, the review examines the utilization of exosomes as drug delivery carriers in the context of neurodegenerative diseases, providing a nuanced understanding of the potential synergies between TCM and modern therapeutic approaches. This synthesis of knowledge aims to contribute to the advancement of our comprehension of the intricate molecular mechanisms underlying neurodegeneration and the potential therapeutic avenues offered by TCcom interventions.}, }
@article {pmid39225106, year = {2024}, author = {Białobrodzka, E and Flis, DJ and Akdogan, B and Borkowska, A and Wieckowski, MR and Antosiewicz, J and Zischka, H and Dzik, KP and Kaczor, JJ and Ziolkowski, W}, title = {Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {5}, pages = {1111-1118}, doi = {10.1002/mus.28237}, pmid = {39225106}, issn = {1097-4598}, support = {//Narodowe Centrum Nauki/ ; DEC-2013/09/NZ7/02538//National Science Centre/ ; 2020/39/B/NZ7/03366//National Science Centre/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/metabolism ; *Muscle, Skeletal/metabolism ; Mice ; *Copper/metabolism ; *Disease Models, Animal ; *Mice, Transgenic ; *Swimming ; Superoxide Dismutase/metabolism ; Copper-Transporting ATPases/metabolism/genetics ; Physical Conditioning, Animal/physiology ; Superoxide Dismutase-1/metabolism/genetics ; Adenosine Triphosphatases/metabolism ; Cation Transport Proteins/metabolism ; Male ; Copper Transporter 1/metabolism ; }, abstract = {INTRODUCTION/AIMS: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice.<br><br>METHODS: SOD1G93A mice (n&#x2009;=&#x2009;6 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n&#x2009;=&#x2009;6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined.<br><br>RESULTS: ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43&#x2009;&#xb1;&#x2009;1.81 and 38.67&#x2009;&#xb1;&#x2009;11.50&#x2009;&#x3bc;g/mg, respectively, p&#x2009;=&#x2009;.0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p&#x2009;=&#x2009;.0021) and 34% (p&#x2009;=&#x2009;.0372), while the CTR1 protein (copper importer) decreased by 45% (p&#x2009;=&#x2009;.002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles.<br><br>DISCUSSION: The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.}, }
@article {pmid39224919, year = {2024}, author = {Kiernan, MC and Kaji, R}, title = {Emerging concepts and therapies for amyotrophic lateral sclerosis.}, journal = {Current opinion in neurology}, volume = {37}, number = {5}, pages = {558-559}, doi = {10.1097/WCO.0000000000001308}, pmid = {39224919}, issn = {1473-6551}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; }, }
@article {pmid39224887, year = {2024}, author = {Yang, J and Tian, M and Zhang, L and Xin, C and Huo, J and Liu, Q and Dong, H and Li, R and Liu, Y}, title = {Assessment of Rab geranylgeranyltransferase subunit beta in amyotrophic lateral sclerosis.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1447461}, pmid = {39224887}, issn = {1664-2295}, abstract = {INTRODUCTION: Geranylgeranyltransferase Subunit Beta (RABGGTB) was expressed at higher levels in patients with Amyotrophic lateral sclerosis (ALS) compared with healthy controls. This study aims to observe the expression of RABGGTB in different cells from patients with ALS and different diseases.<br><br>METHODS: In this case-control study, we collected peripheral blood from patients with ALS and healthy controls, and compared the expression of RABGGTB in natural killer cells (NK), T cells and B cells between patients with ALS and healthy controls by flow cytometry. And compared the expression of RABGGTB in monocytes and monocyte-derived macrophages from patients with ALS, Parkinson's disease (PD), acute cerebrovascular disease (ACVD), and healthy controls by flow cytometry and immunofluorescence. Then flow cytometry was used to detect the expression of RABGGTB in monocytes from SOD1G93A mice and WT mice.<br><br>RESULTS: The expression of RABGGTB was not significantly changed in NK cells, cytotoxic T cells (CTL), helper T cells (Th), regulatory T cells (Treg), and B cells from patients with ALS compared to healthy controls. And the expression of RABGGTB in monocytes and monocyte-derived macrophages was higher in the ALS group than in the PD, ACVD and control group. The expression of RABGGTB was significantly higher in monocytes of SOD1G93A mice compared to WT mice.<br><br>CONCLUSION: These findings suggest that RABGGTB expression was increased in monocytes and monocyte-derived macrophages from patients with ALS, not in NK, CTL, Th, Treg, and B cells. Future studies are needed to find the clinical implication of RABGGTB in ALS.}, }
@article {pmid39223525, year = {2024}, author = {Iakovleva, V and Verde, F and Cinnante, C and Sillani, A and Conte, G and Corsini, E and Ciusani, E and Erbetta, A and Silani, V and Ticozzi, N}, title = {Duropathy as a rare motor neuron disease mimic: from bibrachial amyotrophy to infratentorial superficial siderosis.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {309}, pmid = {39223525}, issn = {1471-2377}, support = {PNC-E3-2022-23683266//Italian Ministry of Education and Research (MUR)/ ; }, mesh = {Humans ; Male ; Middle Aged ; *Motor Neuron Disease/diagnosis/complications/diagnostic imaging ; *Siderosis/complications/diagnosis/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Diagnosis, Differential ; Dura Mater/diagnostic imaging/pathology ; }, abstract = {BACKGROUND: Bibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears.<br><br>CASE PRESENTATION: A 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with [123]I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson's disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting.<br><br>CONCLUSIONS: Based on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of "duropathies". Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation.}, }
@article {pmid39222049, year = {2024}, author = {Santangelo, S and Invernizzi, S and Sorce, MN and Casiraghi, V and Peverelli, S and Brusati, A and Colombrita, C and Ticozzi, N and Silani, V and Bossolasco, P and Ratti, A}, title = {NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.}, journal = {Human molecular genetics}, volume = {33}, number = {21}, pages = {1900-1907}, pmid = {39222049}, issn = {1460-2083}, support = {GR-2016-02364373//BIBLIOSAN/ ; PSR 2021//Italian Ministery of Health/ ; }, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *NIMA-Related Kinase 1/genetics ; *DNA Damage/genetics ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; *C9orf72 Protein/genetics/metabolism ; *Haploinsufficiency/genetics ; *Motor Neurons/metabolism/pathology ; *Frontotemporal Dementia/genetics/pathology ; *Cilia/genetics/pathology/metabolism ; Cell Differentiation/genetics ; DNA Repeat Expansion/genetics ; Mutation ; }, abstract = {The hexanucleotide G4C2 repeat expansion (HRE) in C9ORF72 gene is the major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to both loss- and gain-of-function pathomechanisms. The wide clinical heterogeneity among C9ORF72 patients suggests potential modifying genetic and epigenetic factors. Notably, C9ORF72 HRE often co-occurs with other rare variants in ALS/FTD-associated genes, such as NEK1, which encodes for a kinase involved in multiple cell pathways, including DNA damage response and ciliogenesis. In this study, we generated induced pluripotent stem cells (iPSCs) and differentiated motoneurons (iPSC-MNs) from an ALS patient carrying both C9ORF72 HRE and a NEK1 loss-of-function mutation to investigate the biological effect of NEK1 haploinsufficiency on C9ORF72 pathology in a condition of oligogenicity. Double mutant C9ORF72/NEK1 cells showed increased pathological C9ORF72 RNA foci in iPSCs and higher DNA damage levels in iPSC-MNs compared to single mutant C9ORF72 cells, but no effect on DNA damage response. When we analysed the primary cilium, we observed a defective ciliogenesis in C9ORF72 iPSC-MNs which was not worsened by NEK1 haploinsufficiency in the double mutant iPSC-MNs. Altogether, our study shows that NEK1 haploinsufficiency influences differently DNA damage and cilia length, potentially acting as a modifier at biological level in an in vitro ALS patient-derived disease model of C9ORF72 pathology.}, }
@article {pmid39218769, year = {2024}, author = {Sun, J and Zhang, Y}, title = {Microbiome and micronutrient in ALS: From novel mechanisms to new treatments.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {6}, pages = {e00441}, pmid = {39218769}, issn = {1878-7479}, support = {I01 BX004824/BX/BLRD VA/United States ; R01 DK114126/DK/NIDDK NIH HHS/United States ; R01 DK134343/DK/NIDDK NIH HHS/United States ; }, mesh = {*Amyotrophic Lateral Sclerosis/microbiology/metabolism/therapy ; Humans ; *Micronutrients/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Dysbiosis ; Microbiota/physiology ; }, abstract = {Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.}, }
@article {pmid39218293, year = {2024}, author = {Dibaj, P and Safavi-Abbasi, S and Asadollahi, E}, title = {In vivo spectrally unmixed multi-photon imaging of longitudinal axon-glia changes in injured spinal white matter.}, journal = {Neuroscience letters}, volume = {841}, number = {}, pages = {137959}, doi = {10.1016/j.neulet.2024.137959}, pmid = {39218293}, issn = {1872-7972}, mesh = {Animals ; *White Matter/pathology/metabolism/diagnostic imaging ; *Spinal Cord Injuries/pathology/metabolism/diagnostic imaging ; *Axons/pathology/metabolism ; *Mice, Transgenic ; Neuroglia/metabolism/pathology ; Mice ; Microscopy, Fluorescence, Multiphoton/methods ; Spinal Cord/pathology/metabolism ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; }, abstract = {Understanding the sequence of cellular responses and their contributions to pathomorphogical changes in spinal white matter injuries is a prerequisite for developing efficient therapeutic strategies for spinal cord injury (SCI) as well as neurodegenerative and inflammatory diseases of the spinal cord such as amyotrophic lateral sclerosis and multiple sclerosis. We have developed several types of surgical procedures suitable for acute one-time and chronic recurrent in vivo multiphoton microscopy of spinal white matter [1]. Sophisticated surgical procedures were combined with transgenic mouse technology to image spinal tissue labeled with up to four fluorescent proteins (FPs) in axons, astrocytes, microglia, and blood vessels. To clearly separate the simultaneously excited FPs, spectral unmixing including iterative procedures was performed after imaging the diversely labeled spinal white matter with a custom-made 4-channel two-photon laser-scanning microscope. In our longitudinal multicellular studies of injured spinal white matter, we imaged axonal dynamics and invasion of microglia and astrocytes for a time course of over 200 days after SCI. Our methods offer ideal platforms for investigating acute and chronic cellular dynamics, cell-cell interactions, and metabolite fluctuations in health and disease as well as pharmacological manipulations in vivo.}, }
@article {pmid39218010, year = {2024}, author = {Shojaie, A and Al Khleifat, A and Garrahy, S and Habash-Bailey, H and Thomson, R and Opie-Martin, S and Javidnia, S and Leigh, PN and Al-Chalabi, A}, title = {Investigating the impact of socioeconomic status on amyotrophic lateral sclerosis.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {702-707}, pmid = {39218010}, issn = {2167-9223}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/economics ; Male ; Female ; Middle Aged ; *Social Class ; Aged ; Adult ; Age of Onset ; Risk Factors ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding the impact of SES on health conditions is crucial, as it can influence and be influenced by health-related variables. The role of socioeconomic status in influencing the risk and progression of ALS has not been established, and understanding the various factors that impact ALS is important in developing strategies for treatment and prevention. To investigate this relationship, we recruited 413 participants with definite, probable, or possible ALS according to the El Escorial criteria, from three tertiary centers in London, Sheffield, and Birmingham. Logistic regression was used to examine the association between case-control status, socioeconomic criteria, and ALS risk. Linear regression was used to examine the association between age of onset and socioeconomic variables. Two sensitivity analyses were performed, one using an alternative occupational classifier, and the other using Mendelian Randomization analysis to examine association. There was no significant relationship between any variables and ALS risk. We found an inverse relationship between mean lifetime salary and age of ALS onset (Beta = -0.157, p = 0.011), but no effect of education or occupation on the age of onset. The finding was confirmed in both sensitivity analyses and in Mendelian Randomization. We find that a higher salary is associated with a younger age of ALS onset taking into account sex, occupation, years of education, and clinical presentation.}, }
@article {pmid39217855, year = {2024}, author = {Zhang, J and Chen, K and Chen, Y and Hua, L and Chen, S and Chen, X and Zou, L and Li, S and Yang, X and Shen, Y}, title = {Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.}, journal = {Ultrasonics}, volume = {144}, number = {}, pages = {107449}, doi = {10.1016/j.ultras.2024.107449}, pmid = {39217855}, issn = {1874-9968}, mesh = {Animals ; Male ; Mice ; *Amyotrophic Lateral Sclerosis ; *Disease Models, Animal ; Drug Delivery Systems ; Furans/pharmacology/administration &amp; dosage ; Glucosides/pharmacology/administration &amp; dosage ; *Mice, Transgenic ; Microbubbles ; *Motor Cortex/drug effects/physiopathology ; Mutation ; Superoxide Dismutase-1/genetics ; Ultrasonic Therapy/methods ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders.<br><br>OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model.<br><br>METHODS: The ALS mouse model with the SOD1[G93A] mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining.<br><br>RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord.<br><br>CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.}, }
@article {pmid39217293, year = {2024}, author = {Aljthalin, R and Albalawi, R and Alyahya, A and Alhathlool, R and Alhashemi, M}, title = {Multiple sclerosis and amyotrophic lateral sclerosis: is there an association or a red flag? A case report and literature review.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {307}, pmid = {39217293}, issn = {1471-2377}, mesh = {Humans ; Female ; *Amyotrophic Lateral Sclerosis/diagnosis/complications/pathology ; Middle Aged ; *Multiple Sclerosis/complications/diagnosis/pathology ; Magnetic Resonance Imaging ; }, abstract = {BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that causes damage to the myelin and axons and is caused by genetic or environmental factors. Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive degeneration of the motor neurons resulting in the presence of upper and lower motor-neuron signs and symptoms.<br><br>CASE PRESENTATION: A 46-year-old female patient presented with symmetrical weakness of the lower limbs and numbness that developed over weeks. Magnetic resonance imaging (MRI) of the brain exhibited typical demyelination features, high signal abnormality involving the periventricular and subcortical white matter, and an oval-shaped lesion. The patient was diagnosed with MS based on the clinical presentation and radiological examination. However, there was rapid progression of the symptoms, involvement of bulbar dysfunction, and muscle atrophy. Furthermore, the patient did not respond to acute therapy and immunotherapy, which made the diagnosis of MS less likely or suggested that it could be associated with another diagnosis. Her neurophysiological test met the criteria of ALS, and she was started on riluzole.<br><br>LITERATURE REVIEW: We reviewed all articles from 1986 to 2023, and there were 32 reported cases describing the co-occurrence of ALS and MS in different populations. Our case is the 33rd, and to our knowledge, it is the only case reported in the Middle East and specifically in Saudi Arabia. The main proposed mechanism according to postmortem examinations is a combination of degenerative and inflammatory processes with a cascade of production of reactive oxygen species and nitric oxide, which lead to cell death and apoptosis during concomitant ALS with MS.<br><br>CONCLUSION: The co-occurrence of ALS and MS is extremely rare, but it can be explained by pathogenesis related to neurodegeneration, inflammation, or genetic susceptibility. Rapid progressive motor and bulbar symptoms could be red-flag symptoms, extensive evaluation might be needed for these patients.}, }
@article {pmid39216161, year = {2024}, author = {Wang, J and Qi, J and Ouyang, Y and Zhou, S and Qin, L and Zhang, B and Bai, L and Pan, L}, title = {The mutation Asp-376-Glu in the ALS gene confers resistance to mesosulfuron-methyl in Beckmannia syzigachne.}, journal = {Plant physiology and biochemistry : PPB}, volume = {215}, number = {}, pages = {109083}, doi = {10.1016/j.plaphy.2024.109083}, pmid = {39216161}, issn = {1873-2690}, mesh = {*Acetolactate Synthase/genetics/metabolism ; *Herbicide Resistance/genetics ; *Herbicides/pharmacology ; *Sulfonylurea Compounds/pharmacology ; *Mutation ; Plant Proteins/genetics/metabolism ; Poaceae/genetics/drug effects ; Molecular Docking Simulation ; Plant Weeds/genetics/drug effects ; }, abstract = {Understanding the mechanisms by which weeds develop herbicide resistance is crucial for managing resistance effectively and optimizing herbicide use. Beckmannia syzigachne, a harmful grass weed prevalent in wheat and rice-wheat rotation areas, poses a significant threat to crop productivity. A field herbicide resistance survey identified a resistant population with a new ALS mutation (Asp-376-Glu). The Glu-376-Asp population displayed varying resistance levels to seven ALS herbicides, verified using the dCAPS method. qRT-PCR analysis showed that no significant difference existed in the ALS gene expression between the Asp-376-Glu and S populations. P450 and GST inhibitors failed to reverse resistance to mesosulfuron-methyl, suggesting no involvement of P450- and GST-based metabolic resistance. Molecular docking indicated that the Asp-376-Glu mutation reduces the binding affinity between ALS-inhibitors and BsALS. The findings provide valuable insights into herbicide resistance mechanisms for weed resistance control.}, }
@article {pmid39216080, year = {2024}, author = {Mazurie, Z and Branchereau, P and Cattaert, D and Henkous, N and Savona-Baron, C and Vouimba, RM}, title = {Acute stress differently modulates interneurons excitability and synaptic plasticity in the primary motor cortex of wild-type and SOD1[G93A] mouse model of ALS.}, journal = {The Journal of physiology}, volume = {602}, number = {19}, pages = {4987-5015}, doi = {10.1113/JP285210}, pmid = {39216080}, issn = {1469-7793}, support = {GPR BRAIN-2030//Universit&#xe9; de Bordeaux (University of Bordeaux)/ ; }, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/physiopathology/genetics ; *Interneurons/physiology ; *Neuronal Plasticity ; *Motor Cortex/physiopathology ; Mice ; Male ; *Mice, Transgenic ; Disease Models, Animal ; Stress, Psychological/physiopathology ; Superoxide Dismutase-1/genetics ; Mice, Inbred C57BL ; }, abstract = {Primary motor cortex (M1) network stability depends on activity of inhibitory interneurons, for which susceptibility to stress was previously demonstrated in limbic regions. Hyperexcitability in M1 following changes in the excitatory/inhibitory balance is a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Using electrophysiological approaches, we assessed the impact of acute restraint stress on inhibitory interneurons excitability and global synaptic plasticity in M1 of the SOD1[G93A] ALS mouse model at a late pre-symptomatic stage (10-12.5 weeks). Based on their firing type (continuous, discontinuous, with accommodation or not) and electrophysiological characteristics (resting potential, rheobase, firing frequency), interneurons from M1 slices were separated into four clusters, labelled from 1 to 4. Among them, only interneurons from the first cluster, presenting continuous firing with few accommodations, tended to show increased excitability in wild-type (WT) and decreased excitability in SOD1[G93A] animals following stress. In vivo analyses of evoked field potentials showed that stress suppressed the theta burst-induced plasticity of an excitatory component (N1) recorded in the superficial layers of M1 in WT, with no impact on an inhibitory complex (N2-P1) from the deeper layers. In SOD1[G93A] mice, stress did not affect N1 but suppressed the N2-P1 plasticity. These data suggest that stress can alter M1 network functioning in a different manner in WT and SOD1[G93A] mice, possibly through changes of inhibitory interneurons excitability and synaptic plasticity. This suggests that stress-induced activity changes in M1 may therefore influence ALS outcomes. KEY POINTS: Disruption of the excitatory/inhibitory balance in the primary motor cortex (M1) has been linked to cortical hyperexcitability development, a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Psychological stress was reported to influence excitatory/inhibitory balance in limbic regions, but very little is known about its influence on the M1 functioning under physiological or pathological conditions. Our study revealed that acute stress influences the excitatory/inhibitory balance within the M1, through changes in interneurons excitability along with network plasticity. Such changes were different in pathological (SOD1[G93A] ALS mouse model) vs. physiological (wild-type) conditions. The results of our study help us to better understand how stress modulates the M1 and highlight the need to further characterize stress-induced motor cortex changes because it may be of importance when evaluating ALS outcomes.}, }
@article {pmid39215697, year = {2024}, author = {Burrows, DJ and McGown, A and Abduljabbar, O and Castelli, LM and Shaw, PJ and Hautbergue, GM and Ramesh, TM}, title = {RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1058-1069}, doi = {10.1002/ana.27068}, pmid = {39215697}, issn = {1531-8249}, support = {Apr17/854-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/R024162/1/MRC_/Medical Research Council/United Kingdom ; BB/S005277/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; *Zebrafish ; *C9orf72 Protein/genetics ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; *Animals, Genetically Modified ; *Disease Models, Animal ; *Dipeptides ; Hypothermia, Induced/methods ; Frontotemporal Dementia/genetics/metabolism ; Humans ; Protein Biosynthesis/genetics/physiology ; }, abstract = {OBJECTIVE: Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.<br><br>METHODS: A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.<br><br>RESULTS: Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.<br><br>INTERPRETATION: The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058-1069.}, }
@article {pmid39215690, year = {2024}, author = {Suwa, S and Ando, M and Nakashima, T and Horii, S and Anai, T and Takeyama, H}, title = {In Situ Raman Hyperspectral Analysis of Microbial Colonies for Secondary Metabolites Screening.}, journal = {Analytical chemistry}, volume = {96}, number = {37}, pages = {14909-14917}, pmid = {39215690}, issn = {1520-6882}, mesh = {*Spectrum Analysis, Raman/methods ; *Escherichia coli/metabolism/isolation &amp; purification ; Anti-Bacterial Agents/analysis/metabolism ; Streptomyces/metabolism ; Least-Squares Analysis ; }, abstract = {Since the discovery of penicillin, a vast array of microbial antibiotics has been identified and applied in the medical field. Globally, the search for drug candidates via microbial screening is ongoing. Traditional screening methods, however, are time-consuming and require labor-intensive sample processing, significantly reducing throughput. This research introduces a Raman spectroscopy-based screening system tailored to the in situ analysis of microbial colonies on solid culture media. Employing multivariate curve resolution-alternating least-squares (MCR-ALS) for spectral decomposition, our approach reveals the production of secondary metabolites at the single colony level. We enhanced the microbial culture method, enabling direct, high signal-to-noise (S/N) ratio Raman spectroscopic measurements of colonies of Escherichia coli and actinomycetes species. Through semisupervised MCR analysis using the known spectra of actinorhodin and undecylprodigiosin as references, we accurately assessed the production of these compounds by Streptomyces coelicolor A3(2). Furthermore, we herein successfully detected the production of amphotericin B by Streptomyces nodosus, even in the absence of prior spectral information. This demonstrates the potential of our technique in the discovery of secondary metabolites. In addition to enabling the detection of the above-mentioned compounds, this analysis revealed the heterogeneity of the spatial distribution of their production in each colony. Our technique makes a significant contribution to the advancement of microbial screening, offering a rapid, efficient alternative to conventional methods and opening avenues for secondary metabolites discovery.}, }
@article {pmid39215326, year = {2024}, author = {Carlton, J and Powell, P and Rowen, D and Williams, C and Griffiths, AW and Hobson, E and McDermott, C}, title = {Development of a novel patient reported outcome measure for health-related quality of life in amyotrophic lateral sclerosis (PROQuALS): study protocol.}, journal = {Health and quality of life outcomes}, volume = {22}, number = {1}, pages = {69}, pmid = {39215326}, issn = {1477-7525}, mesh = {*Amyotrophic Lateral Sclerosis/psychology/therapy ; Humans ; *Quality of Life/psychology ; *Patient Reported Outcome Measures ; Surveys and Questionnaires ; Research Design ; Psychometrics ; Cost-Benefit Analysis ; }, abstract = {BACKGROUND: Patient reported outcome measures (PROMs) can be used to assess the impact of health conditions upon an individual's health-related quality of life (HRQoL). Whilst PROMs have been used to quantify the HRQoL impact of amyotrophic lateral sclerosis (ALS), existing instruments may not fully capture what matters to people living with ALS (plwALS) or be appropriate to be used directly to inform the cost-effectiveness of new treatments. This highlights a need for a new condition-specific PROM that can both capture what's important to plwALS and be used in economic evaluation. This study has two key aims: 1) to produce a novel PROM for measuring HRQoL in plwALS (PROQuALS). 2) to value a set of items from the novel PROM to generate an associated preference-weighted measure (PWM) that will enable utility values to be generated.<br><br>METHODS: A mixed-methods study design will be conducted across three stages. Stage 1 involves concept elicitation and the generation of draft PROM content from a robust and comprehensive systematic review of HRQoL in ALS, with input from plwALS. Stage 2 consists of cognitive debriefing of the draft PROM content to ascertain its content validity (Stage 2a), followed by a psychometric survey (Stage 2b) to assess statistical performance. Evidence from Stage 2 will be used to make decisions on the final content and format of the novel PROM. Stage 3 will involve valuation and econometric modeling using health economics methods to generate preference weights, so a PWM derived from the novel PROM can be used in the cost-effectiveness analyses of treatments. Patient and clinical advisory groups will have critical, collaborative input throughout the project.<br><br>DISCUSSION: The novel PROM will be designed to comprehensively assess important aspects of HRQoL to plwALS and to quantify HRQoL in terms of subjective impact. The PROQuALS measure will be available for use in research and healthcare settings. The associated PWM component will extend and enable the use of PROQuALS in cost-effective analyses of new treatments for ALS.<br><br>TRIAL REGISTRATION: Not applicable.}, }
@article {pmid39211392, year = {2024}, author = {Matsuo, K and Nagamatsu, J and Nagata, K and Umeda, R and Shiota, T and Morimoto, S and Suzuki, N and Aoki, M and Okano, H and Nakamori, M and Nishihara, H}, title = {Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP [N345K/+])-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1357204}, pmid = {39211392}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP [N345K/+] carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP [K263E/K263E] and TARDBP [G295S/G295S]) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP [N345K/+] carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP [N345K/+])-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP [N345K/+] carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.}, }
@article {pmid39209824, year = {2024}, author = {Vieira de Sá, R and Sudria-Lopez, E and Cañizares Luna, M and Harschnitz, O and van den Heuvel, DMA and Kling, S and Vonk, D and Westeneng, HJ and Karst, H and Bloemenkamp, L and Varderidou-Minasian, S and Schlegel, DK and Mars, M and Broekhoven, MH and van Kronenburg, NCH and Adolfs, Y and Vangoor, VR and de Jongh, R and Ljubikj, T and Peeters, L and Seeler, S and Mocholi, E and Basak, O and Gordon, D and Giuliani, F and Verhoeff, T and Korsten, G and Calafat Pla, T and Venø, MT and Kjems, J and Talbot, K and van Es, MA and Veldink, JH and van den Berg, LH and Zelina, P and Pasterkamp, RJ}, title = {ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7484}, pmid = {39209824}, issn = {2041-1723}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *Ataxin-2/genetics/metabolism ; Humans ; Animals ; *Peptides/metabolism/genetics ; Mice ; *Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/pathology ; *Disease Models, Animal ; *Mice, Transgenic ; DNA-Binding Proteins/genetics/metabolism ; Phenotype ; Male ; Female ; Mitochondria/metabolism ; Neurites/metabolism ; }, abstract = {Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43[Tg]-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.}, }
@article {pmid39210549, year = {2024}, author = {Yeo, CJJ and Simmons, Z}, title = {Caring for people living with ALS in Korea: challenges and possible paths forward.}, journal = {Muscle &amp; nerve}, volume = {70}, number = {5}, pages = {881-883}, doi = {10.1002/mus.28241}, pmid = {39210549}, issn = {1097-4598}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy ; Republic of Korea/epidemiology ; Caregivers/psychology ; }, }
@article {pmid39210467, year = {2024}, author = {Faggioli, G and Menotti, L and Marchesin, S and Chió, A and Dagliati, A and de Carvalho, M and Gromicho, M and Manera, U and Tavazzi, E and Di Nunzio, GM and Silvello, G and Ferro, N}, title = {An extensible and unifying approach to retrospective clinical data modeling: the BrainTeaser Ontology.}, journal = {Journal of biomedical semantics}, volume = {15}, number = {1}, pages = {16}, pmid = {39210467}, issn = {2041-1480}, support = {101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; 101017598//Horizon 2020 Framework Programme/ ; }, mesh = {*Biological Ontologies ; Humans ; Retrospective Studies ; Amyotrophic Lateral Sclerosis ; Multiple Sclerosis ; Semantics ; }, abstract = {Automatic disease progression prediction models require large amounts of training data, which are seldom available, especially when it comes to rare diseases. A possible solution is to integrate data from different medical centres. Nevertheless, various centres often follow diverse data collection procedures and assign different semantics to collected data. Ontologies, used as schemas for interoperable knowledge bases, represent a state-of-the-art solution to homologate the semantics and foster data integration from various sources. This work presents the BrainTeaser Ontology (BTO), an ontology that models the clinical data associated with two brain-related rare diseases (ALS and MS) in a comprehensive and modular manner. BTO assists in organizing and standardizing the data collected during patient follow-up. It was created by harmonizing schemas currently used by multiple medical centers into a common ontology, following a bottom-up approach. As a result, BTO effectively addresses the practical data collection needs of various real-world situations and promotes data portability and interoperability. BTO captures various clinical occurrences, such as disease onset, symptoms, diagnostic and therapeutic procedures, and relapses, using an event-based approach. Developed in collaboration with medical partners and domain experts, BTO offers a holistic view of ALS and MS for supporting the representation of retrospective and prospective data. Furthermore, BTO adheres to Open Science and FAIR (Findable, Accessible, Interoperable, and Reusable) principles, making it a reliable framework for developing predictive tools to aid in medical decision-making and patient care. Although BTO is designed for ALS and MS, its modular structure makes it easily extendable to other brain-related diseases, showcasing its potential for broader applicability.Database URL https://zenodo.org/records/7886998 .}, }
@article {pmid39209890, year = {2024}, author = {Prabhakaran, A and Thirumoorthi, P and Sri Dhivya Krishnan, K}, title = {Design and development of an intelligent zone based master electronic control unit for power optimization in electric vehicles.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {20142}, pmid = {39209890}, issn = {2045-2322}, abstract = {The development of electric vehicles (EVs) has been incremental because EVs satisfy a significant demand for energy sources. Electronic control unit (ECU) is an important component that processes the electric signals received from various sensors for generating the control signals for the actuators. Automotive control systems were initially operated manually throughout the automotive revolution based on the responses of input signals received from ECUs and drivers. Most of the functions in EV are controlled by the ECU and every ECU consumes power at all times even if it is not in use. The larger power consumption of passive ECUs like adaptive lighting systems (ALS), automatic wiper systems (AWS) brake light systems (BLS), etc., affect the life of ECUs and the range of EVs. This article is primarily concerned with limiting power consumption by switching the power supply to the passive ECUs based on their requirements. Hence, to achieve the objective, the intelligent zone (i-zone) based master ECU is triggered to activate the slave ECUs. Designing suites including Proteus and KiCAD were used for designing the circuits including master as well as slave ECU. This prototype is built using three secondary ECUs such as ALS &amp; AWS and BLS which are controlled using i-zone-based master ECU. The performance of this implemented design is evaluated, and it is discovered that almost 40% of the battery consumption is reduced. This i-zone-based master ECU and all its slave ECUs manage power while ensuring the safety and reliability of EVs.}, }
@article {pmid39208794, year = {2024}, author = {Choi, ES and Hnath, B and Sha, CM and Dokholyan, NV}, title = {Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.}, journal = {Structure (London, England : 1993)}, volume = {32}, number = {10}, pages = {1776-1792.e5}, pmid = {39208794}, issn = {1878-4186}, support = {R35 GM134864/GM/NIGMS NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Male ; Mice ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Brain/metabolism ; Cell Cycle Proteins ; Models, Molecular ; *Motor Neurons/metabolism ; Muscle, Skeletal/metabolism ; *Protein Binding ; *Protein Multimerization ; *Septins/metabolism/genetics/chemistry ; Spinal Cord/metabolism ; *Superoxide Dismutase-1/metabolism/genetics/chemistry ; }, abstract = {Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.}, }
@article {pmid39207717, year = {2024}, author = {Ling, Y and Crotti, A}, title = {Emerging Microglial Therapies and Targets in Clinical Trial.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {623-637}, pmid = {39207717}, issn = {2190-5215}, mesh = {*Microglia/metabolism ; Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/drug therapy/therapy/metabolism ; Nervous System Diseases/drug therapy/metabolism ; }, abstract = {Modulation of microglia function for treatment of neurodegenerative and neuropsychiatric disorders is an emerging field of neuroscience drug development. This is largely attributed to human genetic association studies combined with biological evidence indicating that the innate immune system acts as a causal contributor superimposed on the reactive component of neuronal loss in neurological dysfunction. The identification of disease risk gene variants that encode immune-modulatory proteins in microglia provides tools to evaluate how microglia cellular function or dysfunction affect neuronal health. The development of clinical stage therapeutic compounds that modify myeloid cell function enables us to investigate how modulating microglia function could become a transformational approach to mitigate neurological disorders. Improving our ability to boost microglia-promoting homeostatic and reparative functions hopefully will translate into achieving a better outcome for patients affected by neurological diseases. In this chapter, we aim to provide an overview of the microglial emerging therapies and targets being studied in current clinical trials.}, }
@article {pmid39207711, year = {2024}, author = {Holtman, IR and Glass, CK and Nott, A}, title = {Interpretation of Neurodegenerative GWAS Risk Alleles in Microglia and their Interplay with Other Cell Types.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {531-544}, pmid = {39207711}, issn = {2190-5215}, mesh = {Humans ; *Microglia/metabolism ; *Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics ; *Genetic Predisposition to Disease ; Alleles ; Alzheimer Disease/genetics ; }, abstract = {Microglia have been implicated in numerous neurodegenerative and neuroinflammatory disorders; however, the causal contribution of this immune cell type is frequently debated. Genetic studies offer a unique vantage point in that they infer causality over a secondary consequence. Genome-wide association studies (GWASs) have identified hundreds of loci in the genome that are associated with susceptibility to neurodegenerative disorders. GWAS studies implicate microglia in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and to a lesser degree suggest a role for microglia in vascular dementia (VaD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and other neurodegenerative and neuropsychiatric disorders. The contribution and function of GWAS risk loci on disease progression is an ongoing field of study, in which large genomic datasets, and an extensive framework of computational tools, have proven to be crucial. Several GWAS risk loci are shared between disorders, pointing towards common pleiotropic mechanisms. In this chapter, we introduce key concepts in GWAS and post-GWAS interpretation of neurodegenerative disorders, with a focus on GWAS risk genes implicated in microglia, their interplay with other cell types and shared convergence of GWAS risk loci on microglia.}, }
@article {pmid39207709, year = {2024}, author = {Awogbindin, I and Wanklin, M and Verkhratsky, A and Tremblay, M&#xc8;}, title = {Microglia in Neurodegenerative Diseases.}, journal = {Advances in neurobiology}, volume = {37}, number = {}, pages = {497-512}, pmid = {39207709}, issn = {2190-5215}, mesh = {*Microglia/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism ; Alzheimer Disease/metabolism/pathology ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology/physiopathology ; Animals ; Parkinson Disease/metabolism ; }, abstract = {Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, although the majority of cases are sporadic and linked to various environmental risk factors, with yet an unknown aetiology. Neuroglial changes are fundamental and often lead to the pathophysiology of neurodegenerative diseases. In particular, microglial cells, which are essential for maintaining CNS health, become compromised in their physiological functions with the exposure to environmental risk factors, genetic variants or mutations, as well as disease pathology. In this chapter, we cover the contribution of neuroglia, especially microglia, to several neurodegenerative diseases, including Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, infectious disease-associated neurodegeneration, and metal-precipitated neurodegeneration. Future research perspectives for the field pertaining to the therapeutic targeting of microglia across these disease conditions are also discussed.}, }
@article {pmid39207520, year = {2024}, author = {Bjelica, B and Petri, S}, title = {Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6508-6513}, pmid = {39207520}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy/diagnosis ; *Sialorrhea/etiology/therapy/diagnosis ; *Deglutition Disorders/etiology/therapy/diagnosis/physiopathology ; Disease Management ; }, abstract = {The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.}, }
@article {pmid39207268, year = {2024}, author = {Han, H and Guo, G and Zhang, S and Peng, R and Xia, C}, title = {Reduced Surface Area for the Oxygen Reduction Reaction in Porous Electrode via Electrical Conductivity Relaxation.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {68}, pages = {e202402785}, doi = {10.1002/chem.202402785}, pmid = {39207268}, issn = {1521-3765}, support = {(2021YFB4001401//the National Key R&amp;D Program of China/ ; 52272247//the National Natural Science Foundation of China/ ; }, abstract = {Oxygen reduction reaction (ORR) performance of porous electrodes is critical for solid oxide fuel cells (SOFCs). However, the effects of gas diffusion on the ORR in porous media need further investigation, although some issues, such as nonthermal surface oxygen exchange, have been attributed to gas diffusion. Herein, La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF) with various porosity, pore radii, and gas permeability were investigated via the electrical conductivity relaxation method and analysed via the distributed of characteristic time (DCT) model. The ORR is revealed with three characteristic times, which are gas diffusion, oxygen exchange via the surface corresponding to small pores, and oxygen exchange to large pores. Gas diffusion delays the oxygen surface exchange reaction, resulting in a very low chemical oxygen surface exchange coefficient compared with that obtained with dense samples under the assumption that all the surfaces are active for the ORR. Reduced surface area is thus defined to quantitatively represent the gas diffusion effects. The reduced surface area increases with increasing gas permeability, demonstrating the importance of electrode engineering for fast gas transport. Moreover, reduced surface area is suggested for replacing the specific surface area to calculate the electrode polarization impedance via the ALS model.}, }
@article {pmid39206899, year = {2024}, author = {Ma, J and Liu, J and Chen, S and Zhang, W and Wang, T and Cao, M and Yang, Y and Du, Y and Cui, G and Du, Z}, title = {Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {8}, pages = {291}, doi = {10.31083/j.fbl2908291}, pmid = {39206899}, issn = {2768-6698}, support = {81602893//National Natural Science Foundation of China (NSFC)/ ; ZR2015YL049//Natural Science Foundation of Shandong Province/ ; ZR2021MH218//Natural Science Foundation of Shandong Province/ ; ZR2022MH184//Natural Science Foundation of Shandong Province/ ; 202104020224//Shandong Province Medical and Health Technology Development Plan/ ; 202312010854//Shandong Province Medical and Health Technology Development Plan/ ; Z-2023114//Shandong Province Traditional Chinese Medicine Science and Technology Plan/ ; 202328074//Jinan Science and Technology Plan/ ; }, mesh = {*Ferroptosis/physiology ; Humans ; *Neurodegenerative Diseases/metabolism/physiopathology ; *Iron/metabolism ; Animals ; Neurons/metabolism/pathology ; }, abstract = {Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.}, }
@article {pmid39206288, year = {2024}, author = {Cui, Y and Li, C and Ke, B and Xiao, Y and Wang, S and Jiang, Q and Zheng, X and Lin, J and Huang, J and Shang, H}, title = {Protective role of serum albumin in dementia: a prospective study from United Kingdom biobank.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1458184}, pmid = {39206288}, issn = {1664-2295}, abstract = {BACKGROUND: A number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis.<br><br>METHODS: Utilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis.<br><br>RESULTS: Our results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta&#x2009;=&#x2009;-0.024, SE&#x2009;=&#x2009;0.004, p&#x2009;<&#x2009;0.001). Subgroup and interaction analyses highlighted the impact of factors like body mass index (BMI), age, and alcohol consumption on this relationship. Specifically, participants with higher BMI, younger age, or lower alcohol intake exhibited a stronger protective effect. On the other hand, a higher baseline level of urine microalbumin was connected to a slight increase in dementia risk (beta&#x2009;=&#x2009;0.003, SE&#x2009;=&#x2009;3.30E-04, p&#x2009;<&#x2009;0.001). No significant associations were found between albumin levels and the risk of PD or ALS.<br><br>CONCLUSION: Our study underscores the potential role of serum albumin as a biomarker associated with reduced dementia risk. These findings contribute valuable insights into the understanding of albumin's impact on NDDs, suggesting its utility as a biomarker for dementia in clinical settings and informing future therapeutic strategies in clinical trials.}, }
@article {pmid39206217, year = {2024}, author = {Uzelac, Z and Schwäble, B and Dorst, J and Rosenbohm, A and Wollinsky, K and Wurster, CD and Steinbreier, JS and Ludolph, AC}, title = {Pattern of pareses in 5q-spinal muscular atrophy.}, journal = {Therapeutic advances in neurological disorders}, volume = {17}, number = {}, pages = {17562864241263420}, pmid = {39206217}, issn = {1756-2856}, abstract = {BACKGROUND: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring.<br><br>METHODS: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6&#x2009;&#xb1;&#x2009;15.2&#x2009;years) were included in the study. Most patients had SMA type II (n&#x2009;=&#x2009;28) or SMA type III (n&#x2009;=&#x2009;28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system.<br><br>RESULTS: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5-3.5); lower limbs: 1.5 (0.5-3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5-2.6); p&#x2009;<&#x2009;0.001; lower limbs: 0.5 (0.5-1.5); p&#x2009;<&#x2009;0.001). Thenar muscles were stronger than other small hand muscles (3.0 (2.0-3.5) vs 3.0 (1.5-3.5); p&#x2009;=&#x2009;0.004). Muscles had more strength in upper (2.3 (1.5-3.1)) compared to lower limbs (1.1 (0.5-2.3); p&#x2009;<&#x2009;0.001) and in flexors compared to extensors.<br><br>CONCLUSION: We identified a specific pattern of muscle paresis in SMA which is different from the pattern of paresis in ALS and SBMA. As a rule of thumb, the pattern of pareses is similar, but not identical to ALS in distal, but different in proximal muscle groups.}, }
@article {pmid39205388, year = {2024}, author = {Jafarinia, H and Van der Giessen, E and Onck, PR}, title = {C9orf72 polyPR interaction with the nuclear pore complex.}, journal = {Biophysical journal}, volume = {123}, number = {20}, pages = {3533-3539}, pmid = {39205388}, issn = {1542-0086}, mesh = {*Nuclear Pore/metabolism/chemistry ; *C9orf72 Protein/genetics/metabolism/chemistry ; *Molecular Dynamics Simulation ; Nuclear Pore Complex Proteins/metabolism/chemistry/genetics ; Protein Binding ; Saccharomyces cerevisiae/metabolism/genetics ; Active Transport, Cell Nucleus ; Humans ; }, abstract = {The C9orf72 gene associated with amyotrophic lateral sclerosis/frontotemporal dementia is translated to five dipeptide repeat proteins, among which poly-proline-arginine (PR) is the most toxic in cell and animal models, contributing to a variety of cellular defects. It has been proposed that polyPR disrupts nucleocytoplasmic transport (NCT) through several mechanisms including accumulation in the nuclear pore complex (NPC), accumulation in the nucleolus, and direct interactions with transport receptors. The NPC, which is the key regulator of transport between the cytoplasm and nucleus, plays a central role in these suggested mechanisms. Exploring polyPR interaction with the NPC provides valuable insight into the molecular details of polyPR-mediated NCT defects. To address this, we use coarse-grained molecular dynamics models of polyPR and the yeast NPC lined with intrinsically disordered FG-nucleoporins (FG-Nups). Our findings indicate no aggregation of polyPR within the NPC or permanent binding to FG-Nups. Instead, polyPR translocates through the NPC, following a trajectory through the central low-density region of the pore. In the case of longer polyPRs, we observe a higher energy barrier for translocation and a narrower translocation channel. Our study shows that polyPR and FG-Nups are mainly engaged in steric interactions inside the NPC with only a small contribution of specific cation-pi, hydrophobic, and electrostatic interactions, allowing polyPR to overcome the entropic barrier of the NPC in a size-dependent manner.}, }
@article {pmid39204741, year = {2024}, author = {Xu, X and Zhao, B and Shen, B and Qi, Z and Wang, J and Cui, H and Li, B and Chen, S and Wang, G and Liu, X}, title = {Using RNA-Seq Analysis to Select Key Genes Related to Seed Dormancy in ALS-Inhibiting Resistant Descurainia sophia with Pro-197-Thr Mutation.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {16}, pages = {}, pmid = {39204741}, issn = {2223-7747}, support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; 2022KJCXZX-LYS-13//HAAFS Science and Technology Innovation Special Project/ ; }, abstract = {Flixweed (Descurainia sophia) is a weed that seriously affects wheat fields in China. Over the past 20 years, it has evolved resistance to the herbicide tribenuron-methyl. In the present study, a resistant D. sophia population with a Pro-197-Thr mutation of acetolactate synthetase (ALS) was found to have a resistance index of 457.37 for tribenuron-methyl. Under the same growth conditions, the seeds of resistant (R) and susceptible (S) populations exhibited similar vitality but the germination rates of R seeds were higher than those of S seeds. This result demonstrated that seed dormancy periods were shorter in the R seeds. RNA-Seq transcriptome analysis was then used to choose candidate genes that could regulate seed dormancy pathways in the R population. A total of 504,976,046 clean reads were selected from nine RNA-Seq libraries and assembled into 79,729 unigenes. Among these, 33,476 unigenes were assigned to 51 GO subgroups, and 26,117 unigenes were assigned to 20 KEGG secondary metabolic pathways. Next, 2473 differentially expressed genes (DEGs) were divided into three groups, as follows: G-24 h (germinating seeds) vs. D (dormant seeds); G-48 h (germinated seeds) vs. D; and G-48 h vs. G-24 h. From these 2473 DEGs, 8 were selected as candidate dormancy unigenes for the R population if their expression levels continuously decreased during the seed germination progress and their functional annotations were related to plant seed dormancy. One candidate unigene was annotated as CYP707A2; two unigenes were annotated as the transcription factors TGA4 and TGA2; one unigene was annotated as the cystathionine beta-synthase gene; and four unigenes could not be annotated as any gene listed in the six public databases. However, qRT-PCR-validated results showed that, during the germination of R seeds, the expression of the three candidate unigenes first decreased and then increased, indicating that they may have other growth-regulating functions in R populations. In brief, the dormancy function of the eight candidate dormancy unigenes needs to be further studied.}, }
@article {pmid39204338, year = {2024}, author = {O'Neill, R and Yoo, O and Burcham, P and Lim, LY}, title = {Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.}, journal = {Pharmaceutics}, volume = {16}, number = {8}, pages = {}, pmid = {39204338}, issn = {1999-4923}, support = {000990//Australian Government Research Training Program, Stan Perron Charitable Foundation/ ; }, abstract = {Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.}, }
@article {pmid39203762, year = {2024}, author = {Zarco-Martín, MT and Freire, C and Andreo-López, MC and Leyva-Martínez, S and Fernández-Soto, ML}, title = {Malnutrition in Amyotrophic Lateral Sclerosis: Insights from Morphofunctional Assessment and Global Leadership Initiative on Malnutrition Criteria.}, journal = {Nutrients}, volume = {16}, number = {16}, pages = {}, pmid = {39203762}, issn = {2072-6643}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; Female ; Male ; *Malnutrition/epidemiology/diagnosis ; Middle Aged ; Aged ; Cross-Sectional Studies ; *Nutrition Assessment ; Hand Strength ; Prevalence ; Nutritional Status ; Electric Impedance ; Severity of Illness Index ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease frequently accompanied by malnutrition due to weight loss, increased energy expenditure, and muscle mass loss. This study aimed to evaluate morphofunctional assessment tools as predictors of malnutrition and to investigate their relationship with muscle status and disease severity in ALS patients. A cross-sectional study was conducted with 45 ALS patients at the San Cecilio University Hospital in Granada. Malnutrition was assessed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. Morphofunctional assessment was performed using Bioimpedance Vectorial Analysis (BIVA), handgrip strength (HGS), and Short Physical Performance Battery (SPPB). Malnutrition prevalence was 38% according to GLIM criteria. Significant differences were observed between malnourished and non-malnourished groups in age (70 ± 9 vs. 62 ± 10 years, p = 0.01), sex (female prevalence: 58.8% vs. 25.0%, p = 0.02), dysphagia prevalence (83% vs. 29%, p < 0.001), PEG/PRG use (35.3% vs. 3.6%, p = 0.01), and ALSFRS-R scores (30 ± 12 vs. 34 ± 12, p = 0.02). Malnourished patients had lower values in anthropometric measurements, muscle mass obtained by BIVA, and phase angle (PA) (4.05 ± 0.8° vs. 5.09 ± 0.8°, p < 0.001). No significant differences were found in muscle strength or functional status. PA showed significant correlations with muscle strength (r = 0.52, p < 0.001) and muscle mass measures (r = 0.48, p < 0.001). Moreover, PA was associated with poorer disease progression and physical performance. In our sample, BIVA metrics such as PA (<4.3°), SPA (<-0.8), body cell mass (<9.2 kg/m), and extracellular water (>49.75%) were identified as malnutrition risk factors. The study underscores the critical importance of comprehensive morphofunctional assessment and the use of advanced diagnostic criteria, for early identification and intervention in malnutrition among people with ALS. Further research is warranted to validate these findings and develop targeted nutritional strategies into routine clinical practice.}, }
@article {pmid39202683, year = {2024}, author = {Gianferrari, G and Zucchi, E and Martinelli, I and Simonini, C and Fini, N and Ferro, S and Mercati, A and Ferri, L and Filippini, T and Vinceti, M and Mandrioli, J}, title = {Trends in Hospital Admissions for Patients with Amyotrophic Lateral Sclerosis: Insights from a Retrospective Cohort Study in a Province in Northern Italy.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {8}, pages = {}, pmid = {39202683}, issn = {2075-1729}, support = {//Servizio sanitario dell'Emilia-Romagna/ ; not available//Emilia Romagna Regional Health Authority/ ; }, abstract = {ALS is characterized by a highly heterogeneous course, ranging from slow and uncomplicated to rapid progression with severe extra-motor manifestations. This study investigated ALS-related hospitalizations and their connection to clinical aspects, comorbidities, and prognosis. We performed a retrospective cohort study including patients residing in Modena, Italy, newly diagnosed between 2007 and 2017 and followed up until 31 December 2022. Data were obtained from the Emilia Romagna ALS registry, regional hospitals, and medical records. Among the 249 patients, there were 492 hospital admissions, excluding those for diagnostic purposes; 63% of the patients had at least one hospitalization post-diagnosis, with an average stay of 19.90 ± 23.68 days. Younger patients were more likely to be hospitalized multiple times and experienced longer stays (44.23 ± 51.71 days if <65 years; 26.46 ± 36.02 days if older, p < 0.001). Patients who were hospitalized at least once more frequently underwent gastrostomy (64.97%) or non-invasive (66.24%) and invasive (46.50%) ventilation compared to those never hospitalized (21.74%, 31.52%, 13.04%, respectively, p < 0.001 for all). Emergency procedures led to longer hospitalizations (62.84 ± 48.91 days for non-invasive ventilation in emergencies vs. 39.88 ± 46.46 days electively, p = 0.012). Tracheostomy-free survival was not affected by hospitalizations. In conclusion, younger ALS patients undergo frequent and prolonged hospitalizations, especially after emergency interventions, although these do not correlate with reduced survival.}, }
@article {pmid39201793, year = {2024}, author = {Martin, LJ and Koh, SJ and Price, A and Park, D and Kim, BW}, title = {Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201793}, issn = {1422-0067}, support = {NS34100/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Cell Nucleus/metabolism ; Disease Models, Animal ; *DNA Damage ; *Induced Pluripotent Stem Cells/metabolism ; Mice, Transgenic ; *Motor Neurons/metabolism/pathology ; NADPH Oxidases/metabolism/genetics ; *Oxidative Stress ; Phenotype ; Spinal Cord/metabolism/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.}, }
@article {pmid39201731, year = {2024}, author = {Fang, C and Wu, J and Liang, W}, title = {Systematic Investigation of Aluminum Stress-Related Genes and Their Critical Roles in Plants.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201731}, issn = {1422-0067}, support = {242102111164; 222301420106//Key R&amp;D and Promotion Projects in Henan Province; Henan Science &amp; Technology Research and Development Plan Joint Fund/ ; }, mesh = {*Aluminum/toxicity ; *Stress, Physiological/genetics ; *Gene Expression Regulation, Plant/drug effects ; Plant Proteins/genetics/metabolism ; Zea mays/genetics/growth &amp; development/metabolism/drug effects ; Plants/genetics/metabolism/drug effects ; Genes, Plant ; }, abstract = {Aluminum (Al) stress is a dominant obstacle for plant growth in acidic soil, which accounts for approximately 40-50% of the world's potential arable land. The identification and characterization of Al stress response (Al-SR) genes in Arabidopsis, rice, and other plants have deepened our understanding of Al's molecular mechanisms. However, as a crop sensitive to acidic soil, only eight Al-SR genes have been identified and functionally characterized in maize. In this review, we summarize the Al-SR genes in plants, including their classifications, subcellular localizations, expression organs, functions, and primarily molecular regulatory networks. Moreover, we predict 166 putative Al-SR genes in maize based on orthologue analyses, facilitating a comprehensive understanding of the impact of Al stress on maize growth and development. Finally, we highlight the potential applications of alleviating Al toxicity in crop production. This review deepens our understanding of the Al response in plants and provides a blueprint for alleviating Al toxicity in crop production.}, }
@article {pmid39201466, year = {2024}, author = {Strong, MJ and McLellan, C and Kaplanis, B and Droppelmann, CA and Junop, M}, title = {Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201466}, issn = {1422-0067}, support = {201806SOP-411481/CAPMC/CIHR/Canada ; not applicable//Temerty Family Foundation/ ; }, mesh = {*DNA-Binding Proteins/metabolism/chemistry ; Humans ; *SARS-CoV-2/metabolism/chemistry ; *Coronavirus Nucleocapsid Proteins/metabolism/chemistry/genetics ; *Protein Domains ; COVID-19/virology/metabolism ; Protein Binding ; Biomolecular Condensates/metabolism/chemistry ; RNA, Viral/metabolism/genetics ; Phosphoproteins/metabolism/chemistry ; Phase Separation ; }, abstract = {The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.}, }
@article {pmid39201350, year = {2024}, author = {Bedja-Iacona, L and Richard, E and Marouillat, S and Brulard, C and Alouane, T and Beltran, S and Andres, CR and Blasco, H and Corcia, P and Veyrat-Durebex, C and Vourc'h, P}, title = {Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {16}, pages = {}, pmid = {39201350}, issn = {1422-0067}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; *Protein Processing, Post-Translational ; *Superoxide Dismutase-1/genetics/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; Protein Serine-Threonine Kinases/metabolism/genetics ; Mutation ; Animals ; Phosphorylation ; Acetylation ; }, abstract = {Post-translational modifications (PTMs) affecting proteins during or after their synthesis play a crucial role in their localization and function. The modification of these PTMs under pathophysiological conditions, i.e., their appearance, disappearance, or variation in quantity caused by a pathological environment or a mutation, corresponds to post-translational variants (PTVs). These PTVs can be directly or indirectly involved in the pathophysiology of diseases. Here, we present the PTMs and PTVs of four major amyotrophic lateral sclerosis (ALS) proteins, SOD1, TDP-43, FUS, and TBK1. These modifications involve acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, and enzymatic cleavage. We list the PTM positions known to be mutated in ALS patients and discuss the roles of PTVs in the pathophysiological processes of ALS. In-depth knowledge of the PTMs and PTVs of ALS proteins is needed to better understand their role in the disease. We believe it is also crucial for developing new therapies that may be more effective in ALS.}, }
@article {pmid39200952, year = {2024}, author = {Schwarzenbacher, L and Wassermann, L and Rezar-Dreindl, S and Reiter, GS and Schmidt-Erfurth, U and Stifter, E}, title = {An Analysis of Ocular Biometrics: A Comprehensive Retrospective Study in a Large Cohort of Pediatric Cataract Patients.}, journal = {Journal of clinical medicine}, volume = {13}, number = {16}, pages = {}, pmid = {39200952}, issn = {2077-0383}, abstract = {Objectives: This study aims to provide a comprehensive analysis of ocular biometric parameters in pediatric patients with cataracts to optimize surgical outcomes. By evaluating various biometric data, we seek to enhance the decision-making process for intraocular lens (IOL) placement, particularly with advanced technologies like femtosecond lasers. Methods: This retrospective comparative study included pediatric patients with cataracts who underwent ocular biometric measurements and cataract extraction with anterior vitrectomy at the Medical University of Vienna between January 2019 and December 2021. Parameters measured included corneal diameter (CD), axial length (AL), corneal thickness (CT) and flat and steep keratometry (Kf and Ks). The study explored the correlations between these parameters and IOL placement. Results: A total of 136 eyes from 68 pediatric patients were included in the study. Significant positive correlations were found between corneal diameter, age and AL. The mean CD was 11.4 mm, mean AL was 19.5 mm, CT was 581.2 ± 51.8 µm, Kf was 7.76 ± 0.55 mm and Ks 7.41 ± 0.59 mm, respectively. Older pediatric patients with larger corneal diameters and longer ALs were more likely to receive in-the-bag IOL implantation. Conversely, younger patients often required alternative IOL placements or remained aphakic. Our data indicated that over 95% of the study population and all patients aged one year and older had a corneal diameter of 10 mm or larger. Conclusions: Detailed ocular biometric analysis is crucial for optimizing both surgical outcomes and postoperative care in pediatric cataract patients. The positive correlations between CD, age and AL underline the importance of individualized surgical planning tailored to each patient's unique anatomical features. Additionally, our findings suggest that the use of a femtosecond laser is both feasible and safe for pediatric patients aged one year and older, potentially offering enhanced surgical precision and improved outcomes.}, }
@article {pmid39200200, year = {2024}, author = {Yoo, JK and Kwon, SH and Yoon, SH and Lee, JE and Jeon, JE and Chung, JH and Lee, SY}, title = {Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200200}, issn = {2227-9059}, abstract = {UNLABELLED: The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients.<br><br>METHODS: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure.<br><br>RESULTS: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases.<br><br>CONCLUSIONS: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results.}, }
@article {pmid39200158, year = {2024}, author = {Zhao, M and Wang, J and Liu, M and Xu, Y and Huang, J and Zhang, Y and He, J and Gu, A and Liu, M and Liu, X}, title = {KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.}, journal = {Biomedicines}, volume = {12}, number = {8}, pages = {}, pmid = {39200158}, issn = {2227-9059}, support = {2016YFC0905100//the National Key Research and Development Program of China/ ; 2021JJ30801//the Natural Science Foundation of Hunan Province, China/ ; kq2202077//the Natural Science Foundation of Changsha, China/ ; CX20230291//the Postgraduate Freedom Explo-ration Project of Central South University/ ; }, abstract = {Mutations in the C-terminal of KIF1A (Kinesin family member 1A) may lead to amyotrophic lateral sclerosis (ALS) through unknown mechanisms that are not yet understood. Using iPSC reprogramming technology and motor neuron differentiation techniques, we generated iPSCs from a healthy donor and two ALS patients with KIF1A mutations (R1457Q and P1688L) and differentiated them into spinal motor neurons (iPSC-MN) to investigate KIF1A-related ALS pathology. Our in vitro iPSC-iMN model faithfully recapitulated specific aspects of the disease, such as neurite fragmentation. Through this model, we observed that these mutations led to KIF1A aggregation at the proximal axon of motor neurons and abnormal accumulation of its transport cargo, LAMP1, resulting in autophagy dysfunction and cell death. RNAseq analysis also indicated that the functions of the extracellular matrix, structure, and cell adhesion were significantly disturbed. Notably, using rapamycin during motor neuron differentiation can effectively prevent motor neuron death.}, }
@article {pmid39199527, year = {2024}, author = {Ail, BE and Ramele, R and Gambini, J and Santos, JM}, title = {An Intrinsically Explainable Method to Decode P300 Waveforms from EEG Signal Plots Based on Convolutional Neural Networks.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199527}, issn = {2076-3425}, support = {ITBACyT-2020//Instituto Tecnol&#xf3;gico de Buenos Aires (ITBA)/ ; }, abstract = {This work proposes an intrinsically explainable, straightforward method to decode P300 waveforms from electroencephalography (EEG) signals, overcoming the black box nature of deep learning techniques. The proposed method allows convolutional neural networks to decode information from images, an area where they have achieved astonishing performance. By plotting the EEG signal as an image, it can be both visually interpreted by physicians and technicians and detected by the network, offering a straightforward way of explaining the decision. The identification of this pattern is used to implement a P300-based speller device, which can serve as an alternative communication channel for persons affected by amyotrophic lateral sclerosis (ALS). This method is validated by identifying this signal by performing a brain-computer interface simulation on a public dataset from ALS patients. Letter identification rates from the speller on the dataset show that this method can identify the P300 signature on the set of 8 patients. The proposed approach achieves similar performance to other state-of-the-art proposals while providing clinically relevant explainability (XAI).}, }
@article {pmid39199512, year = {2024}, author = {Turner, N and Faull, C and Palmer, J and Armstrong, A and Bedford, J and Turner, MR and Wilson, E}, title = {Understanding Quality of Life for People with Motor Neurone Disease Who Use Tracheostomy Ventilation and Family Members: A Scoping Review.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199512}, issn = {2076-3425}, support = {Wilson/Oct21/968-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; }, abstract = {Tracheostomy ventilation (TV) can increase survival time for people living with motor neurone disease (MND); however, the use of TV varies between countries. Concerns regarding anticipated quality of life (QoL) are among the reasons given by healthcare professionals for not recommending this intervention, yet little is known about QoL in this context. This scoping review was conducted to examine the evidence on QoL for those with MND who use TV and family members involved in their care. Using the methodological guidance of the Joanna Briggs Institute, 23 papers were identified for inclusion, and findings were inductively analysed to identify key themes. We found that people living with MND tend to rate QoL post TV more positively than anticipated by healthcare professionals or family members. QoL was found to be related to positive relationships and activities the person could maintain. Feeling able to make a choice and an adequate level of financial resources were also important factors. Family members tended to experience lower QoL, associated with the uncertainty surrounding an emergency procedure and the complexity of subsequently required care. More evidence on QoL from the perspectives of people with MND who use TV is needed to support decision making and inform guidance.}, }
@article {pmid39199498, year = {2024}, author = {Kleinerova, J and McKenna, MC and Finnegan, M and Tacheva, A and Garcia-Gallardo, A and Mohammed, R and Tan, EL and Christidi, F and Hardiman, O and Hutchinson, S and Bede, P}, title = {Clinical, Cortical, Subcortical, and White Matter Features of Right Temporal Variant FTD.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199498}, issn = {2076-3425}, support = {JPND-Cofund-2-2019-1 &amp; HRB EIA-2017-019//HRB/ ; }, abstract = {UNLABELLED: The distinct clinical and radiological characteristics of right temporal variant FTD have only been recently recognized.<br><br>METHODS: Eight patients with right temporal variant FTD were prospectively recruited and underwent a standardised neuropsychological assessment, clinical MRI, and quantitative neuroimaging.<br><br>RESULTS: Our voxelwise grey analyses captured bilateral anterior and mesial temporal grey matter atrophy with a clear right-sided predominance. Bilateral hippocampal involvement was also observed, as well as disease burden in the right insular and opercula regions. White matter integrity alterations were also bilateral in anterior temporal and sub-insular regions with a clear right-hemispheric predominance. Extra-temporal white matter alterations have also been observed in orbitofrontal and parietal regions. Significant bilateral but right-predominant thalamus, putamen, hippocampus, and amygdala atrophy was identified based on subcortical segmentation. The clinical profile of our patients was dominated by progressive indifference, decline in motivation, loss of interest in previously cherished activities, incremental social withdrawal, difficulty recognising people, progressive language deficits, increasingly rigid routines, and repetitive behaviours.<br><br>CONCLUSIONS: Right temporal variant FTD has an insidious onset and may be mistaken for depression at symptom onset. It manifests in a combination of apathy, language, and behavioural features. Quantitative MR imaging captures a characteristic bilateral but right-predominant temporal imaging signature with extra-temporal frontal and parietal involvement.}, }
@article {pmid39199454, year = {2024}, author = {Calma, AD and van den Bos, M and Pavey, N and Santos Silva, C and Menon, P and Vucic, S}, title = {Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.}, journal = {Brain sciences}, volume = {14}, number = {8}, pages = {}, pmid = {39199454}, issn = {2076-3425}, abstract = {Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.}, }
@article {pmid39199265, year = {2024}, author = {Proaño, B and Benlloch, M and Sancho-Castillo, S and Privado, J and Bargues-Navarro, G and Sanchis-Sanchis, CE and Martínez Bolós, P and Carriquí-Suárez, AB and Cubero-Plazas, L and Platero Armero, JL and Escriva, D and Ceron, JJ and Tvarijonaviciute, A and de la Rubia Ortí, JE}, title = {Paraoxonase I Activity and Its Relationship with Nutrition in Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199265}, issn = {2076-3921}, support = {2021-203-003//Catholic University of Valencia San Vicente M&#xe1;rtir/ ; }, abstract = {Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, with oxidative stress playing a key role. Paraoxonase 1 (PON1) is an antioxidant enzyme that may influence ALS progression. This study aimed to establish a predictive model for the influence of PON1 activity on functionality in ALS patients and explore its relationship with nutrition. Methods: In this observational cross-sectional study, 70 ALS patients underwent assessments of PON1 activity, lipid profile, functional capacity, respiratory function, and heart rate variability. A structural equation model was developed to determine the relationships between variables. Nutritional intake was analyzed in 65 patients. Results: The predictive model showed that PON1 activity and LDL levels positively influenced functionality, both directly and indirectly through respiratory capacity. Heart rate variability moderately predicted functionality independently. HDL levels were not significantly associated with functionality. Weak to moderate correlations were found between PON1 activity and intake of certain nutrients, with positive associations for monounsaturated fats and vitamin D, and negative associations for carbohydrates, proteins, and some micronutrients. Conclusions: PON1 activity appears to play an important role in ALS patient functionality, both directly and through effects on respiratory capacity. However, its relationship with nutritional intake was not strongly evident in this sample population.}, }
@article {pmid39199129, year = {2024}, author = {Percio, A and Cicchinelli, M and Masci, D and Summo, M and Urbani, A and Greco, V}, title = {Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {8}, pages = {}, pmid = {39199129}, issn = {2076-3921}, abstract = {Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.}, }
@article {pmid39198773, year = {2024}, author = {Lei, Y and Zhang, X and Liu, H and Xu, Z and Xu, P}, title = {Amyotrophic lateral sclerosis associated with Sjögren's syndrome: a case report.}, journal = {BMC neurology}, volume = {24}, number = {1}, pages = {300}, pmid = {39198773}, issn = {1471-2377}, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/drug therapy/pathology ; *Sjogren's Syndrome/complications/diagnosis/drug therapy/pathology ; }, abstract = {BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals.<br><br>CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sj&#xf6;gren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen.<br><br>CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.}, }
@article {pmid39197801, year = {2025}, author = {Zhan, Y and Huang, J and Tang, X and Du, B and Yang, B}, title = {Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {336}, number = {}, pages = {118741}, doi = {10.1016/j.jep.2024.118741}, pmid = {39197801}, issn = {1872-7573}, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Mice ; *Membrane Proteins/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nucleotidyltransferases/metabolism ; Male ; Signal Transduction/drug effects ; Mice, Transgenic ; Neuroinflammatory Diseases/drug therapy ; Spinal Cord/drug effects/metabolism/pathology ; Disease Models, Animal ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive.<br><br>AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms.<br><br>MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L&#xa0;=&#xa0;5.46&#xa0;mg/ml, SSP-M&#xa0;=&#xa0;10.92&#xa0;mg/ml or SSP-H&#xa0;=&#xa0;16.38&#xa0;mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin &amp; Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1[G93A] NSC-34&#xa0;cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway.<br><br>RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1&#x3b2; mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-&#x3b2; mRNA, but also the levels of cGAS and STING protein in hSOD1[G93A] NSC-34&#xa0;cells.<br><br>CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.}, }
@article {pmid39197036, year = {2025}, author = {Sapaly, D and Cheguillaume, F and Weill, L and Clerc, Z and Biondi, O and Bendris, S and Buon, C and Slika, R and Piller, E and Sundaram, VK and da Silva Ramos, A and Amador, MDM and Lenglet, T and Debs, R and Le Forestier, N and Pradat, PF and Salachas, F and Lacomblez, L and Hesters, A and Borderie, D and Devos, D and Desnuelle, C and Rolland, AS and Periou, B and Vasseur, S and Chapart, M and Le Ber, I and Fauret-Amsellem, AL and Millecamps, S and Maisonobe, T and Leonard-Louis, S and Behin, A and Authier, FJ and Evangelista, T and Charbonnier, F and Bruneteau, G}, title = {Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.}, journal = {Brain : a journal of neurology}, volume = {148}, number = {3}, pages = {788-802}, pmid = {39197036}, issn = {1460-2156}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics ; Humans ; *Cholesterol/metabolism ; *Muscle, Skeletal/metabolism ; Middle Aged ; Male ; Female ; Aged ; Adult ; Niemann-Pick C1 Protein ; Muscle Fibers, Skeletal/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism/genetics ; Carrier Proteins/metabolism/genetics ; Cells, Cultured ; Biological Transport ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidaemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analysed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from 13 ALS patients and 10 asymptomatic ALS-mutation gene carriers compared to 16 control subjects. Using human control primary myotubes, we investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.}, }
@article {pmid39196396, year = {2024}, author = {Radakovic, R and Carroll, A and Altiero, A and Reichwein, C and Walsh, S and Niven, E and Abrahams, S and Simmons, Z}, title = {Self-perceived quality of life, cognitive and behavioural impairment in amyotrophic lateral sclerosis.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6822-6838}, pmid = {39196396}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications/physiopathology ; Male ; *Quality of Life/psychology ; Female ; Middle Aged ; Cross-Sectional Studies ; Aged ; Cognitive Dysfunction/etiology/physiopathology/psychology ; Cohort Studies ; Self Concept ; Mental Disorders/psychology/etiology ; Adult ; }, abstract = {BACKGROUND: Self-perceived quality of life (QoL) is important in amyotrophic lateral sclerosis (ALS). Although caregiver burden and strain have been related to cognitive and behavioural impairment, there has been no comprehensive research looking at these impairments and how they may influence self-perceived QoL subdomains.<br><br>AIMS: To explore how cognitive and behavioural impairment are related to different areas of self-perceived QoL using disease-specific measures.<br><br>METHODS: This was a quantitative, cross-sectional, observational cohort study, utilising existing specialist ALS clinic data. Clinical and demographic variables were available as well as multidimensional measures, ALS-specific QoL Short Form (ALSsQoL-SF) results and the data from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Group comparison and regression analyses were performed.<br><br>RESULTS: Data from 121 participants with ALS were analysed. 61.2% (N&#x2009;=&#x2009;74) had either cognitive and/or behavioural impairment, with 28.9% (N&#x2009;=&#x2009;35) with cognitive impairment (ALSci), 14.1% (N&#x2009;=&#x2009;17) with behavioural impairment (ALSbi) and 18.2% (N&#x2009;=&#x2009;22) with both (ALScbi). 38.8% (N&#x2009;=&#x2009;47) were classified as having no impairments (ALSni). Those with ALSbi had significantly lower QoL in the domains of negative emotions and the interaction with people and the environment compared to those with ALSci and ALSni (ps&#x2009;<&#x2009;0.05). Further, those with ALScbi had significantly lower QoL in the intimacy domains than those with ALSci and ALSni (ps&#x2009;<&#x2009;0.05). Regression analysis showed specific cognitive and behavioural (inclusive of psychosis) predictors associated with specific QoL subdomains.<br><br>CONCLUSIONS: Behavioural impairments effect QoL in specific subdomains, namely relating to internalising (negative emotions) and externalising (interaction with people and the environment subdomains, intimacy).}, }
@article {pmid39194682, year = {2024}, author = {Sacharczuk, M and Mickael, ME and Kubick, N and Kamińska, A and Horbańczuk, JO and Atanasov, AG and Religa, P and Ławiński, M}, title = {The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.}, journal = {Current issues in molecular biology}, volume = {46}, number = {8}, pages = {7846-7861}, pmid = {39194682}, issn = {1467-3045}, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.}, }
@article {pmid39193833, year = {2025}, author = {Jalaiei, A and Asadi, MR and Daneshmandpour, Y and Rezazadeh, M and Ghafouri-Fard, S}, title = {Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.}, journal = {Journal of neurochemistry}, volume = {169}, number = {1}, pages = {e16200}, doi = {10.1111/jnc.16200}, pmid = {39193833}, issn = {1471-4159}, mesh = {Humans ; *Receptors, Nicotinic/genetics ; Mutation/genetics ; Neurodegenerative Diseases/genetics/metabolism ; }, abstract = {The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.}, }
@article {pmid39193573, year = {2024}, author = {Soresi, M and Giannitrapani, L}, title = {Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease.}, journal = {World journal of gastroenterology}, volume = {30}, number = {30}, pages = {3541-3547}, pmid = {39193573}, issn = {2219-2840}, mesh = {Humans ; *Non-alcoholic Fatty Liver Disease/drug therapy/pathology/metabolism ; *Glucagon-Like Peptides/therapeutic use ; Liver/drug effects/pathology/metabolism ; Insulin Resistance ; Drug Therapy, Combination/methods ; Glucagon-Like Peptide 1/agonists/metabolism ; Treatment Outcome ; Hypoglycemic Agents/therapeutic use/pharmacology ; Disease Progression ; Incretins/therapeutic use ; *Glucagon-Like Peptide-1 Receptor Agonists ; }, abstract = {In this editorial, we comment on Yin et al's recently published Letter to the editor. In particular, we focus on the potential use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) alone, but even more so in combination therapy, as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease (MASLD), the new definition of an old condition, non-alcoholic fatty liver disease, which aims to better define the spectrum of steatotic pathology. It is well known that GLP-1RAs, having shown outstanding performance in fat loss, weight loss, and improvement of insulin resistance, could play a role in protecting the liver from progressive damage. Several clinical trials have shown that, among GLP-1RAs, semaglutide is a safe, well-studied therapeutic choice for MASLD patients; however, most studies demonstrate that, while semaglutide can reduce steatosis, including steatohepatitis histological signs (in terms of inflammatory cell infiltration and hepatocyte ballooning), it does not improve fibrosis. Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease. In particular, GLP-1RAs associated with antifibrotic drug therapy, dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis, liver biochemistry, and non-invasive fibrosis tests than monotherapy. Therefore, although to date there are no definitive indications from international drug agencies, there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD, one that will certainly include the use of GLP-1RAs as combination therapy.}, }
@article {pmid39193017, year = {2024}, author = {Chen, X and Cai, L and Fan, W and Yang, Q and Mao, X and Yao, L}, title = {Causal relationships between rheumatoid arthritis and neurodegenerative diseases: a two-sample univariable and multivariable Mendelian randomization study.}, journal = {Frontiers in medicine}, volume = {11}, number = {}, pages = {1439344}, pmid = {39193017}, issn = {2296-858X}, abstract = {BACKGROUND: Observational research has highlighted a potential relationship between rheumatoid arthritis (RA) and neurodegenerative diseases (NDs). However, the confirmation of a causal connection is impeded by the inherent limitations of such studies, including vulnerability to confounding factors and the possibility of reverse causality. This study employs a two-sample Mendelian randomization (MR) approach to assess the causal impact of RA on three NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).<br><br>METHODS: We aggregated data from genome-wide association studies (GWASs) targeting RA or NDs within populations of European descent. Single nucleotide polymorphisms (SNPs) with robust associations to RA were identified as instrumental variables (IVs). To estimate the association between RA and AD, PD, and ALS, we utilized the inverse variance weighted (IVW) method in our univariable MR (UVMR) analysis. Validation of the IVW results ensued through supplementary analyses using MR-Egger and weighted median methods. The multivariable MR (MVMR) analysis was conducted, adjusting for body mass index (BMI), alcohol drinking, and type 2 diabetes mellitus (T2DM).<br><br>RESULTS: The UVMR analysis, based on the IVW method, revealed a significantly positive causal association between RA and late-onset (LO) AD (OR [95% CI] = 1.084 [1.020-1.153]; p = 9.980 &#xd7; 10[-3]), while suggesting a possible inverse relationship with PD (OR [95% CI] = 0.727 [0.563-0.938]; p = 0.014). Our study did not detect any causal connections between RA and early-onset (EO) AD, atypical or mixed (AM) AD, and ALS (all p > 0.05). The MVMR analysis results indicated that after adjusting for alcohol drinking, RA remains a risk factor for LOAD (OR [95% CI] = 1.094 [1.024-1.169]; p = 0.008). However, MVMR analysis revealed no causal connections between RA and PD after adjustments for BMI, alcohol drinking, or T2DM (all p > 0.05). Sensitivity analyses showed no evidence of heterogeneity and horizontal pleiotropy.<br><br>CONCLUSIONS: This research provides genetic evidence indicating that RA potentially causes an increased risk of developing LOAD and PD. Such a revelation underscores the importance for individuals suffering from RA to be vigilant about the potential emergence of LOAD and PD. Ongoing monitoring and prompt detection are essential for successfully managing and intervening in this possible risk.}, }
@article {pmid39192891, year = {2024}, author = {Murtazina, A and Subbotin, D and Kuchina, A and Gilvanova, O and Degterev, D and Shchagina, O and Cherevatova, T and Bulakh, M and Sherstyukova, D and Ryzhkova, O and Kurushina, O and Skoblov, M and Borovikov, A and Kutsev, S}, title = {Asymmetric scapuloperoneal phenotype of MATR3-related distal myopathy: case series.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1414928}, pmid = {39192891}, issn = {1664-8021}, abstract = {Recent research has sparked a discussion on the spectrum of diseases linked to the MATR3 gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM. In this study, we present six patients from four unrelated families affected by VCPDM. Our observations include patients exhibiting both the typical phenotype associated with MATR3-related distal myopathy and rare symptomatic manifestations of the disease. Notably, two cases presented with an asymmetric scapuloperoneal phenotype, leading in one case to an initial misdiagnosis of facioscapulohumeral muscular dystrophy.}, }
@article {pmid39192797, year = {2024}, author = {Luo, RC and Wu, XY and Yu, WW and Zheng, YJ and Wang, D}, title = {[Research progress on the relationship between TRAF6 and neurodegenerative diseases].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {76}, number = {4}, pages = {653-662}, pmid = {39192797}, issn = {0371-0874}, mesh = {Animals ; Humans ; Alzheimer Disease/metabolism/etiology ; Amyotrophic Lateral Sclerosis/metabolism/physiopathology/genetics/etiology ; Multiple Sclerosis/metabolism/physiopathology/etiology ; *Neurodegenerative Diseases/metabolism/etiology ; Parkinson Disease/metabolism/physiopathology ; *TNF Receptor-Associated Factor 6/metabolism/genetics/physiology ; Ubiquitination ; }, abstract = {Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.}, }
@article {pmid39192497, year = {2024}, author = {Lee, I and Garret, MA and Wuu, J and Harrington, EA and Berry, JD and Miller, TM and Harms, M and Benatar, M and Shneider, N}, title = {Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {672-679}, pmid = {39192497}, issn = {2167-9223}, support = {K23 NS131586/NS/NINDS NIH HHS/United States ; R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS092091/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *C9orf72 Protein/genetics ; *Body Mass Index ; *Superoxide Dismutase-1/genetics ; Middle Aged ; *Heterozygote ; Adult ; Cohort Studies ; Genotype ; DNA Repeat Expansion/genetics ; Aged ; }, abstract = {Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3-4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9-4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5-4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers.}, }
@article {pmid39192451, year = {2024}, author = {Yan, Y and Huang, SY and Feng, YJ and Zhao, CY and Sheng, GX and Chen, J and Jiang, JJ and Gao, F and Mao, SS}, title = {[Pediatric amyotrophic lateral sclerosis caused by FUS gene variation in 2 cases].}, journal = {Zhonghua er ke za zhi = Chinese journal of pediatrics}, volume = {62}, number = {9}, pages = {893-895}, doi = {10.3760/cma.j.cn112140-20240315-00184}, pmid = {39192451}, issn = {0578-1310}, mesh = {Female ; Humans ; *Amyotrophic Lateral Sclerosis/genetics ; DNA Mutational Analysis ; Exons ; Fatal Outcome ; Heterozygote ; *Mutation ; *RNA-Binding Protein FUS/genetics ; Child ; Adolescent ; }, }
@article {pmid39191336, year = {2024}, author = {Sirtori, CR and Castiglione, S and Pavanello, C}, title = {Metformin: From diabetes to cancer to prolongation of life.}, journal = {Pharmacological research}, volume = {208}, number = {}, pages = {107367}, doi = {10.1016/j.phrs.2024.107367}, pmid = {39191336}, issn = {1096-1186}, mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; Animals ; *Neoplasms/drug therapy/metabolism ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus/drug therapy/metabolism ; Longevity/drug effects ; Antineoplastic Agents/therapeutic use/pharmacology ; }, abstract = {The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.}, }
@article {pmid39191178, year = {2024}, author = {Ruotolo, G and D'Anzi, A and Giovenale, AMG and Giacometti, C and Ferrari, D and Vulcano, E and D'Asdia, C and Lattante, S and Sabatelli, M and Codazzi, F and Consalez, G and Marano, M and Di Lazzaro, V and Pennuto, M and Vescovi, A and Rosati, J}, title = {Induced pluripotent stem cell production (CSSi019-A)(14432) from an asymptomatic subject carrying a expansion of C9orf72 gene.}, journal = {Stem cell research}, volume = {81}, number = {}, pages = {103540}, doi = {10.1016/j.scr.2024.103540}, pmid = {39191178}, issn = {1876-7753}, mesh = {*Induced Pluripotent Stem Cells/metabolism ; Humans ; *C9orf72 Protein/genetics/metabolism ; Aged ; Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; DNA Repeat Expansion ; Male ; Female ; }, abstract = {One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.}, }
@article {pmid39191031, year = {2024}, author = {He, Q and Wang, Y and Zhao, F and Wei, S and Li, X and Zeng, G}, title = {APE1: A critical focus in neurodegenerative conditions.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {179}, number = {}, pages = {117332}, doi = {10.1016/j.biopha.2024.117332}, pmid = {39191031}, issn = {1950-6007}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Animals ; }, abstract = {The global growth of the aging population has resulted in an increased prevalence of neurodegenerative diseases, characterized by the progressive loss of central nervous system (CNS) structure and function. Given the high incidence and debilitating nature of neurodegenerative diseases, there is an urgent need to identify potential biomarkers and novel therapeutic targets thereof. Apurinic/apyrimidinic endonuclease 1 (APE1), has been implicated in several neurodegenerative diseases, as having a significant role. Abnormal APE1 expression has been observed in conditions including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and epilepsy. However, whether this dysregulation is protective or harmful remains unclear. This review aims to comprehensively review the current understanding of the involvement of APE1 in neurodegenerative diseases.}, }
@article {pmid39190906, year = {2024}, author = {Yu, J and Chen, S and Zhang, H and Zhang, S and Dong, D}, title = {Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.}, journal = {JMIR public health and surveillance}, volume = {10}, number = {}, pages = {e57353}, pmid = {39190906}, issn = {2369-2960}, mesh = {Humans ; China/epidemiology ; *Rare Diseases/epidemiology/economics ; Male ; Adult ; Female ; Cross-Sectional Studies ; Middle Aged ; *Cost of Illness ; Adolescent ; Child ; *Internet ; Child, Preschool ; Young Adult ; Surveys and Questionnaires ; Aged ; Infant ; }, abstract = {BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.<br><br>OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.<br><br>METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.<br><br>RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.<br><br>CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.}, }
@article {pmid39190080, year = {2024}, author = {Jensen, BK}, title = {Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.}, journal = {Advances in neurobiology}, volume = {39}, number = {}, pages = {285-318}, pmid = {39190080}, issn = {2190-5215}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/pathology ; Humans ; *Astrocytes/metabolism ; *Disease Progression ; *Motor Neurons/metabolism/pathology ; *Cell Communication/physiology ; Animals ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a complex disease impacting motor neurons of the brain, brainstem, and spinal cord. Disease etiology is quite heterogeneous with over 40 genes causing the disease and a vast ~90% of patients having no prior family history. Astrocytes are major contributors to ALS, particularly through involvement in accelerating disease progression. Through study of genetic forms of disease including SOD1, TDP43, FUS, C9orf72, VCP, TBK1, and more recently patient-derived cells from sporadic individuals, many biological mechanisms have been identified to cause intrinsic or glial-mediated neurotoxicity to motor neurons. Overall, many of the normally supportive and beneficial roles that astrocytes contribute to neuronal health and survival instead switch to become deleterious and neurotoxic. While the exact pathways may differ based on disease-origin, altered astrocyte-neuron communication is a common feature of ALS. Within this chapter, distinct genetic forms are examined in detail, along with what is known from sporadic patient-derived cells. Overall, this chapter highlights the interplay between astrocytes and neurons in this complex disease and describes the key features underlying: astrocyte-mediated motor neuron toxicity, excitotoxicity, oxidative/nitrosative stress, protein dyshomeostasis, metabolic imbalance, inflammation, trophic factor withdrawal, blood-brain/blood-spinal cord barrier involvement, disease spreading, and the extracellular matrix/cell adhesion/TGF-β signaling pathways.}, }
@article {pmid39189114, year = {2024}, author = {Rivera Flores, IV and Monopoli, K and Jackson, S and Echeverria, D and O'Reilly, D and Brown, RH and Khvorova, A}, title = {Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy.}, journal = {Nucleic acid therapeutics}, volume = {34}, number = {5}, pages = {234-244}, pmid = {39189114}, issn = {2159-3345}, support = {R01 NS104022/NS/NINDS NIH HHS/United States ; S10 OD020012/OD/NIH HHS/United States ; T32 GM135751/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *RNA, Small Interfering/genetics/chemistry ; Humans ; Dogs ; Mice ; Rats ; *Superoxide Dismutase-1/genetics ; *Species Specificity ; Sheep ; Base Pair Mismatch/genetics ; Cell Line ; }, abstract = {Small interfering RNAs (siRNAs) represent a novel class of drugs capable of potent and sustained modulation of genes across various tissues. Preclinical development of siRNAs necessitates assessing efficacy and toxicity in animal models. While identifying therapeutic leads with cross-species activity can expedite development, it may compromise efficacy and be infeasible for certain gene targets. Here, we investigate whether deriving species-active siRNAs from potent human-targeting leads-an approach termed mismatch conversion-can yield potent compounds. We systematically altered potent siRNAs targeting human genes associated with diseases-SOD1 (ALS), JAK1 (inflammation), and HTT (HD)-to generate species-matching variants with full complementarity to their target in NHPs, mice, rats, sheep, and dogs. Variants potency and efficacy were measured in corresponding cell lines. We demonstrate that sequence, position, and number of mismatches significantly influence the ability to generate potent species-active compounds via mismatch conversion. Across tested sequences, mismatch conversion strategy ability to identify a species-active lead varied from 0% to 70%. For SOD1, lead compounds identified from species-focus screening in mouse and dog cells were more potent than leads obtained from mismatch conversion. Thus, a focused screening of therapeutic lead and model compounds may represent a more reliable strategy for the clinical advancement of siRNAs.}, }
@article {pmid39188590, year = {2024}, author = {Roca-Pereira, S and Domínguez, R and Moreno León, I and Colomina, MJ and Martínez Yélamos, A and Martínez Yélamos, S and Povedano, M and Andrés-Benito, P}, title = {Increased CXCL12, a potential CSF biomarker for differential diagnosis of amyotrophic lateral sclerosis.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae271}, pmid = {39188590}, issn = {2632-1297}, abstract = {Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential.}, }
@article {pmid39187524, year = {2024}, author = {Femiano, C and Bruno, A and Gilio, L and Buttari, F and Dolcetti, E and Galifi, G and Azzolini, F and Borrelli, A and Furlan, R and Finardi, A and Musella, A and Mandolesi, G and Storto, M and Centonze, D and Stampanoni Bassi, M}, title = {Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19796}, pmid = {39187524}, issn = {2045-2322}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Female ; Male ; *Disease Progression ; Middle Aged ; *Cytokines/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Aged ; Inflammation/cerebrospinal fluid ; Principal Component Analysis ; Adult ; Prognosis ; Case-Control Studies ; }, abstract = {Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.}, }
@article {pmid39187240, year = {2025}, author = {Lenz, M and Egenolf, P and Menzhausen, J and Heck, V and Perera, A and Eysel, P and Scheyerer, M and Oikonomidis, S}, title = {Clinical Outcome after Endoscopic Facet Denervation in Patients with Chronic Low Back Pain.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {167-175}, doi = {10.1055/a-2348-1186}, pmid = {39187240}, issn = {1864-6743}, mesh = {Humans ; *Low Back Pain/surgery ; *Zygapophyseal Joint/innervation/surgery ; Female ; Male ; Middle Aged ; *Denervation/methods ; Retrospective Studies ; Adult ; Aged ; Chronic Pain/surgery ; Treatment Outcome ; Pain Measurement ; Endoscopy/methods ; Risk Factors ; }, abstract = {In mehreren Studien wurde berichtet, dass Kreuzschmerzen in der Bevölkerung mit bis zu 85% eine hohe Prävalenz aufweisen. Die perkutane Radiofrequenz-Facettengelenkdenervation (PRFD) ist heute der Goldstandard bei der Rhizotomie von chronischen Kreuzschmerzen (CLBP). Bisher veröffentlichte Studien zeigen jedoch kontroverse Ergebnisse über die Wirksamkeit der PRFD. Ziel dieser Studie war es daher, den Einsatz der endoskopischen Facettengelenkdenervation (EJE) zur Behandlung chronischer Kreuzschmerzen zu analysieren und potenzielle Risikofaktoren zu ermitteln, die die Indikationen für den Eingriff einschränken könnten.Wir haben retrospektiv 31 Patienten in die Studie eingeschlossen, die seit mindestens 24 Monaten an chronische Kreuzschmerzen leiden. Alle Patienten wurden einer endoskopischen Facettengelenkdenervation unterzogen und mussten postoperativ ODI-, COMI-, EQ-5D- und VRS-Scores ausfüllen, wobei die Nachbeobachtungszeit mindestens 12 Monate betrug. Zur Analyse der Korrelationen wurden grundlegende Patientendaten erfasst.Bei allen gemessenen klinischen Werten, wie ODI, COMI, EQ-5D und VRS, wurde eine signifikante Verbesserung festgestellt. Während das beste Ergebnis bei der 3-monatigen Nachuntersuchung erzielt wurde, wurde bei der 12-monatigen Nachuntersuchung eine leichte Verschlechterung festgestellt. Im Vergleich zu den präoperativen Scores wurde jedoch ein signifikanter Nutzen festgestellt. 28/31 Patienten (93,3%) berichteten bei der Nachuntersuchung nach 12 Monaten über geringere Schmerzen und waren mit dem Verfahren zufrieden. Älteres Alter und psychiatrische Vorerkrankungen wurden als potenzielle Risikofaktoren identifiziert, die mit einem schlechteren Ergebnis einhergehen. Postoperative Komplikationen wie Hämatome, eine Sensibilitätsstörung und eine vorübergehende Muskelschwäche der unteren Extremitäten wurden selten beobachtet.Die endoskopische Facettengelenkdenervation zeigte eine signifikante Verbesserung der klinischen Ergebnisse und der VRS im Vergleich zu den präoperativen Werten von Patienten mit einer mindestens 12 Monate bestehenden chronischen Kreuzschmerzen vor der Operation. Ältere Patienten und Patienten mit psychiatrischen Vorerkrankungen profitieren weniger von dem Eingriff.}, }
@article {pmid39187176, year = {2025}, author = {Althobaiti, NA}, title = {Heavy metals exposure and Alzheimer's disease: Underlying mechanisms and advancing therapeutic approaches.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115212}, doi = {10.1016/j.bbr.2024.115212}, pmid = {39187176}, issn = {1872-7549}, mesh = {Humans ; *Alzheimer Disease/chemically induced ; *Metals, Heavy/adverse effects ; Animals ; Oxidative Stress/drug effects/physiology ; Environmental Exposure/adverse effects ; Brain/drug effects/metabolism ; }, abstract = {Heavy metals such as lead, cadmium, mercury, and arsenic are prevalent in the environment due to both natural and anthropogenic sources, leading to significant public health concerns. These heavy metals are known to cause damage to the nervous system, potentially leading to a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and attention-deficit hyperactivity disorder (ADHD). The present study examines the complex relationship between heavy metal exposure and AD, focusing on the underlying mechanisms of toxicity and potential therapeutic approaches. This review article highlights how these metals can impair brain function through mechanisms such as oxidative stress, inflammation, and neurotransmitter disruption, ultimately contributing to neurodegenerative diseases like AD. It also addresses the challenges in diagnosing heavy metal-induced cognitive impairments and emphasizes the need for further research to explore effective treatment strategies and preventive measures against heavy metal exposure.}, }
@article {pmid39187026, year = {2024}, author = {Rezaei, K and Mastali, G and Abbasgholinejad, E and Bafrani, MA and Shahmohammadi, A and Sadri, Z and Zahed, MA}, title = {Cadmium neurotoxicity: Insights into behavioral effect and neurodegenerative diseases.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143180}, doi = {10.1016/j.chemosphere.2024.143180}, pmid = {39187026}, issn = {1879-1298}, mesh = {*Cadmium/toxicity ; Humans ; *Neurodegenerative Diseases/chemically induced ; Animals ; Environmental Pollutants/toxicity ; Brain/drug effects/metabolism ; Neurotoxicity Syndromes/etiology ; Neurons/drug effects ; }, abstract = {Cadmium (Cd) induced neurotoxicity has become a growing concern due to its potential adverse effects on the Central Nervous System. Cd is a Heavy Metal (HM) that is released into the environment, through several industrial processes. It poses a risk to the health of the community by polluting air, water, and soil. Cd builds up in the brain and other neural tissues, raising concerns about its effect on the nervous system due to its prolonged biological half-life. Cd can enter into the neurons, hence increasing the production of Reactive Oxygen Species (ROS) in them and impairing their antioxidant defenses. Cd disrupts the Calcium (Ca[2+]) balance in neurons, affects the function of the mitochondria, and triggers cell death pathways. As a result of these pathways, the path to the development of many neurological diseases affected by environmental factors, especially Cd, such as Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) is facilitated. There are cognitive deficits associated with long exposure to Cd. Memory disorders are present in both animals and humans. Cd alters the brain's function and performance in critical periods. There are lifelong consequences of Cd exposure during critical brain development stages. The susceptibility to neurotoxic effects is increased by interactions with a variety of risk factors. Cd poses risks to neuronal function and behavior, potentially contributing to neurodegenerative diseases like Parkinson's disease (PD) and AD as well as cognitive issues. This article offers a comprehensive overview of Cd-induced neurotoxicity, encompassing risk assessment, adverse effect levels, and illuminating intricate pathways.}, }
@article {pmid39185513, year = {2024}, author = {Benatar, M and Macklin, EA and Malaspina, A and Rogers, ML and Hornstein, E and Lombardi, V and Renfrey, D and Shepheard, S and Magen, I and Cohen, Y and Granit, V and Statland, JM and Heckmann, JM and Rademakers, R and McHutchison, CA and Petrucelli, L and McMillan, CT and Wuu, J}, title = {Prognostic Clinical and Biological Markers for Amyotrophic Lateral Sclerosis Disease Progression: Validation and Implications for Clinical Trial Design and Analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39185513}, support = {U54 NS092091/NS/NINDS NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; R01 AG066152/AG/NIA NIH HHS/United States ; U01 NS107027/NS/NINDS NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; P01 NS084974/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 NS109260/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R35 NS097273/NS/NINDS NIH HHS/United States ; T32 AG076411/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.<br><br>METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75[ECD], plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.<br><br>FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ~0.5 and 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ~25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75[ECD], and plasma miR-181ab is more limited.<br><br>INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.<br><br>FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).}, }
@article {pmid39185360, year = {2024}, author = {Di Lazzaro, V and Ranieri, F and Doretti, A and Boscarino, M and Maderna, L and Colombo, E and Soranna, D and Zambon, A and Ticozzi, N and Musumeci, G and Capone, F and Silani, V}, title = {Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial.}, journal = {The Lancet regional health. Europe}, volume = {45}, number = {}, pages = {101019}, pmid = {39185360}, issn = {2666-7762}, abstract = {BACKGROUND: Enhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.<br><br>METHODS: In this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.<br><br>FINDINGS: Forty participants were randomly assigned to real (n&#xa0;=&#xa0;21) or placebo stimulation (n&#xa0;=&#xa0;19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean&#xa0;&#xb1;&#xa0;Standard deviation; Real: 1.02&#xa0;&#xb1;&#xa0;0.62, Sham: 1.02&#xa0;&#xb1;&#xa0;0.57, p-value&#xa0;=&#xa0;1.00) and treatment period (Real: 0.90&#xa0;&#xb1;&#xa0;0.55, Sham: 0.94&#xa0;&#xb1;&#xa0;0.55, p-value&#xa0;=&#xa0;0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio&#xa0;=&#xa0;0.27 95% Confidence interval 0.09-0.80, p-value&#xa0;=&#xa0;0.019).<br><br>INTERPRETATION: tSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.<br><br>FUNDING: The "Fondazione 'Nicola Irti' per le opere di carit&#xe0; e di cultura", Rome, Italy, supported present study.}, }
@article {pmid39184484, year = {2024}, author = {Ozceylan, O and Sezgin-Bayindir, Z}, title = {Current Overview on the Use of Nanosized Drug Delivery Systems in the Treatment of Neurodegenerative Diseases.}, journal = {ACS omega}, volume = {9}, number = {33}, pages = {35223-35242}, pmid = {39184484}, issn = {2470-1343}, abstract = {Neurodegenerative diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, prion disease, and Huntington's disease, present a growing health concern as human life expectancy increases. Despite this, effective treatments to halt disease progression remain elusive due to various factors, including challenges in drug delivery across physiological barriers like the blood-brain barrier and patient compliance issues leading to treatment discontinuation. In response, innovative treatment approaches leveraging noninvasive techniques with higher patient compliance are emerging as promising alternatives. This Review aims to synthesize current treatment options and the challenges encountered in managing neurodegenerative diseases, while also exploring innovative treatment modalities. Specifically, noninvasive strategies such as intranasal administration and nanosized drug delivery systems are gaining prominence for their potential to enhance treatment efficacy and patient adherence. Nanosized drug delivery systems, including liposomes, polymeric micelles, and nanoparticles, are evaluated within the context of outstanding studies. The advantages and disadvantages of these approaches are discussed, providing insights into their therapeutic potential and limitations. Through this comprehensive examination, this Review contributes to the ongoing discourse surrounding the development of effective treatments for neurodegenerative diseases.}, }
@article {pmid39184100, year = {2024}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-4750719/v1}, pmid = {39184100}, issn = {2693-5015}, abstract = {Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.}, }
@article {pmid39183919, year = {2024}, author = {Ma, S and Cao, Y and Shi, YF and Shang, C and He, L and Liu, ZP}, title = {Data-driven discovery of active phosphine ligand space for cross-coupling reactions.}, journal = {Chemical science}, volume = {15}, number = {33}, pages = {13359-13368}, pmid = {39183919}, issn = {2041-6520}, abstract = {The design of highly active catalysts is a main theme in organic chemistry, but it still relies heavily on expert experience. Herein, powered by machine-learning global structure exploration, we forge a Metal-Phosphine Catalyst Database (MPCD) with a meticulously designed ligand replacement energy metric, a key descriptor to describe the metal-ligand interactions. It pushes the rational design of organometallic catalysts to a quantitative era, where a ±10 kJ mol[-1] window of relative ligand binding strength, a so-called active ligand space (ALS), is identified for highly effective catalyst screening. We highlight the chemistry interpretability and effectiveness of ALS for various C-N, C-C and C-S cross-coupling reactions via a Sabatier-principle-based volcano plot and demonstrate its predictive power in discovering low-cost ligands in catalyzing Suzuki cross-coupling involving aryl chloride. The advent of the MPCD provides a data-driven new route for speeding up organometallic catalysis and other applications.}, }
@article {pmid39183185, year = {2024}, author = {Adiningrat, DP and Schlund, M and Skidmore, AK and Abdullah, H and Wang, T and Heurich, M}, title = {Mapping temperate old-growth forests in Central Europe using ALS and Sentinel-2A multispectral data.}, journal = {Environmental monitoring and assessment}, volume = {196}, number = {9}, pages = {841}, pmid = {39183185}, issn = {1573-2959}, support = {397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; 397.ID 834709, H2020-EU.1.1//European Research Council,European Union/ ; }, mesh = {*Forests ; *Environmental Monitoring/methods ; Europe ; *Remote Sensing Technology ; Conservation of Natural Resources/methods ; Biodiversity ; Satellite Imagery ; Climate Change ; Lasers ; }, abstract = {Old-growth forests are essential to preserve biodiversity and play an important role in sequestering carbon and mitigating climate change. However, their existence across Europe is vulnerable due to the scarcity of their distribution, logging, and environmental threats. Therefore, providing the current status of old-growth forests across Europe is essential to aiding informed conservation efforts and sustainable forest management. Remote sensing techniques have proven effective for mapping and monitoring forests over large areas. However, relying solely on remote sensing spectral or structural information cannot capture comprehensive horizontal and vertical structure complexity profiles associated with old-growth forest characteristics. To overcome this issue, we combined spectral information from Sentinel-2A multispectral imagery with 3D structural information from high-density point clouds of airborne laser scanning (ALS) imagery to map old-growth forests over an extended area. Four features from the ALS data and fifteen from Sentinel-2A comprising raw band (spectral reflectance), vegetation indices (VIs), and texture were selected to create three datasets used in the classification process using the random forest algorithm. The results demonstrated that combining ALS and Sentinel-2A features improved the classification performance and yielded the highest accuracy for old-growth class, with an F1-score of 92% and producer's and user's accuracies of 93% and 90%, respectively. The findings suggest that features from ALS and Sentinel-2A data sensitive to forest structure are essential for identifying old-growth forests. Integrating open-access satellite imageries, such as Sentinel-2A and ALS data, can benefit forest managers, stakeholders, and conservationists in monitoring old-growth forest preservation across a broader spatial extent.}, }
@article {pmid39182937, year = {2024}, author = {Silva, ST and Costa, IM and Souza, AA and Pondofe, K and Melo, LP and Resqueti, VR and Valentim, R and Gonçalves, F and Ribeiro, TS}, title = {Physical therapy for the management of global function, fatigue and quality of life in amyotrophic lateral sclerosis: systematic review and meta-analyses.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e076541}, pmid = {39182937}, issn = {2044-6055}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/therapy ; *Quality of Life ; *Physical Therapy Modalities ; *Fatigue/therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVES: To critically evaluate the effectiveness of physical therapy interventions in improving global function, quality of life and fatigue in individuals with amyotrophic lateral sclerosis (ALS).<br><br>DESIGN: Systematic review and meta-analyses.<br><br>DATA SOURCES: MEDLINE, EMBASE, Cochrane Library (CENTRAL) and Physiotherapy Evidence Database (PEDro) were searched through 31 January 2023.<br><br>ELIGIBILITY CRITERIA: We included randomised clinical trials (RCTs) that compared physical therapy interventions that act on global function, fatigue and quality of life in individuals with ALS with any other non-physiotherapeutic methods and techniques, placebo or non-intervention. The primary outcome measure was the evaluation of global function. Secondary outcomes were quality of life, fatigue and adverse events.<br><br>DATA EXTRACTION AND SYNTHESIS: Two independent authors used a researcher-developed extraction form and the Rayyan software to search, screen and code included studies. The risk of bias was assessed using the PEDro scale. Meta-analyses were conducted employing random effects. Outcomes were succinctly presented in Grading of Recommendations, Assessment, Development and Evaluation evidence profiles.<br><br>RESULTS: Our searches identified 39 415 references. After study selection, three studies were included in the review. Such studies involved 62 participants with a mean age of 54.6 years. In the evaluated trials, 40 were male, while 22 participants were female. Regarding the type of onset of the disease, 58 participants had spinal onset of ALS, and four had bulbar.<br><br>CONCLUSIONS: Physical therapy intervention may improve the global function of individuals with ALS in the short term; however, clinically, it was inconclusive. In terms of quality of life and fatigue, physical therapy intervention is not more effective than control in the short term. Adverse events are not increased by physical therapy intervention in the short term. Due to significant methodological flaws, small sample sizes, wide CIs and clinical interpretation, our confidence in the effect estimate is limited.<br><br>PROSPERO REGISTRATION NUMBER: CRD42021251350.}, }
@article {pmid39182589, year = {2024}, author = {Pupillo, E and Bianchi, E and Bonetto, V and Pasetto, L and Bendotti, C and Paganoni, S and Mandrioli, J and Mazzini, L and , }, title = {Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis.}, journal = {Brain, behavior, and immunity}, volume = {122}, number = {}, pages = {456-462}, doi = {10.1016/j.bbi.2024.08.044}, pmid = {39182589}, issn = {1090-2139}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/physiopathology ; Male ; Female ; Middle Aged ; Double-Blind Method ; Vital Capacity ; Aged ; *Disease Progression ; Biomarkers/blood ; Treatment Outcome ; Adult ; Neurofilament Proteins ; }, abstract = {BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS).<br><br>OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.<br><br>STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.<br><br>RESULTS: Mean duration of follow-up was 2.8&#xa0;years. Long-term median survival was six months longer in the RNS60 group (p&#xa0;=&#xa0;0.0519). Baseline FVC, and rates of FVC decline during the first 4&#xa0;weeks of trial participation, were balanced between the active and placebo treatment arms. After 6&#xa0;months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7&#xa0;years in slow FVC progressors; 1.6&#xa0;years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3&#xa0;years in low NfL - placebo group; 1.9&#xa0;years in high NfL - RNS60 group; 1.8&#xa0;years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7&#xa0;years in low MCP-1 - RNS60 group; 2.3&#xa0;years in low MCP-1 - placebo group; 2.8&#xa0;years in high MCP-1 - RNS60 group; 2.6&#xa0;years in high MCP-1 - placebo group) levels at baseline.<br><br>CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.<br><br>TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.}, }
@article {pmid39182251, year = {2024}, author = {Peng, Y and Liu, G and Li, S and Li, Z and Song, J}, title = {A machine learning system for artificial ligaments with desired mechanical properties in ACL reconstruction applications.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {159}, number = {}, pages = {106691}, doi = {10.1016/j.jmbbm.2024.106691}, pmid = {39182251}, issn = {1878-0180}, mesh = {*Machine Learning ; *Mechanical Phenomena ; *Anterior Cruciate Ligament Reconstruction/methods ; Materials Testing ; Humans ; Anterior Cruciate Ligament/surgery ; Neural Networks, Computer ; Biomechanical Phenomena ; Ligaments/surgery ; Artificial Organs ; Mechanical Tests ; }, abstract = {The anterior cruciate ligament is one of the important tissues to maintain the stability of the human knee joint, but it is difficult for this ligament to self-heal after injury. Consequently, transplantation of artificial ligaments (ALs) has gained widespread attention as an important alternative treatment method in recent years. However, accurately predicting the intricate mechanical properties of ALs remains a formidable challenge, particularly when employing theoretical frameworks such as braiding theory. This obstacle presents a significant impediment to achieving optimal AL design. Therefore, in this study, a high-precision machine learning model based on an artificial neural network was developed to rapidly and accurately predict the mechanical properties of ALs. The results showed that the proposed model achieved a reduction of 45.22% and 50.17% in the normalized root mean square error on the testing set when compared to traditional machine learning models (Random Forest and Support Vector Machine), demonstrating its higher accuracy. In addition, the design of ALs with desired mechanical properties was achieved by optimizing the braiding parameters, and its effectiveness was verified through experiments. The mechanical properties of the prepared ALs were able to fully meet the desired targets and were at least 2% higher. Finally, the influence weights of different braiding parameters on the mechanical properties of ALs were analyzed by feature importance.}, }
@article {pmid39182178, year = {2024}, author = {Serizawa, S}, title = {Exploration of the Factors Impacting Sustained Clinical Care by Multidisciplinary Professionals for Amyotrophic Lateral Sclerosis.}, journal = {The Tokai journal of experimental and clinical medicine}, volume = {49}, number = {3}, pages = {110-116}, pmid = {39182178}, issn = {2185-2243}, mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; Surveys and Questionnaires ; *Patient Care Team ; Japan ; Female ; Male ; Self-Assessment ; Motivation ; Health Personnel ; Middle Aged ; Adult ; Time Factors ; }, abstract = {OBJECTIVE: This study examined the experiences of multidisciplinary medical professionals in providing daily clinical care for patients with amyotrophic lateral sclerosis (ALS), with a focus placed on their persistence in sustaining clinical care for this patient group.<br><br>METHODS: A questionnaire survey was administered to multidisciplinary medical professionals involved in ALS care at three hospitals in western Kanagawa Prefecture, Japan. The questionnaire results were used to examine the relationships between years of medical experience, years of ALS care experience, self-evaluation, and motivation to continue providing clinical care to patients with ALS.<br><br>RESULTS: Of the 269 questionnaires distributed and 164 collected by the multidisciplinary medical professionals, 143 (53%) were deemed valid. Analysis revealed an association between "years of medical experience" with both "self-assessment of clinical care for ALS patients practice experience" and "commitment to continue clinical care for ALS patients," as well as between "years of ALS medical experience" and "self-assessment of clinical care for ALS patients."<br><br>CONCLUSION: Medical professionals with more than ten years of medical experience expressed their commitment to continue providing medical care in a comprehensive self-assessment of both the positive and negative aspects of their practice. Negative evaluations can be used to identify and improve ALS medical practices.}, }
@article {pmid39182146, year = {2024}, author = {Kill, C and Manegold, RK and Fistera, D and Risse, J}, title = {Airway management and ventilation techniques in resuscitation during advanced life support: an update.}, journal = {Journal of anesthesia, analgesia and critical care}, volume = {4}, number = {1}, pages = {58}, pmid = {39182146}, issn = {2731-3786}, abstract = {For many years, ventilation has been an essential part of advanced life support (ALS) in cardiopulmonary resuscitation (CPR). Nevertheless, there is little evidence about the best method of ventilation during resuscitation for both out-of-hospital cardiac arrest (OHCA) and inhospital cardiac arrest (IHCA) patients. Effective ventilation is one of the two main keys to successful resuscitation. In this context, the question always arises as to which airway management, along with which ventilation mode, constitutes the best strategy. Conventional ventilation modes are not designed for cardiac arrest and show important limitations that must be considered when used in CPR. Manual ventilation without the use of an automated transport ventilator (ATV) could be shown to be uncontrolled in applied volumes and pressures and should be avoided. Mechanical ventilation with an ATV is therefore superior to manual ventilation, but both volume- and pressure-controlled ventilation modes are significantly influenced by chest compressions. With the newly designed chest compression synchronized ventilation (CCSV), a special ventilation mode for resuscitation is available. Further research should be conducted to obtain more evidence of the effect of ventilation during CPR on outcomes following OHCA and not only about how to secure the airway for ventilation during CPR.}, }
@article {pmid39181624, year = {2024}, author = {Mousele, C and Holden, D and Gnanapavan, S}, title = {Neurofilaments in neurologic disease.}, journal = {Advances in clinical chemistry}, volume = {123}, number = {}, pages = {65-128}, doi = {10.1016/bs.acc.2024.06.010}, pmid = {39181624}, issn = {2162-9471}, mesh = {Humans ; *Nervous System Diseases/pathology/metabolism/diagnosis ; *Biomarkers ; Neurofilament Proteins/cerebrospinal fluid/metabolism ; Intermediate Filaments/metabolism ; Animals ; }, abstract = {Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.}, }
@article {pmid39181183, year = {2024}, author = {Ko, YH and Lokareddy, RK and Doll, SG and Yeggoni, DP and Girdhar, A and Mawn, I and Klim, JR and Rizvi, NF and Meyers, R and Gillilan, RE and Guo, L and Cingolani, G}, title = {Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin α1/β Signaling.}, journal = {Journal of molecular biology}, volume = {436}, number = {20}, pages = {168751}, pmid = {39181183}, issn = {1089-8638}, support = {P30 GM124166/GM/NIGMS NIH HHS/United States ; RF1 NS121143/NS/NINDS NIH HHS/United States ; R21 NS128396/NS/NINDS NIH HHS/United States ; S10 OD017987/OD/NIH HHS/United States ; R01 NS121143/NS/NINDS NIH HHS/United States ; R35 GM140733/GM/NIGMS NIH HHS/United States ; S10 OD023479/OD/NIH HHS/United States ; R35 GM138109/GM/NIGMS NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {*Nuclear Localization Signals/metabolism/genetics ; Humans ; *DNA-Binding Proteins/metabolism/genetics ; *alpha Karyopherins/metabolism/genetics ; *beta Karyopherins/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Acetylation ; *Signal Transduction ; Mutation ; Protein Processing, Post-Translational ; Active Transport, Cell Nucleus ; Protein Binding ; Cell Nucleus/metabolism ; }, abstract = {Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α1/β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.}, }
@article {pmid39181135, year = {2024}, author = {Wu, R and Ye, Y and Dong, D and Zhang, Z and Wang, S and Li, Y and Wright, N and Redding-Ochoa, J and Chang, K and Xu, S and Tu, X and Zhu, C and Ostrow, LW and Roca, X and Troncoso, JC and Wu, B and Sun, S}, title = {Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.}, journal = {Neuron}, volume = {112}, number = {20}, pages = {3434-3451.e11}, pmid = {39181135}, issn = {1097-4199}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; R01 NS107347/NS/NINDS NIH HHS/United States ; RF1 NS113820/NS/NINDS NIH HHS/United States ; RF1 NS127925/NS/NINDS NIH HHS/United States ; R01 AG078948/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; *C9orf72 Protein/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism/pathology ; Mice ; Animals ; *RNA Splicing/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Induced Pluripotent Stem Cells/metabolism ; DNA Repeat Expansion/genetics ; Neurons/metabolism ; Male ; Female ; }, abstract = {Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.}, }
@article {pmid39180957, year = {2024}, author = {Harkins, AL and Ambegaokar, PP and Keeler, AM}, title = {Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference?.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {21}, number = {4}, pages = {e00435}, pmid = {39180957}, issn = {1878-7479}, mesh = {Humans ; *Dependovirus/genetics/immunology ; *Genetic Therapy/methods ; *Genetic Vectors/immunology/administration &amp; dosage ; Animals ; Central Nervous System/immunology ; Gene Transfer Techniques ; Central Nervous System Diseases/therapy/immunology ; }, abstract = {Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.}, }
@article {pmid39180748, year = {2024}, author = {Liu, Z and Zhang, H and Lu, K and Chen, L and Zhang, Y and Xu, Z and Zhou, H and Sun, J and Xu, M and Ouyang, Q and Thompson, GJ and Yang, Y and Su, N and Cai, X and Cao, L and Zhao, Y and Jiang, L and Zheng, Y and Zhang, X}, title = {Low-intensity pulsed ultrasound modulates disease progression in the SOD1[G93A] mouse model of amyotrophic lateral sclerosis.}, journal = {Cell reports}, volume = {43}, number = {9}, pages = {114660}, doi = {10.1016/j.celrep.2024.114660}, pmid = {39180748}, issn = {2211-1247}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/pathology/therapy/metabolism ; *Disease Models, Animal ; Mice ; *Disease Progression ; *Ultrasonic Waves ; *Mice, Transgenic ; *Motor Cortex/pathology/metabolism ; TRPV Cation Channels/metabolism/genetics ; Superoxide Dismutase-1/genetics/metabolism ; Cerebrovascular Circulation ; Ultrasonic Therapy/methods ; Mice, Inbred C57BL ; Male ; Endothelial Cells/metabolism ; Motor Neurons/pathology/metabolism ; Humans ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord, and there are no effective drug treatments. Low-intensity pulsed ultrasound (LIPUS) has garnered attention as a promising noninvasive neuromodulation method. In this study, we investigate its effects on the motor cortex and underlying mechanisms using the SOD1[G93A] mouse model of ALS. Our results show that LIPUS treatment delays disease onset and prolongs lifespan in ALS mice. LIPUS significantly increases cerebral blood flow in the motor cortex by preserving vascular endothelial cell integrity and increasing microvascular density, which may be mediated via the ion channel TRPV4. RNA sequencing analysis reveals that LIPUS substantially reduces the expression of genes associated with neuroinflammation. These findings suggest that LIPUS applied to the motor cortex may represent a potentially effective therapeutic tool for the treatment of ALS.}, }
@article {pmid39180568, year = {2024}, author = {Yang, J and Tang, C}, title = {Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.}, journal = {Mammalian genome : official journal of the International Mammalian Genome Society}, volume = {35}, number = {4}, pages = {711-723}, pmid = {39180568}, issn = {1432-1777}, mesh = {Humans ; *Mendelian Randomization Analysis ; *Neurodegenerative Diseases/genetics/diagnostic imaging ; *Phenotype ; *Amyotrophic Lateral Sclerosis/genetics/diagnostic imaging ; Alzheimer Disease/genetics/diagnostic imaging ; Frontotemporal Dementia/genetics/diagnostic imaging/pathology ; Parkinson Disease/genetics/diagnostic imaging ; Brain/diagnostic imaging/pathology/metabolism ; Multiple Sclerosis/genetics/diagnostic imaging ; Neuroimaging/methods ; }, abstract = {Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.}, }
@article {pmid39180054, year = {2024}, author = {Spittel, S and Meyer, T and Weyen, U and Grehl, T and Weydt, P and Steinbach, R and Petri, S and Baum, P and Metelmann, M and Sperfeld, AD and Kettemann, D and Norden, J and Rödiger, A and Ilse, B and Grosskreutz, J and Hildebrandt, B and Walter, B and Münch, C and Maier, A}, title = {User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.}, journal = {Neurological research and practice}, volume = {6}, number = {1}, pages = {42}, pmid = {39180054}, issn = {2524-3489}, abstract = {OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.<br><br>METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n&#x2009;=&#x2009;85) and user experiences after provision (experience group, n&#x2009;=&#x2009;14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.<br><br>RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n&#x2009;=&#x2009;85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n&#x2009;=&#x2009;14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n&#x2009;=&#x2009;10), and 28.6% (n&#x2009;=&#x2009;4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was&#x2009;+&#x2009;57 demonstrating strong patient satisfaction.<br><br>CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.}, }
@article {pmid39179240, year = {2025}, author = {Sisti, HM and Beebe, A and Gabrielsson, E and Bishop, M}, title = {Postmovement Beta Rebound in Real and Imagined Movement.}, journal = {Motor control}, volume = {29}, number = {1}, pages = {53-68}, doi = {10.1123/mc.2023-0033}, pmid = {39179240}, issn = {1087-1640}, mesh = {Humans ; *Imagination/physiology ; Male ; Female ; Adult ; *Beta Rhythm/physiology ; *Electroencephalography ; *Movement/physiology ; *Psychomotor Performance/physiology ; Young Adult ; Sensorimotor Cortex/physiology ; }, abstract = {Movement disorders, such as stroke and amyotrophic lateral sclerosis, result in loss of upper limb function and, hence, severe impairments of bimanual coordination. Although motor imagery is increasingly used to enhance neurorehabilitation, cognitive and neurophysiological parameters that inform effective strategies remain elusive. The aim of the present study is to elucidate the neural dynamics that underlie learning during real and imagined movement using both unimanual and bimanual coordination patterns. The post movement beta rebound (PMBR) has been implicated as a biomarker of motor control and therefore was the focus of this study. Healthy adults (n = 21) learned a visuomotor tracking task in a single session using either one or both hands while brainwaves were captured using electroencephalography. Postmovement beta rebound was evident in the sensorimotor cortex for both unimanual and bimanual conditions. Task-related power of the beta band demonstrated that actual unimanual movement requires greater contralateral activity compared with both actual bimanual movement and imagined movement of either condition. Notably, the PMBR was evident even in imagined movement, although to a lesser extent than real movement. Neurophysiological results support a functional role for beta band in movement. Results of these data may inform neurorehabilitation strategies for patients recovering from movement disorders of the upper limbs.}, }
@article {pmid39178140, year = {2024}, author = {Briois, V and Itié, JP and Polian, A and King, A and Traore, AS and Marceau, E and Ersen, O and La Fontaine, C and Barthe, L and Beauvois, A and Roudenko, O and Belin, S}, title = {Hyperspectral full-field quick-EXAFS imaging at the ROCK beamline for monitoring micrometre-sized heterogeneity of functional materials under process conditions.}, journal = {Journal of synchrotron radiation}, volume = {31}, number = {Pt 5}, pages = {1084-1104}, pmid = {39178140}, issn = {1600-5775}, support = {ANR-10-EQPX-0045//Agence Nationale de la Recherche/ ; ANR-20-CE42-007//Agence Nationale de la Recherche/ ; ANR-07-Stock-E-0 PULSSE//Agence Nationale de la Recherche/ ; }, abstract = {Full-field transmission X-ray microscopy has been recently implemented at the hard X-ray ROCK-SOLEIL quick-EXAFS beamline, adding micrometre spatial resolution to the second time resolution characterizing the beamline. Benefiting from a beam size versatility due to the beamline focusing optics, full-field hyperspectral XANES imaging has been successfully used at the Fe K-edge for monitoring the pressure-induced spin transition of a 150 µm × 150 µm Fe(o-phen)2(NCS)2 single crystal and the charge of millimetre-sized LiFePO4 battery electrodes. Hyperspectral imaging over 2000 eV has been reported for the simultaneous monitoring of Fe and Cu speciation changes during activation of a FeCu bimetallic catalyst along a millimetre-sized catalyst bed. Strategies of data acquisition and post-data analysis using Jupyter notebooks and multivariate data analysis are presented, and the gain obtained using full-field hyperspectral quick-EXAFS imaging for studies of functional materials under process conditions in comparison with macroscopic information obtained by non-spatially resolved quick-EXAFS techniques is discussed.}, }
@article {pmid39177232, year = {2024}, author = {Witzel, S and Huss, A and Nagel, G and Rosenbohm, A and Rothenbacher, D and Peter, RS and Bäzner, H and Börtlein, A and Dempewolf, S and Schabet, M and Hecht, M and Kohler, A and Opherk, C and Naegele, A and Sommer, N and Lindner, A and Alexudis, C and Bachhuber, F and Halbgebauer, S and Brenner, D and Ruf, W and Weiland, U and Mayer, B and Schuster, J and Dorst, J and Tumani, H and Ludolph, AC and , }, title = {Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.}, journal = {Annals of neurology}, volume = {96}, number = {6}, pages = {1040-1057}, doi = {10.1002/ana.27054}, pmid = {39177232}, issn = {1531-8249}, support = {577631//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/diagnosis ; *Biomarkers/blood ; *Neurofilament Proteins/blood ; Middle Aged ; Female ; Male ; Aged ; Prognosis ; Intermediate Filaments/metabolism ; Adult ; }, abstract = {OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.<br><br>METHODS: We measured serum NfL and pNfH levels in all ALS patients (n&#x2009;=&#x2009;790) and general population controls (n&#x2009;=&#x2009;570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA&#x2122;) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.<br><br>RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.<br><br>INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.}, }
@article {pmid39177131, year = {2024}, author = {Sheremeta, CL and Yarlagadda, S and Smythe, ML and Noakes, PG}, title = {Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.}, journal = {Current drug targets}, volume = {25}, number = {13}, pages = {885-908}, pmid = {39177131}, issn = {1873-5592}, support = {Project grant,//Muscular Dystrophy Association/ ; }, mesh = {Humans ; *Prostaglandins/metabolism ; Animals ; *Central Nervous System/metabolism/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Signal Transduction/drug effects ; Multiple Sclerosis/drug therapy/metabolism ; Inflammation/drug therapy/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy/metabolism ; Central Nervous System Diseases/drug therapy/metabolism ; }, abstract = {The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.}, }
@article {pmid39176909, year = {2024}, author = {Tiffet, T and Pikaar, A and Trombert-Paviot, B and Jaulent, MC and Bousquet, C}, title = {Comparing a Large Language Model with Previous Deep Learning Models on Named Entity Recognition of Adverse Drug Events.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {781-785}, doi = {10.3233/SHTI240528}, pmid = {39176909}, issn = {1879-8365}, mesh = {*Deep Learning ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; Natural Language Processing ; Adverse Drug Reaction Reporting Systems ; }, abstract = {The ability to fine-tune pre-trained deep learning models to learn how to process a downstream task using a large training set allow to significantly improve performances of named entity recognition. Large language models are recent models based on the Transformers architecture that may be conditioned on a new task with in-context learning, by providing a series of instructions or prompt. These models only require few examples and such approach is defined as few shot learning. Our objective was to compare performances of named entity recognition of adverse drug events between state of the art deep learning models fine-tuned on Pubmed abstracts and a large language model using few-shot learning. Hussain et al's state of the art model (PMID: 34422092) significantly outperformed the ChatGPT-3.5 model (F1-Score: 97.6% vs 86.0%). Few-shot learning is a convenient way to perform named entity recognition when training examples are rare, but performances are still inferior to those of a deep learning model fine-tuned with several training examples. Perspectives are to evaluate few-shot prompting with GPT-4 and perform fine-tuning on GPT-3.5.}, }
@article {pmid39176644, year = {2024}, author = {Turner, J and Impey, S and Gibbons, F and Bolger, A and Stephens, G and Hederman, L and Hamed, R and O'Meara, C and de la Varga, F and Kommala, J and Nicholson, M and Farrell, D and Galvin, M and Heverin, M and Mac Domhnaill, &#xc9; and McFarlane, R and Meldrum, D and Murray, D and Hardiman, O}, title = {Data and Process Harmonisation of Multi-National, Multi-Site Research Data.}, journal = {Studies in health technology and informatics}, volume = {316}, number = {}, pages = {1411-1412}, doi = {10.3233/SHTI240675}, pmid = {39176644}, issn = {1879-8365}, mesh = {Humans ; *Data Collection ; Amyotrophic Lateral Sclerosis/therapy ; Biomedical Research ; }, abstract = {To achieve a single fully harmonised research data set suitable for analysis from data collected at multiple sites requires not only semantic integration of collection concepts and convergence onto single collection units, but harmonisation of data collection processes. We describe our experience of identifying harmonisation challenges in the Precision ALS project, with particular focus on process alignment challenges in a multi-site multi-national research data collection project.}, }
@article {pmid39176177, year = {2024}, author = {Al Dera, H and AlQahtani, B}, title = {Molecular mechanisms and antisense oligonucleotide therapies of familial amyotrophic lateral sclerosis.}, journal = {Molecular therapy. Nucleic acids}, volume = {35}, number = {3}, pages = {102271}, pmid = {39176177}, issn = {2162-2531}, abstract = {Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, presents considerable challenges in both diagnosis and treatment. It is categorized into sporadic and familial amyotrophic lateral sclerosis (fALS); the latter accounts for approximately 10% of cases and is primarily inherited in an autosomal dominant manner. This review summarizes the molecular genetics of fALS, highlighting key mutations that contribute to its pathogenesis, such as mutations in SOD1, FUS, and C9orf72. Central to this discourse is exploring antisense oligonucleotides (ASOs) that target these genetic aberrations, providing a promising therapeutic strategy. This review provides a detailed overview of the molecular mechanisms underlying fALS and the potential therapeutic value of ASOs, offering new insights into treating neurodegenerative diseases.}, }
@article {pmid39175128, year = {2024}, author = {Wu, A and Lee, D and Xiong, WC}, title = {VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.}, journal = {Expert opinion on therapeutic targets}, volume = {28}, number = {8}, pages = {701-712}, pmid = {39175128}, issn = {1744-7631}, support = {R01 AG045781/AG/NIA NIH HHS/United States ; RF1 AG045781/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Neurodegenerative Diseases/physiopathology/drug therapy ; *Vesicular Transport Proteins/metabolism ; Animals ; *Molecular Targeted Therapy ; Protein Transport ; Parkinson Disease/physiopathology/drug therapy ; Mutation, Missense ; Drug Development ; }, abstract = {INTRODUCTION: Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge.<br><br>AREAS COVERED: This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target.<br><br>EXPERT OPINION: VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.}, }
@article {pmid39174972, year = {2024}, author = {Zhou, J and Li, F and Jia, B and Wu, Z and Huang, Z and He, M and Weng, H and So, KF and Qu, W and Fu, QL and Zhou, L}, title = {Intranasal delivery of small extracellular vesicles reduces the progress of amyotrophic lateral sclerosis and the overactivation of complement-coagulation cascade and NF-ĸB signaling in SOD1[G93A] mice.}, journal = {Journal of nanobiotechnology}, volume = {22}, number = {1}, pages = {503}, pmid = {39174972}, issn = {1477-3155}, support = {202310183302//2023 University Innovation and Entrepreneurship Training Plan/ ; 2022YFA1104900//National Key Research and Development Program of China/ ; 2021B1515120062//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023B03J1233, 20220600003//Guangzhou Key R&amp;D Program/ ; }, mesh = {Animals ; Male ; Mice ; Administration, Intranasal ; *Amyotrophic Lateral Sclerosis/metabolism ; Blood Coagulation ; Disease Models, Animal ; *Extracellular Vesicles/metabolism ; Mesenchymal Stem Cells/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neurons/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motoneuron degeneration, and effective clinical treatments are lacking. In this study, we evaluated whether intranasal delivery of mesenchymal stem cell-derived small extracellular vesicles (sEVs) is a strategy for ALS therapy using SOD1[G93A] mice. In vivo tracing showed that intranasally-delivered sEVs entered the central nervous system and were extensively taken up by spinal neurons and some microglia. SOD1[G93A] mice that intranasally received sEV administration showed significant improvements in motor performances and survival time. After sEV administration, pathological changes, including spinal motoneuron death and synaptic denervation, axon demyelination, neuromuscular junction degeneration and electrophysiological defects, and mitochondrial vacuolization were remarkably alleviated. sEV administration attenuated the elevation of proinflammatory cytokines and glial responses. Proteomics and transcriptomics analysis revealed upregulation of the complement and coagulation cascade and NF-ĸB signaling pathway in SOD1[G93A] mouse spinal cords, which was significantly inhibited by sEV administration. The changes were further confirmed by detecting C1q and NF-ĸB expression using Western blots. In conclusion, intranasal administration of sEVs effectively delays the progression of ALS by inhibiting neuroinflammation and overactivation of the complement and coagulation cascades and NF-ĸB signaling pathway and is a potential option for ALS therapy.}, }
@article {pmid39174694, year = {2024}, author = {Layalle, S and Aimond, F and Brugioti, V and Guissart, C and Raoul, C and Soustelle, L}, title = {The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {19540}, pmid = {39174694}, issn = {2045-2322}, mesh = {Animals ; *Kinesins/genetics/metabolism ; *Motor Neurons/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Mutation ; Humans ; Drosophila Proteins/genetics/metabolism ; Drosophila ; Neuromuscular Junction/metabolism/pathology ; Drosophila melanogaster/genetics ; Synaptic Transmission/genetics ; Disease Models, Animal ; Axons/metabolism/pathology ; Larva/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.}, }
@article {pmid39174305, year = {2025}, author = {Mohamed Yusoff, AA and Mohd Khair, SZN}, title = {Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.}, journal = {Reviews in the neurosciences}, volume = {36}, number = {1}, pages = {53-90}, pmid = {39174305}, issn = {2191-0200}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Mitochondria/metabolism ; Animals ; Mitochondrial Dynamics/physiology ; Mitochondrial Diseases/metabolism ; Mitophagy/physiology ; }, abstract = {Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.}, }
@article {pmid39174072, year = {2024}, author = {Yoon, R and Wong, JP and Chung-Lee, L and Akbarian, A and Abdulai, AF and Hou, R and Ho, M and Zinaic, R and Anoushka, A}, title = {Scoping review protocol: what is the state of evidence for the use of communication apps with immigrant seniors in long-term care and community settings?.}, journal = {BMJ open}, volume = {14}, number = {8}, pages = {e089939}, pmid = {39174072}, issn = {2044-6055}, mesh = {Humans ; *Emigrants and Immigrants ; *Long-Term Care ; *Mobile Applications ; Aged ; Research Design ; Communication Barriers ; Scoping Reviews As Topic ; }, abstract = {INTRODUCTION: First language care is critical for older immigrant adults with limited English proficiency, especially in long-term care settings where most residents require staff assistance and experience complex chronic conditions, resulting in multiple communication interactions where language poses a barrier. Although there are a myriad of cultural-language translation apps and devices available, there is a gap in both research and practice on the acceptability and feasibility of these digital resources within the context of long-term care and community settings for older immigrant adults, from a cultural relevance and digital health equity perspective. Our paper outlines a scoping review protocol to examine the state of the literature on the extent to which cultural-language translation apps are used in long-term care settings and community-based elder care. We will also examine the extent to which such apps bridge or further gaps in equitable, accessible and acceptable care for older immigrant adults with limited English language proficiency.<br><br>METHODS AND ANALYSIS: This scoping review protocol will employ an adapted five-stage framework outlined by Arksey and O'Malley guided by enhancements recommended by Levac et al and Colquhoun et al. Using the Joanna Briggs Institute's population, concept and context framework, we defined the scope of the scoping review by identifying the target population, concepts for investigation and the context within which the research is situated. We will conduct a search of the literature from 2005 to 2024 using five bibliographic databases from health sciences (Healthstar OVID, MEDLINE OVID and Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO), engineering (Engineering Village Elsevier) and a cross-disciplinary database (Web of Science Clarivate). The research team will adopt a critical, equity-focused approach for the scoping review by integrating Richardson et al's framework for Digital Health Equity into our analysis of the findings. This will ensure that health and social equity perspectives are integrated within our methodology and analytical lens. Our analysis will specifically examine selected studies for their engagement with health equity and their ability to address issues such as ageism, ableism and the digital divide within geriatric care.<br><br>ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review as it involves secondary analysis of published works and no primary data collection involving human subjects. Findings of the review will be shared with community partners and disseminated through publications, conferences and peer-reviewed publications.}, }
@article {pmid39174002, year = {2024}, author = {Javaudin, F and Papin, M and Le Bastard, Q and Thibault, M and Boishardy, T and Brau, F and Laribi, S and Petrovic, T and Peluchon, T and Markarian, T and Volteau, C and Arnaudet, I and Pes, P and Le Conte, P}, title = {Early point-of-care echocardiography as a predictive factor for absence of return of spontaneous circulatory in out-of-hospital cardiac arrests: A multicentre observational study.}, journal = {Resuscitation}, volume = {203}, number = {}, pages = {110373}, doi = {10.1016/j.resuscitation.2024.110373}, pmid = {39174002}, issn = {1873-1570}, mesh = {Humans ; Male ; Female ; *Out-of-Hospital Cardiac Arrest/therapy ; Aged ; Prospective Studies ; Middle Aged ; *Echocardiography/methods ; *Cardiopulmonary Resuscitation/methods ; *Return of Spontaneous Circulation ; *Predictive Value of Tests ; Point-of-Care Systems ; Prognosis ; }, abstract = {INTRODUCTION: Early assessment of the prognosis of a patient in cardiac arrest during cardiopulmonary resuscitation is highly challenging. This study aims to evaluate the predictive outcome value of early point-of-care ultrasound (POCUS) in out-of-hospital settings.<br><br>METHODS: This observational, prospective, multicentre study's primary endpoint was the positive predictive value (PPV) of POCUS cardiac standstill within the first 12&#xa0;min of advanced life support (ALS) initiation in determining the absence of return of spontaneous circulation (ROSC). A multivariate logistic regression model was constructed with adjustments for known predictive variables typically used in termination of resuscitation (TOR) rules.<br><br>RESULTS: A total of 293 patients were analysed, with a mean age of 66.6&#xa0;&#xb1;&#xa0;14.6&#xa0;years, and a majority were men (75.8%). POCUS was performed on average 7.9&#xa0;&#xb1;&#xa0;2.6&#xa0;min after ALS initiation. Among patients with cardiac standstill (72.4%), 16.0% achieved ROSC compared with 48.2% in those with visible cardiac motions. The PPV of early POCUS cardiac standstill for the absence of ROSC was 84.0%, 95% CI [78.3-88.6]. In multivariable analysis, only POCUS cardiac standstill (adjusted odds ratio [aOR] 3.89, 95% CI [1.86-8.17]) and end-tidal CO2 (ETCO2) value &#x2264;37&#xa0;mmHg (aOR 4.27, 95% CI [2.21-8.25]) were associated with the absence of ROSC.<br><br>CONCLUSION: Early POCUS cardiac standstill during CPR for out-of-hospital cardiac arrest was a reliable predictor of the absence of ROSC. However, its presence alone was not sufficient to determine the termination of resuscitation efforts.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03494153. Registered March 29, 2018.}, }
@article {pmid39173710, year = {2025}, author = {Weber, MP and Strobel, RJ and Norman, AV and Kareddy, A and Young, A and Young, S and El Moheb, M and Noona, SWW and Wisniewski, AM and Quader, M and Mazzeffi, M and Yarboro, LT and Teman, NR}, title = {Cardiac Surgical Unit-Advanced Life Support-certified centers are associated with improved failure to rescue after cardiac arrest: A propensity score-matched analysis.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {169}, number = {4}, pages = {1271-1281}, doi = {10.1016/j.jtcvs.2024.08.014}, pmid = {39173710}, issn = {1097-685X}, mesh = {Humans ; *Heart Arrest/mortality/therapy ; Female ; Male ; *Propensity Score ; Middle Aged ; Aged ; *Certification ; Retrospective Studies ; Advanced Cardiac Life Support/standards ; Failure to Rescue, Health Care/statistics &amp; numerical data ; Patient Readmission/statistics &amp; numerical data ; Cardiac Surgical Procedures/adverse effects/mortality ; Risk Factors ; Time Factors ; Risk Assessment ; }, abstract = {OBJECTIVE: The impact of Cardiac Surgical Unit-Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA.<br><br>METHODS: Patients undergoing Society of Thoracic Surgeons index operations from 2020 to 2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS-certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with FTR-CA.<br><br>RESULTS: A total of 12,209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, 2 patient cohorts were formed (n&#xa0;=&#xa0;3557). Patients at CSU-ALS centers had greater rates of intensive care unit readmission (3.9% vs 2.3%, P&#xa0;<&#xa0;.01) and total operating room time (340&#xa0;minutes vs 323&#xa0;minutes, P&#xa0;<&#xa0;.01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, P&#xa0;<&#xa0;.01). There was no difference in the rate of postoperative cardiac arrest (1.8% vs 2.2%, P&#xa0;=&#xa0;.24) or operative mortality (2.5% vs 2.9%, P&#xa0;=&#xa0;.30). After risk adjustment, CSU-ALS centers (odds ratio, 0.30; 95% confidence interval, 0.12-0.72, P&#xa0;<&#xa0;.01) and greater-volume centers (odds ratio, 0.15; confidence interval, 0.03-0.74, P&#xa0;=&#xa0;.02) had reduced odds of FTR-CA.<br><br>CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR-CA. This highlights the importance of well-trained staff and treatment algorithms in the care of patients postcardiac surgery.}, }
@article {pmid39172789, year = {2024}, author = {Ahmed, R and Liang, M and Hudson, RP and Rangadurai, AK and Huang, SK and Forman-Kay, JD and Kay, LE}, title = {Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {35}, pages = {e2408554121}, pmid = {39172789}, issn = {1091-6490}, support = {FND-503573//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; 2015-04347//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; FDN-148375//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; PJT-190060//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; }, mesh = {*Superoxide Dismutase-1/chemistry/metabolism/genetics ; Humans ; *Solvents/chemistry ; Protein Unfolding ; Protein Binding ; Protein Folding ; Models, Molecular ; Stress Granules/metabolism/chemistry ; RNA-Binding Proteins/metabolism/chemistry ; Protein Conformation ; Magnetic Resonance Spectroscopy ; }, abstract = {Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1:SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates.}, }
@article {pmid39171600, year = {2025}, author = {Nogueira-Machado, JA and das Chagas Lima E Silva, F and Rocha-Silva, F and Gomes, N}, title = {Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {24}, number = {2}, pages = {83-90}, pmid = {39171600}, issn = {1996-3181}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Signal Transduction ; *Mutation ; Animals ; }, abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and incurable disease. Sporadic (sALS) accounts for ninety percent of ALS cases, while familial ALS (fALS) accounts for around ten percent. Reports have identified over 30 different forms of familial ALS. Multiple types of fALS exhibit comparable symptoms with mutations in different genes and possibly with different predominant metabolic signals. Clinical diagnosis takes into account patient history but not genetic mutations, misfolded proteins, or metabolic signaling. As research on genetics and metabolic pathways advances, it is expected that the intricate complexity of ALS will compound further. Clinicians discuss whether a gene's presence is a cause of the disease or just an association or consequence. They believe that a mutant gene alone is insufficient to diagnose ALS. ALS, often perceived as a single disease, appears to be a complex collection of diseases with similar symptoms. This review highlights gene mutations, metabolic pathways, and muscle-neuron interactions.}, }
@article {pmid39170988, year = {2024}, author = {Baroni, LM and Funari, MP and So Taa Kum, A and Bestetti, AM and de Oliveira, LB and de Carvalho, MF and Franzini, TAP and de Moura, DTH and Bernardo, WM and de Moura, EGH}, title = {Endoscopic Versus Surgical Treatment for Ampullary Lesions: A Systematic Review With Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e65076}, pmid = {39170988}, issn = {2168-8184}, abstract = {Ampullary lesions (ALs) can be treated through either an endoscopic approach (EA) or a surgical approach (SA). However, it is important to note that EAs carry a significant risk of incomplete resection, while opting for surgical interventions can result in substantial morbidity. We performed a systematic review and meta-analysis for R0 resection, recurrence, adverse events in general, major adverse events, mortality, and length of hospital stay between SAs and EAs. Electronic databases were searched from inception to 2023. We identified nine independent studies. The risk difference was -0.32 (95% CI: -0.50, -0.15; p <0.001) for R0, 0.12 (95% CI: 0.06, 0.19; p < 0.001) for recurrence, -0.22 (95% CI: -0.43, 0.00; p 0.05) for overall adverse events, -0.11 (95% CI: -0.32, 0.10; p = 0.31) for major complications, -0.01 (95% CI: -0.02, 0.01; p = 0.43) for mortality, and -14.69 (95% CI: -19.91, -9.47; p < 0.001) for length of hospital stay. As expected, our data suggest a higher complete resection rate and lower recurrence from surgical interventions, but this is associated with an elevated risk of adverse events and a longer hospital stay.}, }
@article {pmid39170265, year = {2024}, author = {Pain, O and Jones, A and Al Khleifat, A and Agarwal, D and Hramyka, D and Karoui, H and Kubica, J and Llewellyn, DJ and Ranson, JM and Yao, Z and Iacoangeli, A and Al-Chalabi, A}, title = {Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e35342}, pmid = {39170265}, issn = {2405-8440}, support = {MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.<br><br>METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.<br><br>RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R [2]&#xa0;=&#xa0;5.1&#xa0;%; p-value&#xa0;=&#xa0;3.2&#xa0;&#xd7;&#xa0;10[-27]) and clinical characteristics.<br><br>CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.}, }
@article {pmid39170125, year = {2024}, author = {Wenzhi, Y and Xiangyi, L and Dongsheng, F}, title = {The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.}, journal = {Heliyon}, volume = {10}, number = {15}, pages = {e34963}, pmid = {39170125}, issn = {2405-8440}, abstract = {Pathological proteins in amyotrophic lateral sclerosis (ALS), such as superoxide dismutase 1, TAR DNA-binding protein 43, and fused in sarcoma, exhibit a prion-like pattern. All these proteins have a low-complexity domain and seeding activity in cells. In this review, we summarize the studies on the prion-like effect of these proteins and list six prion-like protein targeting strategies that we believe have potential for ALS therapy, including antisense oligonucleotides, antibody-based technology, peptide, protein chaperone, autophagy enhancement, and heteromultivalent compounds. Considering the pathological complexity and heterogeneity of ALS, we believe that the final solution to ALS therapy is most likely to be an individualized cocktail therapy, including clearance of toxicity, blockage of pathological progress, and protection of neurons.}, }
@article {pmid39170062, year = {2024}, author = {Wang, H and Yao, G and He, K and Wang, Z and Cheng, CK}, title = {ACL reconstruction combined with anterolateral structures reconstruction for treating ACL rupture and knee injuries: a finite element analysis.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {12}, number = {}, pages = {1437684}, pmid = {39170062}, issn = {2296-4185}, abstract = {Introduction: The biomechanical indication for combining anterolateral structures reconstruction (ASLR) with ACL reconstruction (ACLR) to reduce pivot shift in the knee remains unclear. This study aims to investigate knee functionality after ACL rupture with different combinations of injuries, and to compare the effectiveness of ALSR with ACLR for treating these injuries. Methods: A validated finite element model of a human cadaveric knee was used to simulate pivot shift tests on the joint in different states, including 1) an intact knee; 2) after isolated ACL rupture; 3) after ACL rupture combined with different knee injuries or defect, including a posterior tibial slope (PTS) of 20°, an injury to the anterolateral structures (ALS) and an injury to the posterior meniscotibial ligament of the lateral meniscus (LP); 4) after treating the different injuries using isolated ACLR; v. after treating the different injuries using ACLR with ALSR. The knee kinematics, maximum von Mises stress (Max.S) on the tibial articular cartilage (TC) and force in the ACL graft were compared among the different simulation groups. Results and discussion: Comparing with isolated ACL rupture, combined injury to the ALS caused the largest knee laxity, when a combined PTS of 20° induced the largest Max.S on the TC. The joint stability and Max.S on the TC in the knee with an isolated ACL rupture or a combined rupture of ACL and LP were restored to the intact level after being treated with isolated ACLR. The knee biomechanics after a combined rupture of ACL and ALS were restored to the intact level only when being treated with a combination of ACLR and ALSR using a large graft diameter (6 mm) for ALSR. However, for the knee after ACL rupture combined with a PTS of 20°, the ATT and Max.S on the TC were still greater than the intact knee even after being treated with a combination of ACLR and ALSR. The finite element analysis showed that ACLR should include ALSR when treating ACL ruptures accompanied by ALS rupture. However, pivot shift in knees with a PTS of 20° was not eliminated even after a combined ACLR and ALSR.}, }
@article {pmid39168583, year = {2024}, author = {Memudu, AE and Olukade, BA and Adebayo, OS and Raza, ML}, title = {Coffee and amyotrophic lateral sclerosis (ALS).}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {81-105}, doi = {10.1016/bs.pbr.2024.06.003}, pmid = {39168583}, issn = {1875-7855}, mesh = {*Amyotrophic Lateral Sclerosis/pathology ; Humans ; *Coffee ; Animals ; Neuroprotective Agents/pharmacology ; Oxidative Stress/physiology/drug effects ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive loss of motor neurons. The effective treatments for ALS remain elusive, necessitating exploration into novel preventive strategies. ALS pathogenesis is triggered by oxidative stress which results in neuroinflammation, exicitotoxicity and neuronal cell death. Nutritional mechanism for halting progression of neurodegeneration is through dietary compounds with antioxidants, anti-inflammatory or neuromodulating activity. Coffee is a widely consumed beverage made up of polyphenols, caffeine and other compounds with possible antioxidants and neuro-protective roles. It is important to say that various epidemiological studies have documented association between coffee intake and ALS. This chapter is aimed to present a comprehensive review of existing literature on coffee consumption and ALS, involving epidemiological studies, preclinical research, and its mechanism of actions in animal model of ALS. It highlights key findings regarding the potential neuroprotective properties of coffee constituents such as caffeine, polyphenols, and other bioactive compounds. Furthermore, it discusses possible pathways through which coffee may modulate ALS pathogenesis, including suppressing oxidative stress and neuroinflammation while boosting adenosine function via the adenosine receptor two on the motor neuron cells membrane in the spinal cord to enhance motor function via the corticospinal tract. Overall, this chapter underscores the significance of further research to unravel the specific mechanisms by which coffee exerts its neuroprotective effects in ALS, with the ultimate goal of identifying dietary strategies for ALS prevention and management.}, }
@article {pmid39168577, year = {2024}, author = {Rai, SP and Ansari, AH and Singh, D and Singh, S}, title = {Coffee, antioxidants, and brain inflammation.}, journal = {Progress in brain research}, volume = {289}, number = {}, pages = {123-150}, doi = {10.1016/bs.pbr.2024.06.005}, pmid = {39168577}, issn = {1875-7855}, mesh = {*Coffee/chemistry ; Humans ; *Antioxidants/pharmacology ; Animals ; Neurodegenerative Diseases ; Encephalitis ; Caffeine/pharmacology/administration &amp; dosage ; Neuroinflammatory Diseases ; }, abstract = {Coffee is the most popular beverage in the world and, aside from tea and water, the most often consumed caffeine-containing beverage. Because of its high caffeine concentration, it is typically classified as a stimulant. There are other bioactive ingredients in coffee besides caffeine. The coffee beverage is a blend of several bioactive substances, including diterpenes (cafestol and kahweol), alkaloids (caffeine and trigonelline), and polyphenols (particularly chlorogenic acids in green beans and caffeic acid in roasted coffee beans). Caffeine has also been linked to additional beneficial benefits such as antioxidant and anti-inflammatory properties, which change cellular redox and inflammatory status in a dose-dependent manner. Pyrocatechol, a constituent of roasted coffee that is created when chlorogenic acid is thermally broken down, has anti-inflammatory properties as well. It is postulated that coffee consumption reduces neuroinflammation, which is intimately linked to the onset of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). This review provides an overview of the most recent studies regarding coffee's possible benefits in preventing brain inflammation and neurodegenerative disorders.}, }
@article {pmid39168358, year = {2024}, author = {Ueno, Y and Morishima, Y and Hata, T and Shindo, A and Murata, H and Saito, T and Nakamura, Y and Shindo, K}, title = {Current progress in microRNA profiling of circulating extracellular vesicles in amyotrophic lateral sclerosis: A systematic review.}, journal = {Neurobiology of disease}, volume = {200}, number = {}, pages = {106639}, doi = {10.1016/j.nbd.2024.106639}, pmid = {39168358}, issn = {1095-953X}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood/genetics/diagnosis ; Biomarkers/blood ; *Extracellular Vesicles/metabolism/genetics ; *MicroRNAs/blood/genetics ; }, abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons, leading to death resulting mainly from respiratory failure, for which there is currently no curative treatment. Underlying pathological mechanisms for the development of ALS are diverse and have yet to be elucidated. Non-invasive testing to isolate circulating molecules including microRNA to diagnose ALS has been reported, but circulating extracellular vesicle (EV)-derived microRNA has not been fully studied in the ALS population.<br><br>METHODS: A systematic literature review to explore studies investigating the profile of microRNAs in EVs from blood samples of ALS patients was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.<br><br>RESULTS: Eleven studies including a total of 263 patients with ALS were included in the present systematic review. The majority of patients had sporadic ALS, though a small number of patients with ALS having genetic mutations were included. Seven studies used plasma-derived EVs, and the remaining four studies used serum-derived EVs. RNA sequencing or microarrays were used in eight studies, and quantitative PCR was used in eight studies, of which five studies used RNA sequencing or microarrays for screening and quantitative PCR for validation. There was overlap of miR-199a-3p and miR-199a-5p in three studies.<br><br>CONCLUSIONS: Overall, the systematic review addressed the current advances in the profiling of microRNAs in circulating EVs of ALS patients. Blood samples, isolation of EVs, and microRNA analysis were diverse. Although there was an overlap of miR-199a-3p and miR-199a-5p, collection of further evidence is warranted.}, }
@article {pmid39167487, year = {2024}, author = {Alirzayeva, H and Loureiro, R and Koyuncu, S and Hommen, F and Nabawi, Y and Zhang, WH and Dao, TTP and Wehrmann, M and Lee, HJ and Vilchez, D}, title = {ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114626}, doi = {10.1016/j.celrep.2024.114626}, pmid = {39167487}, issn = {2211-1247}, mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Humans ; *Histones/metabolism ; *RNA-Binding Protein FUS/metabolism/genetics ; *Caenorhabditis elegans/metabolism/genetics ; Animals ; *Mutation/genetics ; *Poly (ADP-Ribose) Polymerase-1/metabolism/genetics ; Motor Neurons/metabolism/pathology ; Poly ADP Ribosylation ; Induced Pluripotent Stem Cells/metabolism ; Protein Binding ; }, abstract = {The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUS[P525L] variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUS[P525L] with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUS[P525L] aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.}, }
@article {pmid39167140, year = {2024}, author = {Yu, L and Wu, N and Choi, O and Nguyen, KD}, title = {Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {73}, number = {11}, pages = {1847-1857}, pmid = {39167140}, issn = {1420-908X}, mesh = {Animals ; *Amyotrophic Lateral Sclerosis/immunology/drug therapy ; *Immunity, Innate/drug effects ; *Glycolysis/drug effects ; *Spinal Cord/immunology/pathology/drug effects/metabolism ; *Mice, Transgenic ; Mice ; Inflammation ; Male ; Disease Models, Animal ; Monocytes/drug effects/immunology ; Mice, Inbred C57BL ; Microglia/drug effects/immunology/metabolism ; Female ; }, abstract = {BACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease.<br><br>METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development.<br><br>RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C&#x2009;+&#x2009;monocytes and spinal cord F4/80&#x2009;+&#x2009;CD45[hi] infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b&#x2009;+&#x2009;cells, comprising both resident F4/80&#x2009;+&#x2009;CD45[low] microglia and F4/80&#x2009;+&#x2009;CD45[hi] infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b&#x2009;+&#x2009;cells, enhances motor function, and prolongs survival in SOD1-G93A mice.<br><br>CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.}, }
@article {pmid39163160, year = {2024}, author = {Purcell, N and Manousakis, G}, title = {Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {42-46}, doi = {10.1097/CND.0000000000000501}, pmid = {39163160}, issn = {1537-1611}, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics ; *Distal Myopathies/genetics/diagnosis ; Founder Effect ; *Mutation ; *Pedigree ; *Phenotype ; T-Cell Intracellular Antigen-1/genetics ; Aged ; Aged, 80 and over ; }, abstract = {Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.}, }
@article {pmid39163156, year = {2024}, author = {Takahashi, K and Hamada, Y and Kobayashi, M and Kobayashi, S and Kanbayashi, T and Hatanaka, Y and Nakayama, T and Imafuku, I and Matsuno, H and Iguchi, Y and Katada, F and Fukutake, T and Ando, T and Mikata, T and Usui, T and Uchino, K and Nishiyama, K and Sonoo, M}, title = {Utility of the Repetitive Nerve Stimulation Test and Needle EMG in the Trapezius Muscle for the Early Diagnosis of ALS.}, journal = {Journal of clinical neuromuscular disease}, volume = {26}, number = {1}, pages = {1-11}, doi = {10.1097/CND.0000000000000479}, pmid = {39163156}, issn = {1537-1611}, support = {19K07966 and 22K07524//Ministry of Education, Science, Sports and Culture of Japan/ ; 19ek0109252h0003//AMED/ ; }, mesh = {Humans ; *Electromyography/methods ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Aged ; Retrospective Studies ; *Electric Stimulation ; *Superficial Back Muscles/physiopathology ; *Sensitivity and Specificity ; Adult ; Early Diagnosis ; }, abstract = {OBJECTIVES: To document the utility of decremental responses in the repetitive nerve stimulation test (RNS) and spontaneous activities in needle electromyography (EMG) in the trapezius muscle for the diagnosis of amyotrophic lateral sclerosis.<br><br>METHODS: Subjects were retrospectively identified from our EMG database. Cervical spondylosis was represented as a disease control group. We investigated the sensitivity and specificity of RNS and EMG in the trapezius muscle and those of diagnostic criteria including the Gold Coast criteria (GCC).<br><br>RESULTS: We reviewed 120 patients with amyotrophic lateral sclerosis and 17 patients with cervical spondylosis. "RNS or EMG" achieved the highest sensitivity (85%). The specificity was the highest for RNS (94%). Addition of RNS of the deltoid muscle achieved 98% sensitivity in the upper-limb onset amyotrophic lateral sclerosis. The sensitivity of the GCC was very high (88%).<br><br>CONCLUSIONS: Neurophysiological parameters investigated in this study having close to 100% specificities or sensitivities are useful as complements to the GCC.}, }
@article {pmid39163111, year = {2024}, author = {Fenoy, A}, title = {Scientific plurality and amyotrophic lateral sclerosis (ALS): A philosophical and historical perspective on Charcot's texts.}, journal = {Journal of the history of the neurosciences}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/0964704X.2024.2380635}, pmid = {39163111}, issn = {1744-5213}, abstract = {The history of amyotrophic lateral sclerosis (ALS)-also known as Charcot's disease, Lou Gehrig's disease, and motor neuron disease (MND)-freezes the texts of the scientist and physician Jean-Martin Charcot in a hagiographic narrative describing a brilliant discovery, based on the anatomo-clinical method. This narrative is often used by biologists and physicians as a reference point. This article shows that the use of the hagiographic register faces limitations. In particular, it obscures points of interest from Charcot's texts on ALS, such as the epistemological and ontological implications of scientific plurality in medicine. Although Charcot recognized the importance of scientific plurality in medicine, he prioritized the approaches and conferred the most important epistemic authority on clinical and pathological observations. In his view, animal modeling remains secondary to the understanding of disease. The concept of ALS and its diagnostic operability are the result of symptoms and lesions. By studying the past, we can highlight the specific features of the present. Today, although the ALS concept retains its diagnostic and clinical relevance, it is increasingly called into question in etiological and mechanistic research. Despite these differences, Charcot's reflections are a reminder of the importance of theoretical thinking on scientific plurality, all the more so today in the context of ALS research, in which combining different approaches is increasingly valued to understand the phenotypic and genetic heterogeneity of ALS.}, }
@article {pmid39162129, year = {2024}, author = {Mazzini, L and De Marchi, F and Buzanska, L and Follenzi, A and Glover, JC and Gelati, M and Lombardi, I and Maioli, M and Mesa-Herrera, F and Mitrečić, D and Olgasi, C and Pivoriūnas, A and Sanchez-Pernaute, R and Sgromo, C and Zychowicz, M and Vescovi, A and Ferrari, D}, title = {Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis.}, journal = {Expert opinion on biological therapy}, volume = {24}, number = {9}, pages = {933-954}, doi = {10.1080/14712598.2024.2392307}, pmid = {39162129}, issn = {1744-7682}, mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Stem Cell Transplantation ; Disease Models, Animal ; Clinical Trials as Topic ; }, abstract = {INTRODUCTION: Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published.<br><br>AREAS COVERED: This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined.<br><br>EXPERT OPINION: Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.}, }
@article {pmid39161942, year = {2024}, author = {Marcu, IR and Rogoveanu, OC and Pădureanu, R and Pădureanu, V and Dop, D}, title = {Diagnostic elements in amyotrophic lateral sclerosis: A case report.}, journal = {Biomedical reports}, volume = {21}, number = {4}, pages = {141}, pmid = {39161942}, issn = {2049-9442}, abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that involves the degeneration of both upper and lower motor neurons responsible for controlling voluntary muscle activity. Most people with ALS die within 3-5 years due to respiratory failure. The current study presents the case of a 68-year-old woman diagnosed with ALS based on the subjective and objective findings from the patient's initial physiotherapy assessment and on neurophysiological tests. Physiotherapy interventions are aiming to maintain the patient's strength, balance and functional independence for as long as possible. The present case report aimed to highlight that a multidisciplinary team approach is necessary for the management of a progressive degenerative disease such as ALS.}, }
@article {pmid39158304, year = {2024}, author = {Tong, Z and Zhang, X and Guo, X and Wu, G and Cao, S and Zhang, Y and Meng, X and Wang, T and Wang, Y and Song, Y and Yang, R and Du, Z}, title = {Delivery of Yersinia pestis antigens via Escherichia coli outer membrane vesicles offered improved protection against plague.}, journal = {mSphere}, volume = {9}, number = {9}, pages = {e0033024}, pmid = {39158304}, issn = {2379-5042}, support = {2022YFC2303503//National Key Research and Development of China/ ; 32070136//MOST | National Natural Science Foundation of China (NSFC)/ ; }, mesh = {Animals ; *Plague/prevention &amp; control/immunology ; *Antigens, Bacterial/immunology/genetics ; *Bacterial Outer Membrane Proteins/immunology/genetics ; *Escherichia coli/genetics/immunology ; *Yersinia pestis/immunology/genetics ; Mice ; *Pore Forming Cytotoxic Proteins/immunology/genetics ; *Plague Vaccine/immunology/administration &amp; dosage/genetics ; Female ; *Antibodies, Bacterial/blood/immunology ; Mice, Inbred BALB C ; Recombinant Fusion Proteins/immunology/genetics ; Bacterial Outer Membrane/immunology ; Bacterial Proteins ; }, abstract = {Outer membrane vesicles (OMVs) from Gram-negative bacteria can be used as a vaccine platform to deliver heterologous antigens. Here, the major protective antigens of Yersinia pestis, F1 and LcrV, were fused either with the leader sequence or the transmembrane domain of the outer membrane protein A (OmpA), resulting in chimeric proteins OmpA-ls-F1V and OmpA46-159-F1V, respectively. We show that OmpA-ls-F1V and OmpA46-159-F1V can be successfully delivered into the lumen and membrane of the OMVs of Escherichia coli, respectively. Mutation of ompA but not tolR in E. coli enhanced the delivery efficiency of OmpA-ls-F1V into OMVs. The OmpA-ls-F1V protein comprises up to 20% of the total protein in OMVs derived from the ompA mutant (OMVdA-ALS-F1V), a proportion significantly higher than the 1% observed for OmpA46-159-F1V in OMVs produced by an ompA mutant that expresses OmpA46-159-F1V, referred to as OMVdA-LATM5-F1V. Intramuscular (i.m.) immunization of mice with OMVdA-ALS-F1V induced significantly higher levels of serum anti-LcrV and anti-F1 IgG, and provided higher efficacy in protection against subcutaneous (s.c.) Y. pestis infection compared to OMVdA-LATM5-F1V and the purified recombinant F1V (rF1V) protein adsorbed to aluminum hydroxide. The three-dose i.m. immunization with OMVdA-ALS-F1V, administered at 14-day intervals, provides complete protection to mice against s.c. infection with 130 LD50 of Y. pestis 201 and conferred 80% against intranasal (i.n.) challenge with 11.4 LD50 of Y. pestis 201. Taken together, our findings indicate that the engineered OMVs containing F1V fused with the leader sequence of OmpA provide significantly higher protection than rF1V against both s.c. and i.n. infection of Y. pestis and more balanced Th1/Th2 responses.IMPORTANCEThe two major protective antigens of Y. pestis, LcrV and F1, have demonstrated the ability to elicit systemic and local mucosal immune responses as subunit vaccines. However, these vaccines have failed to provide adequate protection against pneumonic plague in African green monkeys. Here, Y. pestis F1 and LcrV antigens were successfully incorporated into the lumen and the surface of the outer membrane vesicles (OMVs) of E. coli by fusion either with the leader sequence or the transmembrane domain of OmpA. We compared the humoral immune response elicited by these OMV formulations and their protective efficacy in mice against Y. pestis. Our results demonstrate that the plague OMV vaccine candidates can induce robust protective immunity against both s.c. and i.n. Y. pestis infections, surpassing the effectiveness of rF1V. In addition, immunization with OMVs generated a relatively balanced Th1/Th2 immune response compared to rF1V immunization. These findings underscore the potential of OMVs-based plague vaccines for further development.}, }
@article {pmid39157517, year = {2024}, author = {Zhang, Y and Zhang, Q and Liu, Q and Zhao, Y and Xu, W and Hong, C and Xu, C and Qi, X and Qi, X and Liu, B}, title = {Fine mapping and functional validation of the maize nicosulfuron-resistance gene CYP81A9.}, journal = {Frontiers in plant science}, volume = {15}, number = {}, pages = {1443413}, pmid = {39157517}, issn = {1664-462X}, abstract = {Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 (CYP81A9), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo. Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9, thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.}, }
@article {pmid39156974, year = {2024}, author = {Fenili, G and Scaricamazza, S and Ferri, A and Valle, C and Paronetto, MP}, title = {Physical exercise in amyotrophic lateral sclerosis: a potential co-adjuvant therapeutic option to counteract disease progression.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1421566}, pmid = {39156974}, issn = {2296-634X}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the selective degeneration of upper and lower motor neurons, leading to progressive muscle weakness and atrophy. The mean survival time is two to five years. Although the hunt for drugs has greatly advanced over the past decade, no cure is available for ALS yet. The role of intense physical activity in the etiology of ALS has been debated for several decades without reaching a clear conclusion. The benefits of organized physical activity on fitness and mental health have been widely described. Indeed, by acting on specific mechanisms, physical activity can influence the physiology of several chronic conditions. It was shown to improve skeletal muscle metabolism and regeneration, neurogenesis, mitochondrial biogenesis, and antioxidant defense. Interestingly, all these pathways are involved in ALS pathology. This review will provide a broad overview of the effect of different exercise protocols on the onset and progression of ALS, both in humans and in animal models. Furthermore, we will discuss challenges and opportunities to exploit physiological responses of imposed exercise training for therapeutic purposes.}, }
@article {pmid39156432, year = {2024}, author = {Kaye, AD and Sala, KR and Dethloff, D and Norton, M and Moss, C and Plessala, MJ and Derouen, AG and Lopez Torres, Y and Kim, J and Tirumala, S and Shekoohi, S and Varrassi, G}, title = {The Evolving Use of Gold Nanoparticles as a Possible Reversal Agent for the Symptoms of Neurodegenerative Diseases: A Narrative Review.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64846}, pmid = {39156432}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are broadly hallmarked by impaired energy metabolism and toxic intracellular accumulations such as damaged organelles or reactive oxygen species (ROS). Gold nanoparticles readily cross the blood-brain barrier and increase nicotinamide adenine dinucleotide + hydrogen (NADH) oxidation to nicotinamide adenine dinucleotide (NAD+), which is vital for intracellular energy generation, cellular repair, and protection from ROS. Thus, the use of gold nanoparticles to treat and potentially reverse cellular injury seen in neurodegenerative disease has been an area of ongoing research. This systematic review explores current literature regarding the use of gold nanoparticle therapy in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In vitro studies of CNM-Au8 (Clene Nanomedicine, Salt Lake City, UT) have been shown to reduce TDP-43 aggregates associated with ALS. These studies also exhibited the neuroprotective effects of CNM-Au8 in rat primary neurons exposed to amyloid-beta peptides, which are associated with Alzheimer's disease. In animal models of MS, oral delivery of CNM-Au8 was demonstrated to produce robust and significant remyelination activity, oligodendrocyte maturation, and expression of myelin markers. In these same MS animal models, CNM-Au8 improved the motor function of cuprizone-treated mice in both open-field and kinematic gait studies. Recent phase II trials of CNM-Au8 in 13 patients with Parkinson's disease and 11 patients with stable relapsing MS demonstrated a statistically significant increase in the NAD+/NADH ratio across two cohorts. As the current data repeatedly suggest, these gold nanoparticles are efficacious for the treatment and reversal of symptoms across these varying neurodegenerative pathologies. Further opportunities exist for increasing human trials and eventually incorporating this new technology into existing treatment regimens.}, }
@article {pmid39154890, year = {2024}, author = {Brebner, C and Asamoah-Boaheng, M and Zaidel, B and Yap, J and Scheuermeyer, F and Mok, V and Hutton, J and Meckler, G and Schlamp, R and Christenson, J and Grunau, B}, title = {The association of intravenous vs. humeral-intraosseous vascular access with patient outcomes in adult out-of-hospital cardiac arrests.}, journal = {Resuscitation}, volume = {202}, number = {}, pages = {110360}, doi = {10.1016/j.resuscitation.2024.110360}, pmid = {39154890}, issn = {1873-1570}, mesh = {Humans ; *Out-of-Hospital Cardiac Arrest/therapy/mortality ; Male ; Female ; *Infusions, Intraosseous/methods ; Middle Aged ; *Cardiopulmonary Resuscitation/methods ; *Registries ; Aged ; Humerus ; Emergency Medical Services/methods ; Treatment Outcome ; Adult ; Propensity Score ; }, abstract = {AIM: While intravenous (IV) vascular access for out-of-hospital cardiac arrest (OHCA) resuscitation is standard, humeral-intraosseous (IO) access is commonly used, despite few supporting data. We investigated the association between IV vs. humeral-IO and outcomes.<br><br>METHODS: We utilized BC Cardiac Arrest Registry data, including adult OHCA where the first-attempted intra-arrest vascular access route performed by advanced life support (ALS)-trained paramedics was IV or humeral-IO. We fit a propensity-score adjusted model with inverse probability treatment weighting to estimate the association between IV vs. humeral-IO routes and favorable neurological outcomes (CPC 1-2) and survival at hospital discharge. We repeated models within subgroups defined by initial cardiac rhythm.<br><br>RESULTS: We included 2,112 cases; the first-attempted route was IV (n&#xa0;=&#xa0;1,575) or humeral-IO (n&#xa0;=&#xa0;537). Time intervals from ALS-paramedic on-scene arrival to vascular access (6.6 vs. 6.9&#xa0;min) and epinephrine administration (9.0 vs. 9.3&#xa0;min) were similar between IV and IO groups, respectively. Among IV and humeral-IO groups, 98 (6.2%) and 20 (3.7%) had favorable neurological outcomes. Compared to humeral-IO, an IV-first approach was associated with improved hospital-discharge favorable neurological outcomes (AOR 1.7; 95% CI 1.1-2.7) and survival (AOR 1.5; 95% CI 1.0-2.3). Among shockable rhythm cases, an IV-first approach was associated with improved favorable neurological outcomes (AOR 4.2; 95% CI 2.1-8.2), but not among non-shockable rhythm cases (AOR 0.73; 95% CI 0.39-1.4).<br><br>CONCLUSION: An IV-first approach, compared to humeral-IO, for intra-arrest resuscitation was associated with an improved odds of favorable neurological outcomes and survival to hospital discharge. This association was seen among an initial shockable rhythm, but not non-shockable rhythm, subgroups.}, }
@article {pmid39154745, year = {2024}, author = {Vu, D and Park, M and Alhusayen, R}, title = {Response to Chawla et al, "Response to Vu et al's "Efficacy of moxifloxacin as a mono-antibiotic therapy for hidradenitis suppurativa: A retrospective cohort study"".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e177-e178}, doi = {10.1016/j.jaad.2024.08.013}, pmid = {39154745}, issn = {1097-6787}, }
@article {pmid39154744, year = {2024}, author = {Li, JN and Sechi, A and Tosti, A}, title = {Response to Costa Fechine et al's "Correlation of clinical and trichoscopy features with the degree of histologic inflammation in lichen planopilaris and frontal fibrosing alopecia in a cross-sectional study".}, journal = {Journal of the American Academy of Dermatology}, volume = {91}, number = {6}, pages = {e187-e188}, doi = {10.1016/j.jaad.2024.07.1495}, pmid = {39154744}, issn = {1097-6787}, }
@article {pmid39153378, year = {2024}, author = {Maramai, S and Saletti, M and Paolino, M and Giuliani, G and Cazzola, J and Spaiardi, P and Talpo, F and Frosini, M and Pifferi, A and Ballarotto, M and Carotti, A and Poggialini, F and Vagaggini, C and Dreassi, E and Giorgi, G and Dondio, G and Cappelli, A and Rosario Biella, G and Anzini, M}, title = {Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {112}, number = {}, pages = {117872}, doi = {10.1016/j.bmc.2024.117872}, pmid = {39153378}, issn = {1464-3391}, mesh = {Animals ; Humans ; Dose-Response Relationship, Drug ; Ligands ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Riluzole/pharmacology/chemical synthesis/chemistry ; Structure-Activity Relationship ; Thiazepines/chemical synthesis/chemistry/pharmacology ; }, abstract = {Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na[+] and K[+] currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.}, }
@article {pmid39153346, year = {2025}, author = {Khazaei, K and Roshandel, P and Parastar, H}, title = {Visible-short wavelength near infrared hyperspectral imaging coupled with multivariate curve resolution-alternating least squares for diagnosis of breast cancer.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {124966}, doi = {10.1016/j.saa.2024.124966}, pmid = {39153346}, issn = {1873-3557}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis ; Least-Squares Analysis ; *Principal Component Analysis ; *Spectroscopy, Near-Infrared/methods ; *Hyperspectral Imaging/methods ; Multivariate Analysis ; Discriminant Analysis ; }, abstract = {This study investigates the application of visible-short wavelength near-infrared hyperspectral imaging (Vis-SWNIR HSI) in the wavelength range of 400-950 nm and advanced chemometric techniques for diagnosing breast cancer (BC). The research involved 56 ex-vivo samples encompassing both cancerous and non-cancerous breast tissue from females. First, HSI images were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) to exploit pure spatial and spectral profiles of active components. Then, the MCR-ALS resolved spatial profiles were arranged in a new data matrix for exploration and discrimination between benign and cancerous tissue samples using principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The PLS-DA classification accuracy of 82.1 % showed the potential of HSI and chemometrics for non-invasive detection of BC. Additionally, the resolved spectral profiles by MCR-ALS can be used to track the changes in the breast tissue during cancer and treatment. It is concluded that the proposed strategy in this work can effectively differentiate between cancerous and non-cancerous breast tissue and pave the way for further studies and potential clinical implementation of this innovative approach, offering a promising avenue for improving early detection and treatment outcomes in BC patients.}, }
@article {pmid39153108, year = {2024}, author = {Hosseini, L and Babaie, S and Shahabi, P and Fekri, K and Shafiee-Kandjani, AR and Mafikandi, V and Maghsoumi-Norouzabad, L and Abolhasanpour, N}, title = {Klotho: molecular mechanisms and emerging therapeutics in central nervous system diseases.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {913}, pmid = {39153108}, issn = {1573-4978}, mesh = {*Klotho Proteins ; Humans ; *Central Nervous System Diseases/metabolism/drug therapy ; *Signal Transduction ; Animals ; Oxidative Stress ; Glucuronidase/metabolism/genetics ; Autophagy ; Aging/metabolism/genetics ; }, abstract = {Klotho is recognized as an aging-suppressor protein that is implicated in a variety of processes and signaling pathways. The anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-tumor bioactivities of klotho have extended its application in neurosciences and made the protein popular for its lifespan-extending capacity. Furthermore, it has been demonstrated that klotho levels would reduce with aging and numerous pathologies, particularly those related to the central nervous system (CNS). Evidence supports the idea that klotho can be a key therapeutic target in CNS diseases such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and Alzheimer's disease. Reviewing the literature suggests that the upregulation of klotho expression regulates various signaling pathways related to autophagy, oxidative stress, inflammation, cognition, and ferroptosis in neurological disorders. Therefore, it has been of great interest to develop drugs or agents that boost or restore klotho levels. In this regard, the present review was designed and aimed to gather the delegated documents regarding the therapeutic potential of Klotho in CNS diseases focusing on the molecular and cellular mechanisms.}, }
@article {pmid39152573, year = {2024}, author = {Dubbioso, R and Iannotti, FA and Senerchia, G and Verde, R and Iuzzolino, VV and Spisto, M and Fasolino, I and Manganelli, F and Di Marzo, V and Piscitelli, F}, title = {Circulating endocannabinoidome signatures of disease activity in amyotrophic lateral sclerosis.}, journal = {European journal of neurology}, volume = {31}, number = {10}, pages = {e16400}, pmid = {39152573}, issn = {1468-1331}, support = {E53D23019760001//National Recovery and Resilience Plan (NRRP)/ ; E53D23011330006//Ministry of University and Research (MUR)/ ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/blood ; *Endocannabinoids/blood ; Male ; Female ; Middle Aged ; Aged ; Adult ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood ; }, abstract = {BACKGROUND AND PURPOSE: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients.<br><br>METHODS: Serum concentrations of 2-arachidonoylglycerol and N-arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.<br><br>RESULTS: Most circulating mediators were higher in ALS than HCs (all p&#x2009;<&#x2009;0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p&#x2009;<&#x2009;0.02), which were confirmed by the longitudinal study (all p&#x2009;<&#x2009;0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the 'severe' cluster showed significantly higher levels of OEA and PEA and lower levels of 2-DHG compared to NALS and HCs.<br><br>CONCLUSION: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a 'one-fits-all', therapeutic approach targeting the endocannabinoidome.}, }
@article {pmid39150867, year = {2024}, author = {Pienaar, K and Kelaita, P and Murphy, D}, title = {COVID-19 and the biopolitics of stigma in public housing: dividing practices and community boundaries in pandemic times.}, journal = {Health sociology review : the journal of the Health Section of the Australian Sociological Association}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/14461242.2024.2390019}, pmid = {39150867}, issn = {1446-1242}, abstract = {The COVID-19 'hard lockdowns' in Melbourne, Australia in 2020 targeted public housing estates thus trading on perceptions of risk associated with public housing as some of the most stigmatised sites in post-industrial cities. This article draws on interviews with Melbourne public housing tenants on their experience of COVID-19 lockdowns to analyse the place of stigma in residents' accounts. Pairing Wacquant et al's (2014) concept of 'territorial stigma' with sociological work on the biopolitics of stigma we consider the dynamics of stigma, tracing how it functions to delimit community boundaries and justify pandemic containment measures. Residents navigate multiple layers of stigma, including stereotypes of public housing, normative judgements of neighbouring residents, and a broader public housing system riven with structural issues. Members of these communities are both the targets of stigma and seek to distance themselves from those seen as vectors of stigma. Our participants report mobilising social distancing strategies couched in normative assessments of perceived risk based on physical appearance, presumed drug use and past conduct. We explore the implications of these enactments of territorial stigma and trace the logics of abjection that construct public housing as deprived urban zones, home to abject 'Others' perceived as threatening the health of the community.}, }
@article {pmid39149866, year = {2024}, author = {Cabeza-Fernández, S and Hernández-Rojas, R and Casillas-Bajo, A and Patel, N and de la Fuente, AG and Cabedo, H and Gomez-Sanchez, JA}, title = {Schwann cell JUN expression worsens motor performance in an amyotrophic lateral sclerosis mouse model.}, journal = {Glia}, volume = {72}, number = {12}, pages = {2178-2189}, doi = {10.1002/glia.24604}, pmid = {39149866}, issn = {1098-1136}, support = {PID2019-109762RB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; PID2022-141062OB-I00//Agencia Estatal de Investigaci&#xf3;n/ ; CIPROM/2021/048//Conselleria d'Educaci&#xf3;, Investigaci&#xf3;, Cultura i Esport/ ; GRISOLIAP/2021/026//Conselleria d'Educaci&#xf3;, Investigaci&#xf3;, Cultura i Esport/ ; }, mesh = {Animals ; *Schwann Cells/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism/physiopathology ; *Mice, Transgenic ; *Disease Models, Animal ; *Motor Neurons/pathology/metabolism ; Proto-Oncogene Proteins c-jun/metabolism/genetics ; Mice ; Spinal Cord/metabolism/pathology ; Superoxide Dismutase/genetics/metabolism ; Axons/pathology/metabolism/physiology ; Mice, Inbred C57BL ; }, abstract = {Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1[G93A] mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1[G93A] mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.}, }
@article {pmid39147172, year = {2024}, author = {Acton, S and O'Donnell, MM and Periyasamy, K and Dixit, B and Eishingdrelo, H and Hill, C and Paul Ross, R and Chesnel, L}, title = {LPA3 agonist-producing Bacillus velezensis ADS024 is efficacious in multiple neuroinflammatory disease models.}, journal = {Brain, behavior, and immunity}, volume = {121}, number = {}, pages = {384-402}, doi = {10.1016/j.bbi.2024.08.024}, pmid = {39147172}, issn = {1090-2139}, mesh = {*Bacillus/metabolism ; Animals ; Mice ; Humans ; *Neuroinflammatory Diseases/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Multiple Sclerosis/metabolism ; Male ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14-3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component.}, }
@article {pmid39146882, year = {2024}, author = {Aizawa, H and Nagumo, S and Hideyama, T and Kato, H and Kwak, S and Terashi, H and Suzuki, Y and Kimura, T}, title = {Morphometric analysis of spinal motor neuron degeneration in sporadic amyotrophic lateral sclerosis.}, journal = {Journal of the neurological sciences}, volume = {464}, number = {}, pages = {123177}, doi = {10.1016/j.jns.2024.123177}, pmid = {39146882}, issn = {1878-5883}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/metabolism ; Male ; Female ; Middle Aged ; Aged ; *DNA-Binding Proteins/metabolism ; *Spinal Cord/pathology/metabolism ; *Nerve Degeneration/pathology ; Anterior Horn Cells/pathology ; Motor Neurons/pathology/metabolism ; }, abstract = {OBJECTIVES: This study aimed to clarify the relationship between 43-kDa TAR DNA-binding protein (TDP-43) pathology and spinal cord anterior horn motor neuron (AHMN) atrophy in sporadic amyotrophic lateral sclerosis (SALS).<br><br>METHODS: Eight patients with SALS and 12 controls were included in this study. Formalin-fixed specimens of lumbar spinal cord samples were paraffin-embedded and sectioned at the level of the fourth lumbar spinal cord with a 4&#xa0;&#x3bc;m thickness. Using a microscope, the long diameters of the neurons with nucleoli were measured in spinal AHMNs stained with an anti-SMI-32 antibody. AHMNs were divided into medial and lateral nuclei for statistical analysis. We also used previously reported data to measure the long diameter of AHMNs with initial TDP-43 pathology, in which TDP-43 was present both in the nucleus and cytoplasm.<br><br>RESULTS: The long diameter of the lumbar spinal AHMNs in patients with SALS was smaller in the medial nucleus (42.54&#xa0;&#xb1;&#xa0;9.33&#xa0;&#x3bc;m, n&#xa0;=&#xa0;24) and the lateral nucleus (49.41&#xa0;&#xb1;&#xa0;13.86&#xa0;&#x3bc;m, n&#xa0;=&#xa0;129) than in controls (medial nucleus: 55.84&#xa0;&#xb1;&#xa0;13.49&#xa0;&#x3bc;m, n&#xa0;=&#xa0;85, p&#xa0;<&#xa0;0.001; lateral nucleus: 62.39&#xa0;&#xb1;&#xa0;13.29&#xa0;&#x3bc;m, n&#xa0;=&#xa0;756, p&#xa0;<&#xa0;0.001, Mann-Whitney U test). All 21 motor neurons with initial TDP-43 pathology were in the lateral nucleus, and their long diameter (67.60&#xa0;&#xb1;&#xa0;18.3&#xa0;&#x3bc;m, p&#xa0;=&#xa0;0.352) was not significantly different from that of controls.<br><br>CONCLUSION: Motor neuron atrophy in SALS does not occur during the initial stages of TDP-43 pathology, and TDP-43 pathology is already advanced in the atrophied motor neurons.}, }
@article {pmid39146816, year = {2025}, author = {Sun, Q and Chai, L and Yang, X and Zhang, W and Li, Z}, title = {Hollow tubular sea-urchin structure with high catalytic activity of NiCo2Se4@CS2 cathodes for high-performance Al/S batteries.}, journal = {Journal of colloid and interface science}, volume = {677}, number = {Pt B}, pages = {284-292}, doi = {10.1016/j.jcis.2024.08.071}, pmid = {39146816}, issn = {1095-7103}, abstract = {The shuttle effect of aluminum polysulfides (AlPSs) have been a source of concern for studying Al/S batteries. Due to the weak adsorption of CS composites, research on cathode materials for Al/S batteries has been delayed. As it is generally known that Al2S3 decomposition demands a large Gibbs free energy, this work has tried to reduce the Al2S3 decomposition potential energy. Herein, the Ni/Co bimetallic selenide reduces the energy barrier conversion and mitigates the polarization effects, while morphology control enables the storage and anchoring of S, alleviating the shuttle effect. Additionally, the intermediate products serve as single-atom catalysts, increasing the active sites, synergistically enhancing the ion diffusion kinetics. DFT calculations verify that NiCo2Se4 has a moderate Gibbs free energy change during the rate-limiting step of S reduction and the most robust adsorption energy to Al2S3. NiCo2Se4@CS2/Al has a remaining capacity of 135 mAh/g after 450 cycles (at 200 mA g[-1]), pioneering novel ideas for the development of Al/S batteries.}, }
@article {pmid39146722, year = {2024}, author = {Ginanneschi, F and Pucci, B and Casali, S and Lissandri, C and Giannini, F and Rossi, A}, title = {Factors associated with Edinburgh Cognitive and Behavioural ALS Screen (ECAS) alteration at time of diagnosis, in amyotrophic lateral sclerosis.}, journal = {Clinical neurology and neurosurgery}, volume = {245}, number = {}, pages = {108499}, doi = {10.1016/j.clineuro.2024.108499}, pmid = {39146722}, issn = {1872-6968}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; Male ; Female ; Middle Aged ; Aged ; C9orf72 Protein/genetics ; Neuropsychological Tests ; Adult ; Mutation ; Cohort Studies ; }, abstract = {BACKGROUND: Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a validated assessment designed to screen cognitive functions and behavioral disorders in amyotrophic lateral sclerosis (ALS). Objective of this study is to determine the factors associated with ECAS impairment in a cohort of ALS patients without a co-morbid diagnosis of dementia, at the time of diagnosis.<br><br>METHODS: We enrolled 71 non-demented ALS patient. We collected clinical and demographic data, ALS familiarity, analysis of the most commonly mutated genes in ALS, ALS Milano Torino Staging System and ALS Functional Rate Scale revised scores, progression rate; finally, we recorded whether symptoms onset involved spinal or bulbar area. The alteration of the ECAS was estimated based on age and education-adjusted-validated cut off for each of the items included in ECAS. A multivariable regression analysis was done.<br><br>RESULTS: The significant determinants of ECAS alterations were: bulbar onset in both ALS-specific test and total ECAS score; bulbar onset and familiarity in ALS-non-specific test; finally, familiarity and diagnosis delay in ALS-behavioral test. All the subjects carrying C9orf72 mutations had alteration of both total ECAS score and ALS-specific tests.<br><br>DISCUSSION: At diagnosis, bulbar-onset ALS, family history, diagnosis delay and C9orf72 hexanucleotide repeat expansion may contribute to impairment of ECAS.}, }
@article {pmid39146246, year = {2024}, author = {Hutten, S and Chen, JX and Isaacs, AM and Dormann, D}, title = {Poly-GR Impairs PRMT1-Mediated Arginine Methylation of Disease-Linked RNA-Binding Proteins by Acting as a Substrate Sink.}, journal = {Biochemistry}, volume = {63}, number = {17}, pages = {2141-2152}, doi = {10.1021/acs.biochem.4c00308}, pmid = {39146246}, issn = {1520-4995}, mesh = {*Protein-Arginine N-Methyltransferases/metabolism/genetics ; Humans ; *Arginine/metabolism ; Methylation ; *Repressor Proteins/metabolism/genetics ; *RNA-Binding Proteins/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism/genetics ; Frontotemporal Dementia/metabolism/genetics ; C9orf72 Protein/metabolism/genetics ; HEK293 Cells ; }, abstract = {Dipeptide repeat proteins (DPRs) are aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases characterized by the cytoplasmic mislocalization and aggregation of RNA-binding proteins (RBPs). In particular, arginine (R)-rich DPRs (poly-GR and poly-PR) have been suggested to promiscuously interact with multiple cellular proteins and thereby exert high cytotoxicity. Components of the protein arginine methylation machinery have been identified as modulators of DPR toxicity and/or potential cellular interactors of R-rich DPRs; however, the molecular details and consequences of such an interaction are currently not well understood. Here, we demonstrate that several members of the family of protein arginine methyltransferases (PRMTs) can directly interact with R-rich DPRs in vitro and in the cytosol. In vitro, R-rich DPRs reduce solubility and promote phase separation of PRMT1, the main enzyme responsible for asymmetric arginine-dimethylation (ADMA) in mammalian cells, in a concentration- and length-dependent manner. Moreover, we demonstrate that poly-GR interferes more efficiently than poly-PR with PRMT1-mediated arginine methylation of RBPs such as hnRNPA3. We additionally show by two alternative approaches that poly-GR itself is a substrate for PRMT1-mediated arginine dimethylation. We propose that poly-GR may act as a direct competitor for arginine methylation of cellular PRMT1 targets, such as disease-linked RBPs.}, }
@article {pmid39145860, year = {2024}, author = {Gondo, TF and Huang, F and Marungruang, N and Heyman-Lindén, L and Turner, C}, title = {Investigating the quality of extraction and quantification of bioactive compounds in berries through liquid chromatography and multivariate curve resolution.}, journal = {Analytical and bioanalytical chemistry}, volume = {416}, number = {24}, pages = {5387-5400}, pmid = {39145860}, issn = {1618-2650}, support = {2018-01863//Svenska Forskningsr&#xe5;det Formas/ ; }, mesh = {*Fruit/chemistry ; Multivariate Analysis ; Chromatography, Liquid/methods ; Polyphenols/analysis ; Least-Squares Analysis ; Plant Extracts/chemistry ; Anthocyanins/analysis/chemistry ; Phenols/analysis/chemistry ; Chromatography, High Pressure Liquid/methods ; Antioxidants/analysis/chemistry ; }, abstract = {Berries are a rich source of natural antioxidant compounds, which are essential to profile, as they add to their nutritional value. However, the complexity of the matrix and the structural diversity of these compounds pose challenges in extraction and chromatographic separation. By relying on multivariate curve resolution alternating least squares (MCR-ALS) ability to extract components from complex spectral mixtures, our study evaluates the contributions of various extraction techniques to interference, extractability, and quantifying different groups of overlapping compounds using liquid chromatography diode array detection (LC-DAD) data. Additionally, the combination of these methods extends its applicability to evaluate polyphenol degradation in stored berry smoothies, where evolving factor analysis (EFA) is also used to elucidate degradation products. Results indicate that among the extraction techniques, ultrasonication-assisted extraction employing 1% formic acid in methanol demonstrated superior extractability and selectivity for the different phenolic compound groups, compared with both pressurized liquid extraction and centrifugation of the fresh berry smoothie. Employing MCR-ALS on the LC-DAD data enabled reliable estimation of total amounts of compound classes with high spectral overlaps. Degradation studies revealed significant temperature-dependent effects on anthocyanins, with at least 50% degradation after 7 months of storage at room temperature, while refrigeration and freezing maintained fair stability for at least 12 months. The EFA model estimated phenolic derivatives as the main possible degradation products. These findings enhance the reliability of quantifying polyphenolic compounds and understanding their stability during the storage of berry products.}, }
@article {pmid39145609, year = {2024}, author = {Adil, O and Adeyeye, C and Shamsi, MH}, title = {Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.}, journal = {ACS sensors}, volume = {9}, number = {9}, pages = {4748-4757}, doi = {10.1021/acssensors.4c01150}, pmid = {39145609}, issn = {2379-3694}, mesh = {*Graphite/chemistry ; Humans ; *Biomarkers/cerebrospinal fluid ; *Electrochemical Techniques/methods ; *Lasers ; Immunoassay/methods ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; Electrodes ; Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Limit of Detection ; Biosensing Techniques/methods ; }, abstract = {There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.}, }
@article {pmid39144751, year = {2024}, author = {Szebényi, K and Vargová, I and Petrova, V and Turečková, J and Gibbons, GM and Řehořová, M and Abdelgawad, M and Sándor, A and Marekova, D and Kwok, JCF and Jendelová, P and Fawcett, JW and Lakatos, A}, title = {Inhibition of PHLDA3 expression in human superoxide dismutase 1-mutant amyotrophic lateral sclerosis astrocytes protects against neurotoxicity.}, journal = {Brain communications}, volume = {6}, number = {4}, pages = {fcae244}, pmid = {39144751}, issn = {2632-1297}, abstract = {Pleckstrin homology-like domain family A-member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin homology-like domain family A-member 3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of pleckstrin homology-like domain family A-member 3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that pleckstrin homology-like domain family A-member 3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced ALS and even control spinal astrocytes with a lower pleckstrin homology-like domain family A-member 3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing pleckstrin homology-like domain family A-member 3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.}, }
@article {pmid39144569, year = {2024}, author = {Choudhury, C and Egleton, JE and Butcher, NJ and Russell, AJ and Minchin, RF}, title = {Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration.}, journal = {ACS pharmacology &amp; translational science}, volume = {7}, number = {8}, pages = {2326-2332}, pmid = {39144569}, issn = {2575-9108}, abstract = {Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.}, }
@article {pmid39144302, year = {2024}, author = {Chen, XF and Lin, JP and Zhou, H and Kang, BZ and Nayak, R and Gao, L and Jiang, SS and Wang, F}, title = {The relationship between the collagen score at the anastomotic site of esophageal squamous cell carcinoma and anastomotic leakage.}, journal = {Journal of thoracic disease}, volume = {16}, number = {7}, pages = {4515-4524}, pmid = {39144302}, issn = {2072-1439}, abstract = {BACKGROUND: Anastomotic leakage (AL) has always been one of the most serious complications of esophagectomy with gastric conduit reconstruction. There are many strong risk factors for AL in clinical practice. Notably, the tension at the esophagogastric anastomosis and the blood supply to the gastric conduit directly affect the integrity of the anastomosis. However, there has been a lack of quantitative research on the tension and blood supply of the gastric conduit. Changes in extracellular matrix collagen reflect tension and blood supply, which affect the quality of the anastomosis. This study aimed to establish a quantitative collagen score to describe changes in the collagen structure in the extracellular matrix and to identify patients at high risk of postoperative AL.<br><br>METHODS: A retrospective study of 213 patients was conducted. Clinical and pathological data were collected at baseline. Optical imaging of the "donut" specimen at the anastomotic gastric end and collagen feature extraction were performed. Least absolute shrinkage and selection operator (LASSO) regression models were used to select the significant collagen features, compute collagen scores, and validate the predictive efficacy of the collagen scores for ALs.<br><br>RESULTS: LASSO regression analysis revealed three collagen-related parameters in the gastric donuts: histogram mean, histogram variance, and histogram energy. Based on this analysis, we established a formula to calculate the collagen score. The results of the univariate analysis revealed significant differences in the preoperative low albumin values (P=0.002) and collagen scores between the AL and non-AL groups (P=0.001), while the results of the multivariate analysis revealed significant differences in the collagen scores between the AL and non-AL groups (P=0.002). The areas under the curve (AUCs) of the experimental and validation cohorts were 0.978 [95% confidence interval (CI): 0.931-0.996] and 0.900 (95% CI: 0.824-0.951), respectively.<br><br>CONCLUSIONS: The collagen score established herein was shown to be related to AL and can be used to predict AL in patients who underwent esophagectomy.}, }
@article {pmid39144033, year = {2024}, author = {Xiao, XY and Zeng, JY and Cao, YB and Tang, Y and Zou, ZY and Li, JQ and Chen, HJ}, title = {Cortical microstructural abnormalities in amyotrophic lateral sclerosis: a gray matter-based spatial statistics study.}, journal = {Quantitative imaging in medicine and surgery}, volume = {14}, number = {8}, pages = {5774-5788}, pmid = {39144033}, issn = {2223-4292}, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS)-related white-matter microstructural abnormalities have received considerable attention; however, gray-matter structural abnormalities have not been fully elucidated. This study aimed to evaluate cortical microstructural abnormalities in ALS and determine their association with disease severity.<br><br>METHODS: This study included 34 patients with ALS and 30 healthy controls. Diffusion-weighted data were used to estimate neurite orientation dispersion and density imaging (NODDI) parameters, including neurite density index (NDI) and orientation dispersion index (ODI). We performed gray matter-based spatial statistics (GBSS) in a voxel-wise manner to determine the cortical microstructure difference. We used the revised ALS Functional Rating Scale (ALSFRS-R) to assess disease severity and conducted a correlation analysis between NODDI parameters and ALSFRS-R.<br><br>RESULTS: In patients with ALS, the NDI reduction involved several cortical regions [primarily the precentral gyrus, postcentral gyrus, temporal cortex, prefrontal cortex, occipital cortex, and posterior parietal cortex; family-wise error (FWE)-corrected P<0.05]. ODI decreased in relatively few cortical regions (including the precentral gyrus, postcentral gyrus, prefrontal cortex, and inferior parietal lobule; FWE-corrected P<0.05). The NDI value in the left precentral and postcentral gyrus was positively correlated with the ALS disease severity (FWE-corrected P<0.05).<br><br>CONCLUSIONS: The decreases in NDI and ODI involved both motor-related and extra-motor regions and indicated the presence of gray-matter microstructural impairment in ALS. NODDI parameters are potential imaging biomarkers for evaluating disease severity in vivo. Our results showed that GBSS is a feasible method for identifying abnormalities in the cortical microstructure of patients with ALS.}, }
@article {pmid39143255, year = {2024}, author = {Gehlen, M and Schwarz-Eywill, M and Mahn, K and Pfeiffer, A and Bauer, JM and Maier, A}, title = {[Sonography of muscles : Rheumatology-Neurology-Geriatrics-Sports medicine-Orthopedics].}, journal = {Zeitschrift fur Rheumatologie}, volume = {83}, number = {10}, pages = {829-843}, pmid = {39143255}, issn = {1435-1250}, mesh = {Humans ; *Ultrasonography/methods ; Magnetic Resonance Imaging ; Rheumatology/methods ; Muscle, Skeletal/diagnostic imaging ; Athletic Injuries/diagnostic imaging ; Sarcopenia/diagnostic imaging ; Sports Medicine/methods ; Rheumatic Diseases/diagnostic imaging ; Geriatrics ; Aged ; Neurology ; Muscular Diseases/diagnostic imaging ; Evidence-Based Medicine ; }, abstract = {Muscle sonography is used in rheumatology, neurology, geriatrics, sports medicine and orthopedics. Muscular atrophy with fatty and connective tissue degeneration can be visualized and must be interpreted in conjunction with the sonographic findings of the supplying nerves. Sonography is becoming increasingly more important for the early diagnosis of sarcopenia in rheumatology, geriatrics and osteology. Even if its significance has not yet been conclusively clarified, many publications confirm the high reliability of the method. Sonography can ideally be used in addition to magnetic resonance imaging (MRI) in the diagnostics of myositis as it can speed up the diagnosis, muscle groups that were not imaged by MRI can also be assessed sonographically and all muscle groups can be examined during the course of the procedure. Sonography also helps to make a quick and uncomplicated diagnosis of many sports injuries in addition to MRI and is therefore the basis for a targeted therapeutic approach.}, }
@article {pmid39142444, year = {2024}, author = {Tan, X and Su, X and Wang, Y and Liang, W and Wang, D and Huo, D and Wang, H and Qi, Y and Zhang, W and Han, L and Zhang, D and Wang, M and Xu, J and Feng, H}, title = {RBM5 induces motor neuron apoptosis in hSOD1[G93A]-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways.}, journal = {Brain research bulletin}, volume = {216}, number = {}, pages = {111049}, doi = {10.1016/j.brainresbull.2024.111049}, pmid = {39142444}, issn = {1873-2747}, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; Animals ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Motor Neurons/metabolism/pathology ; *Apoptosis/physiology ; *RNA-Binding Proteins/metabolism/genetics ; Mice ; Humans ; *Signal Transduction/physiology ; *Proto-Oncogene Proteins c-akt/metabolism ; Mice, Transgenic ; Superoxide Dismutase/metabolism/genetics ; Male ; DNA-Binding Proteins ; Cell Cycle Proteins ; Tumor Suppressor Proteins ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by gradual depletion of motor neurons. RNA binding motif protein 5 (RBM5), an abundantly expressed RNA-binding protein, plays a critical role in the process of cellular death. However, little is known about the role of RBM5 in the pathogenesis of ALS. Here, we found that RBM5 was upregulated in ALS hSOD1[G93A]-NSC34 cell models and hSOD1[G93A] mice due to a reduction of miR-141-5p. The upregulation of RBM5 increased the apoptosis of motor neurons by inhibiting Rac1-mediated neuroprotection. In contrast, genetic knockdown of RBM5 rescued motor neurons from hSOD1[G93A]-induced degeneration by activating Rac1 signaling. The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling.}, }
@article {pmid39141854, year = {2024}, author = {Vansteensel, MJ and Leinders, S and Branco, MP and Crone, NE and Denison, T and Freudenburg, ZV and Geukes, SH and Gosselaar, PH and Raemaekers, M and Schippers, A and Verberne, M and Aarnoutse, EJ and Ramsey, NF}, title = {Longevity of a Brain-Computer Interface for Amyotrophic Lateral Sclerosis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {619-626}, pmid = {39141854}, issn = {1533-4406}, support = {INTENSE, 17619//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; UH3 NS114439/NS/NINDS NIH HHS/United States ; U01DC016686/DC/NIDCD NIH HHS/United States ; U01 DC016686/DC/NIDCD NIH HHS/United States ; UH3NS114439/NS/NINDS NIH HHS/United States ; UGT7685, Economic Affairs SSM06011 and STW 12803//Netherlands Institute of Government/ ; }, mesh = {Female ; Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/diagnostic imaging/rehabilitation ; *Atrophy/diagnostic imaging/etiology/prevention &amp; control ; Brain/diagnostic imaging ; *Brain-Computer Interfaces ; Communication Devices for People with Disabilities ; Time Factors ; Treatment Failure ; Electrodes, Implanted ; }, abstract = {The durability of communication with the use of brain-computer interfaces in persons with progressive neurodegenerative disease has not been extensively examined. We report on 7 years of independent at-home use of an implanted brain-computer interface for communication by a person with advanced amyotrophic lateral sclerosis (ALS), the inception of which was reported in 2016. The frequency of at-home use increased over time to compensate for gradual loss of control of an eye-gaze-tracking device, followed by a progressive decrease in use starting 6 years after implantation. At-home use ended when control of the brain-computer interface became unreliable. No signs of technical malfunction were found. Instead, the amplitude of neural signals declined, and computed tomographic imaging revealed progressive atrophy, which suggested that ALS-related neurodegeneration ultimately rendered the brain-computer interface ineffective after years of successful use, although alternative explanations are plausible. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02224469.).}, }
@article {pmid39141853, year = {2024}, author = {Card, NS and Wairagkar, M and Iacobacci, C and Hou, X and Singer-Clark, T and Willett, FR and Kunz, EM and Fan, C and Vahdati Nia, M and Deo, DR and Srinivasan, A and Choi, EY and Glasser, MF and Hochberg, LR and Henderson, JM and Shahlaie, K and Stavisky, SD and Brandman, DM}, title = {An Accurate and Rapidly Calibrating Speech Neuroprosthesis.}, journal = {The New England journal of medicine}, volume = {391}, number = {7}, pages = {609-618}, pmid = {39141853}, issn = {1533-4406}, support = {U01DC17844/DC/NIDCD NIH HHS/United States ; AL220043//Congressionally Directed Medical Research Programs/ ; U01 DC019430/DC/NIDCD NIH HHS/United States ; R01 MH060974/MH/NIMH NIH HHS/United States ; 872146SPI//Simons Foundation/ ; A2295-R//U.S. Department of Veterans Affairs/ ; DP2DC021055/DC/NIDCD NIH HHS/United States ; U01DC019430/DC/NIDCD NIH HHS/United States ; I01 RX002295/RX/RRD VA/United States ; DP2 DC021055/DC/NIDCD NIH HHS/United States ; U01 DC017844/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; Male ; Middle Aged ; *Amyotrophic Lateral Sclerosis/complications/rehabilitation ; *Brain-Computer Interfaces ; Calibration ; Communication Devices for People with Disabilities ; *Dysarthria/rehabilitation/etiology ; Electrodes, Implanted ; Microelectrodes ; Quadriplegia/etiology/rehabilitation ; *Speech ; }, abstract = {BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy.<br><br>METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice.<br><br>RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours.<br><br>CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).}, }
@article {pmid39141064, year = {2024}, author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, &#xd6; and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC}, title = {Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.}, journal = {Journal of neurology}, volume = {271}, number = {10}, pages = {6667-6679}, pmid = {39141064}, issn = {1432-1459}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/diagnosis ; *Superoxide Dismutase-1/genetics ; Male ; Female ; Germany ; Middle Aged ; Aged ; *Disease Progression ; Mutation ; Adult ; Phenotype ; }, abstract = {Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.}, }
@article {pmid39140323, year = {2024}, author = {Nakamura, T and He, X and Hattori, N and Hida, E and Hirata, M}, title = {Dilemma in patients with amyotrophic lateral sclerosis and expectations from brain-machine interfaces.}, journal = {Annals of medicine}, volume = {56}, number = {1}, pages = {2386516}, pmid = {39140323}, issn = {1365-2060}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/therapy ; *Brain-Computer Interfaces ; Male ; Female ; Middle Aged ; Aged ; Surveys and Questionnaires ; *Motivation ; *Caregivers/psychology ; *Anxiety/psychology/etiology ; Adult ; Tracheostomy ; Caregiver Burden/psychology ; Locked-In Syndrome/psychology ; }, abstract = {OBJECTIVE: We hypothesized that patients with amyotrophic lateral sclerosis (ALS) face a dilemma between motivation to live and difficulty in living, and brain-machine interfaces (BMIs) can reduce this dilemma. This study aimed to investigate the present situation of patients with ALS and their expectations from BMIs.<br><br>MATERIALS AND METHODS: Our survey design consisted of an anonymous mail-in questionnaire comprising questions regarding the use of tracheostomy positive pressure ventilation (TPPV), motivation to live, anxiety about the totally locked-in state (TLS), anxiety about caregiver burden, and expectations regarding the use of BMI. Primary outcomes were scores for motivation to live and anxiety about caregiver burden and the TLS. Outcomes were evaluated using the visual analogue scale.<br><br>RESULTS: Among 460 participants, 286 (62.6%) were already supported by or had decided to use TPPV. The median scores for motivation to live, anxiety about TLS, and anxiety about caregiver burden were 8.0, 9.0, and 7.0, respectively. Overall, 49% of patients intended to use BMI. Among patients who had refused TPPV, 15.9% intended to use BMI and TPPV. Significant factors for the use of BMI were motivation to live (p = .003), anxiety about TLS (p < .001), younger age (p < .001), and advanced disease stage (p < .001).<br><br>CONCLUSIONS: These results clearly revealed a serious dilemma among patients with ALS between motivation to live and their anxiety about TLS and caregiver burden. Patients expected BMI to reduce this dilemma. Thus, the development of better BMIs may meet these expectations.}, }
@article {pmid39139642, year = {2024}, author = {Liu, X and Li, Y and Huang, L and Kuang, Y and Wu, X and Ma, X and Zhao, B and Lan, J}, title = {Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1450704}, pmid = {39139642}, issn = {1663-9812}, abstract = {The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.}, }
@article {pmid39139312, year = {2024}, author = {Kaur, B and Samagh, N and Narang, A and Paliwal, S}, title = {Anesthetic Management of a Neurosurgical Patient With Amyotrophic Lateral Sclerosis: A Case Report.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64492}, pmid = {39139312}, issn = {2168-8184}, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive form of neurological disorder that affects both the upper and lower motor neurons. Anesthesia management in these patients is always challenging as they can develop respiratory complications because of pre-existing muscle involvement. We report a middle-aged male with ALS posted for chronic subdural hematoma evacuation (CSDH) surgery. Surgery was done under scalp block with monitored anesthesia care. The choice of anesthesia in these patients should be one that interferes the least with the disease pattern while still providing optimal conditions for surgery.}, }
@article {pmid39138961, year = {2024}, author = {Rosano, A and Bicaj, M and Cillerai, M and Ponzano, M and Cabona, C and Gemelli, C and Caponnetto, C and Pardini, M and Signori, A and Uccelli, A and Schenone, A and Ferraro, PM}, title = {Psychological resilience is protective against cognitive deterioration in motor neuron diseases.}, journal = {Amyotrophic lateral sclerosis &amp; frontotemporal degeneration}, volume = {25}, number = {7-8}, pages = {717-725}, doi = {10.1080/21678421.2024.2385690}, pmid = {39138961}, issn = {2167-9223}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Resilience, Psychological ; *Motor Neuron Disease/psychology/complications ; Aged ; *Cognitive Dysfunction/psychology/etiology ; Neuropsychological Tests ; Longitudinal Studies ; Adult ; }, abstract = {OBJECTIVES: Recent studies suggest that psychological resilience (PR) is associated with more well-preserved cognition in healthy subjects (HS), but an investigation of such phenomenon in patients with motor neuron diseases (MNDs) is still lacking. The aim of our study was therefore to evaluate PR and its relationship with baseline cognitive/behavioral and mood symptoms, as well as longitudinal cognitive functioning, in MNDs.<br><br>METHODS: 94 MND patients and 87 demographically matched HS were enrolled. PR was assessed using the Connor-Davidson Resilience Scale (CD-RISC). Patients were further evaluated both at baseline and every 6 months for cognitive/behavioral disturbances using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and for mood symptoms using the Hospital Anxiety and Depression Scale (HADS). CD-RISC scores were compared between patients and HS using the Mann-Whitney U test, and regression models were applied to evaluate the role of CD-RISC scores in predicting baseline cognitive/behavioral and mood measures, as well as longitudinal cognitive performances, in MND patients.<br><br>RESULTS: MND cases showed significantly greater PR compared to HS (p from <0.001 to 0.02). In MNDs, higher PR levels were significant predictors of both greater cognitive performance (p from 0.01 to 0.05) and milder mood symptoms (p from <0.001 to 0.04) at baseline, as well as less severe memory decline (p from 0.001 to 0.04) longitudinally.<br><br>CONCLUSIONS: PR is an important protective factor against the onset and evolution of cognitive/mood disturbances in MNDs, suggesting the usefulness of resilience enhancement psychological interventions to prevent or delay cognitive and mood disorders in these neurodegenerative conditions.}, }
@article {pmid39138578, year = {2024}, author = {Wasielewska, JM and Chaves, JCS and Cabral-da-Silva, MC and Pecoraro, M and Viljoen, SJ and Nguyen, TH and Bella, V and Oikari, LE and Ooi, L and White, AR}, title = {A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.}, journal = {Fluids and barriers of the CNS}, volume = {21}, number = {1}, pages = {65}, pmid = {39138578}, issn = {2045-8118}, support = {PhD Scholarship//University of Queensland/ ; PhD Top-Up Scholarship//QIMR Berghofer Medical Research Institute/ ; APP1125796 and 1118452//National Health and Medical Research Council/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/metabolism/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Microbubbles ; *DNA-Binding Proteins/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Antibodies/administration &amp; dosage ; Ultrasonic Waves ; Cells, Cultured ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS[+ MB]) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS[+ MB]-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS[+ MB] on human ALS BBB cells remain unexplored.<br><br>METHODS: Here we established the first FUS[+&#x2009;MB]-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS[+&#x2009;MB] bioeffects in vitro.<br><br>RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS[+&#x2009;MB] as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS[+&#x2009;MB] treated cells. This was accompanied by the molecular bioeffects of FUS[+&#x2009;MB] in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS[+&#x2009;MB] in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS[+&#x2009;MB] can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model.<br><br>CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS[+&#x2009;MB] and provides a fully-human platform for FUS[+&#x2009;MB]-mediated drug delivery screening on an ALS BBB in vitro model.}, }
@article {pmid39138120, year = {2024}, author = {Euler, L and Deinert, K and Wagener, F and Walpurgis, K and Thevis, M}, title = {Identification of human metabolites of fast skeletal troponin activators Tirasemtiv and Reldesemtiv for doping control purposes.}, journal = {Drug testing and analysis}, volume = {}, number = {}, pages = {}, doi = {10.1002/dta.3786}, pmid = {39138120}, issn = {1942-7611}, support = {//Federal Ministry of Interior, Building and Community/ ; //Manfred-Donike-Institute for Doping Analysis/ ; }, abstract = {The fast skeletal troponin activators (FSTAs) Reldesemtiv and Tirasemtiv were developed for patients suffering from neuro-degenerative diseases of the motor nervous system, e.g. amyotrophic lateral sclerosis (ALS). The drug candidates can increase the sensitivity of troponin C to calcium by selectively activating the troponin complex resulting in increased skeletal muscle contraction. Although the development of the drug candidates is currently discontinued because of missed end points in phase III clinical studies with patients with ALS, phase I clinical trials showed an increase in muscle contraction force in healthy humans. This effect could be abused by athletes to enhance performance in sports. As the substances are listed on the 2024 edition of the World Anti-Doping Agency's Prohibited List, the aim of this study was to identify and characterize metabolites of Reldesemtiv and Tirasemtiv to ensure their reliable identification in doping control analyses. The biotransformation of the drug candidates was studied in vitro using pooled human liver microsomes and 3D cultivated human hepatic cells of the cell line HepaRG, yielding a total of 11 metabolites of Reldesemtiv and eight of Tirasemtiv. In addition, a human elimination study was conducted to investigate the metabolism and elimination profile of Tirasemtiv and Reldesemtiv in vivo, suggesting the N-glucuronide of Tirasemtiv and hydroxylated 3-fluoro-2-(3-fluoro-1-methylcyclobutyl)pyridine as well as its glucuronide as suitable target analytes for routine doping controls. Applying a validating HPLC-MS/MS method, optimized to detect Reldesemtiv and Tirasemtiv in human urine, microdosing (50 μg) of each substance was traceable for 24-72 h.}, }
@article {pmid39138039, year = {2024}, author = {Candelo, E and Vasudevan, SS and Orellana, D and Williams, AM and Rutt, AL}, title = {Exploring the Impact of Amyotrophic Lateral Sclerosis on Otolaryngological Functions.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jvoice.2024.07.025}, pmid = {39138039}, issn = {1873-4588}, abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons at the spinal or bulbar level.<br><br>OBJECTIVE: We aim to describe the most frequent otolaryngology (ORL) complaints and voice disturbances in patients with bulbar onset ALS.<br><br>DESIGN: Retrospective cohort study.<br><br>SETTING: Single-center study with combined ORL and ALS clinic evaluation.<br><br>PARTICIPANTS: Patients with a confirmed diagnosis of ALS following an ORL visit and who underwent comprehensive voice assessments between January 2021 and January 2023.<br><br>EXPOSURE: Objective voice assessments.<br><br>MAIN OUTCOMES AND MEASURES: Glottal functional index (GFI), voice handicap index (VHI), reflux system index (RSI), and voice quality characteristics such as shimmer, jitter, maximum phonation time (MPT), and other essential parameters were assessed.<br><br>RESULTS: One hundred and thirty-three patients (age 62.17&#xa0;&#xb1;&#xa0;10.79, 54.48% female) were included. Three patients were referred from the ORL department to the ALS clinic. The most frequent symptoms were; dysphagia, dysarthria, facial weakness, pseudobulbar affect, and sialorrhea. The mean of forced vital capacity was 59.85%, EAT-10 15.91&#xa0;&#xb1;&#xa0;11.66, RSI 25.84&#xa0;&#xb1;&#xa0;9.03, GFI 14.12&#xa0;&#xb1;&#xa0;5.58, VHI-10 42.81&#xa0;&#xb1;&#xa0;34.94, MPT 15.22&#xa0;s&#xa0;&#xb1;&#xa0;8.06. Many patients reported voice impairments mainly related to spastic dysarthria and the combination of lower and upper motor neuron dysarthria, hypernasality, reduced verbal expression, and articulatory accuracy. Shimmer was increased to 8.46%&#xa0;&#xb1;&#xa0;7.20, and jitter to 2.26%&#xa0;&#xb1;&#xa0;1.39.<br><br>CONCLUSIONS AND RELEVANCE: Based on our cohort, this population with bulbar onset ALS has a higher frequency of voice disturbance characterized by hypernasality, spastic dysarthria, and reduced verbal expression.<br><br>LEVEL OF EVIDENCE: Level 3.}, }
@article {pmid39137976, year = {2024}, author = {Pavey, N and Hannaford, A and Higashihara, M and van den Bos, M and Geevasinga, N and Vucic, S and Menon, P}, title = {Cortical inexcitability in ALS: correlating a clinical phenotype.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2024-333928}, pmid = {39137976}, issn = {1468-330X}, abstract = {BACKGROUND: Cortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic and clinical characteristics were contrasted with normal or hyperexcitable ALS cohorts to assess the impact of cortical inexcitability on ALS phenotype and survival.<br><br>METHODS: Threshold-tracking transcranial magnetic stimulation (TMS) technique with measurement of mean short interval intracortical inhibition (SICI) differentiated ALS patients into three groups (1) inexcitable (no TMS response at maximal stimulator output in the setting of preserved lower motor neuron (LMN) function), (2) hyperexcitable (SICI&#x2264;5.5%) and (3) normal cortical excitability (SICI>5.5%). Clinical phenotyping and neurophysiological assessment of LMN function were undertaken, and survival was recorded in the entire cohort.<br><br>RESULTS: 417 ALS patients were recruited, of whom 26.4% exhibited cortical inexcitability. Cortical inexcitability was associated with a younger age of disease onset (p<0.05), advanced Awaji criteria (p<0.01) and Kings stage (p<0.01) scores. Additionally, patients with cortical inexcitability had higher UMN score (p<0.01), lower revised ALS Functional Rating Scale score (p<0.01) and reduced upper limb strength score (MRC UL, p<0.01). Patient survival (p=0.398) was comparable across the groups, despite lower riluzole use in the cortical inexcitability patient group (p<0.05).<br><br>CONCLUSION: The present study established that cortical inexcitability was associated with a phenotype characterised by prominent UMN signs, greater motor and functional decline, and a younger age of onset. The present findings inform patient management and could improve patient stratification in clinical trials.}, }
@article {pmid39135084, year = {2024}, author = {Ma, H and Zhu, M and Chen, M and Li, X and Feng, X}, title = {The role of macrophage plasticity in neurodegenerative diseases.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {81}, pmid = {39135084}, issn = {2050-7771}, support = {PX2023037//Beijing Municipal Administration of Hospitals Incubating Program/ ; }, abstract = {Tissue-resident macrophages and recruited macrophages play pivotal roles in innate immunity and the maintenance of brain homeostasis. Investigating the involvement of these macrophage populations in eliciting pathological changes associated with neurodegenerative diseases has been a focal point of research. Dysregulated states of macrophages can compromise clearance mechanisms for pathological proteins such as amyloid-β (Aβ) in Alzheimer's disease (AD) and TDP-43 in Amyotrophic lateral sclerosis (ALS). Additionally, recent evidence suggests that abnormalities in the peripheral clearance of pathological proteins are implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, numerous genome-wide association studies have linked genetic risk factors, which alter the functionality of various immune cells, to the accumulation of pathological proteins. This review aims to unravel the intricacies of macrophage biology in both homeostatic conditions and neurodegenerative disorders. To this end, we initially provide an overview of the modifications in receptor and gene expression observed in diverse macrophage subsets throughout development. Subsequently, we outlined the roles of resident macrophages and recruited macrophages in neurodegenerative diseases and the progress of targeted therapy. Finally, we describe the latest advances in macrophage imaging methods and measurement of inflammation, which may provide information and related treatment strategies that hold promise for informing the design of future investigations and therapeutic interventions.}, }
@article {pmid39134696, year = {2024}, author = {Visser, BS and Lipiński, WP and Spruijt, E}, title = {The role of biomolecular condensates in protein aggregation.}, journal = {Nature reviews. Chemistry}, volume = {8}, number = {9}, pages = {686-700}, pmid = {39134696}, issn = {2397-3358}, mesh = {Humans ; *Biomolecular Condensates/metabolism/chemistry ; *Protein Aggregates ; Neurodegenerative Diseases/metabolism ; Amyloid/metabolism/chemistry ; Protein Aggregation, Pathological/metabolism ; Proteins/chemistry/metabolism ; }, abstract = {There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.}, }
@article {pmid39134599, year = {2024}, author = {Mikawy, NN and Magdy, N and Mohamed, MH and El-Kosasy, AM}, title = {Green highly sensitive and selective spectroscopic detection of guaifenesin in multiple dosage forms and spiked human plasma.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18694}, pmid = {39134599}, issn = {2045-2322}, mesh = {*Guaifenesin/analysis/administration &amp; dosage ; Humans ; *Limit of Detection ; *Spectrometry, Fluorescence/methods ; Tablets ; Green Chemistry Technology/methods ; }, abstract = {Guaifenesin (GUA) is determined in dosage forms and plasma using two methods. The spectrofluorimetric technique relies on the measurement of native fluorescence intensity at 302 nm upon excitation wavelength "223 nm". The method was validated according to ICH and FDA guidelines. A concentration range of 0.1-1.1 μg/mL was used, with limit of detection (LOD) and quantification (LOQ) values 0.03 and 0.08 µg/mL, respectively. This method was used to measure GUA in tablets and plasma, with %recovery of 100.44% ± 0.037 and 101.03% ± 0.751. Furthermore, multivariate chemometric-assisted spectrophotometric methods are used for the determination of GUA, paracetamol (PARA), oxomemazine (OXO), and sodium benzoate (SB) in their lab mixtures. The concentration ranges of 2.0-10.0, 4.0-16.0, 2.0-10.0, and 3.0-10.0 µg/mL for OXO, GUA, PARA, and SB; respectively, were used. LOD and LOQ were 0.33, 0.68, 0.28, and 0.29 µg/mL, and 1.00, 2.06, 0.84, and 0.87 µg/mL for PARA, GUA, OXO, and SB. For the suppository application, the partial least square (PLS) model was used with %recovery 98.49% ± 0.5, 98.51% ± 0.64, 100.21% ± 0.36 &amp; 98.13% ± 0.51, although the multivariate curve resolution alternating least-squares (MCR-ALS) model was used with %recovery 101.39 ± 0.45, 99.19 ± 0.2, 100.24 ± 0.12, and 98.61 ± 0.32 for OXO, GUA, PARA, and SB. Analytical Eco-scale and Analytical Greenness Assessment were used to assess the greenness level of our techniques.}, }
@article {pmid39134031, year = {2025}, author = {Aziz, M and Kniep, I and Ondruschka, B and Püschel, K and Hessler, C}, title = {Cement Leakage after Augmentation of Osteoporotic Vertebral Bodies.}, journal = {Zeitschrift fur Orthopadie und Unfallchirurgie}, volume = {163}, number = {2}, pages = {146-152}, doi = {10.1055/a-2343-4100}, pmid = {39134031}, issn = {1864-6743}, mesh = {Humans ; Male ; Female ; Aged ; *Spinal Fractures/surgery ; *Osteoporotic Fractures/surgery ; *Bone Cements/adverse effects ; Aged, 80 and over ; Middle Aged ; Germany/epidemiology ; Risk Factors ; Extravasation of Diagnostic and Therapeutic Materials ; Vertebroplasty/adverse effects ; Postoperative Complications/surgery ; Incidence ; }, abstract = {Der Zementaustritt ist die häufigste Komplikation bei der Zementaugmentation von Wirbelkörpern. In der vorliegenden Studie wurden die Zementaustrittsraten bei Zementaugmentationen an der Wirbelsäule untersucht und potenzielle Risikofaktoren für einen Zementaustritt identifiziert.Es wurden 140 Fälle von 131 Patienten und Patientinnen und 9 Verstorbenen ausgewertet. Insgesamt wurden 258 zementaugmentierte Wirbelkörper untersucht. Die Daten dafür stammen aus den Krankenhausdokumentationen von 131 Patienten und Patientinnen, die sich in 2 orthopädisch-unfallchirurgischen Kliniken in der BRD solchen Operationen unterzogen, sowie aus den Untersuchungen von 9 Sterbefällen im Institut für Rechtsmedizin der Universitätsklinikums Hamburg-Eppendorf.Zementaustritte wurden in 64 der 140 Fälle (45,7%) ermittelt. Lokale Zementaustritte waren mit 73,4% (n = 47) die häufigste Austrittsart. Venöse Austritte wurden in 15 Fällen (23,4%) und Lungenzementembolisationen in 2 Fällen (3,1%) evaluiert. Innerhalb des Kollektivs der retrospektiv untersuchten Fälle (n = 131) erlitt lediglich 1 Patient (0,8%) einen symptomatischen Zementaustritt. Als Risikofaktoren für Zementaustritte konnten Zementaugmentationen von Frakturen an Lendenwirbelkörpern sowie eine hohe applizierte Zementmenge identifiziert werden.Sowohl die Daten in der assoziierten Literatur als auch die Ergebnisse dieser Arbeit belegen eine hohe Inzidenz von Zementaustritten nach Wirbelkörperaugmentationen. Trotz des geringen prozentualen Anteils symptomatischer Fälle sollten bei der Planung und Durchführung von Zementaugmentationen an Wirbelkörpern die möglichen Einflussfaktoren für einen Zementaustritt berücksichtigt und in die OP-Planung einbezogen werden.}, }
@article {pmid39131911, year = {2024}, author = {Ikeda, A and Meng, H and Taniguchi, D and Mio, M and Funayama, M and Nishioka, K and Yoshida, M and Li, Y and Yoshino, H and Inoshita, T and Shiba-Fukushima, K and Okubo, Y and Sakurai, T and Amo, T and Aiba, I and Saito, Y and Saito, Y and Murayama, S and Atsuta, N and Nakamura, R and Tohnai, G and Izumi, Y and Morita, M and Tamura, A and Kano, O and Oda, M and Kuwabara, S and Yamashita, T and Sone, J and Kaji, R and Sobue, G and Imai, Y and Hattori, N}, title = {CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca[2+] homeostasis.}, journal = {PNAS nexus}, volume = {3}, number = {8}, pages = {pgae319}, pmid = {39131911}, issn = {2752-6542}, abstract = {CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca[2+] buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca[2+]-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca[2+] facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca[2+] dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.}, }
@article {pmid39130445, year = {2024}, author = {Phipps, AJ and Dwyer, S and Collins, JM and Kabir, F and Atkinson, RA and Chowdhury, MA and Matthews, L and Dixit, D and Terry, RS and Smith, J and Gueven, N and Bennett, W and Cook, AL and King, AE and Perry, S}, title = {HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1[G93A] mouse model of ALS.}, journal = {Heliyon}, volume = {10}, number = {14}, pages = {e34587}, pmid = {39130445}, issn = {2405-8440}, abstract = {The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1[G93A] mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1[G93A] mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.}, }
@article {pmid39128808, year = {2024}, author = {Farhangian, M and Azarafrouz, F and Valian, N and Dargahi, L}, title = {The role of interferon beta in neurological diseases and its potential therapeutic relevance.}, journal = {European journal of pharmacology}, volume = {981}, number = {}, pages = {176882}, doi = {10.1016/j.ejphar.2024.176882}, pmid = {39128808}, issn = {1879-0712}, mesh = {Humans ; Animals ; *Interferon-beta/therapeutic use/metabolism ; Nervous System Diseases/drug therapy/metabolism ; Signal Transduction/drug effects ; }, abstract = {Interferon beta (IFNβ) is a member of the type-1 interferon family and has various immunomodulatory functions in neuropathological conditions. Although the level of IFNβ is low under healthy conditions, it is increased during inflammatory processes to protect the central nervous system (CNS). In particular, microglia and astrocytes are the main sources of IFNβ upon inflammatory insult in the CNS. The protective effects of IFNβ are well characterized in reducing the progression of multiple sclerosis (MS); however, little is understood about its effects in other neurological/neurodegenerative diseases. In this review, different types of IFNs and their signaling pathways will be described. Then we will focus on the potential role and therapeutic effect of IFNβ in several CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury, prion disease and spinocerebellar ataxia 7.}, }
@article {pmid39128727, year = {2024}, author = {George, G and Ajayan, A and Varkey, J and Pandey, NK and Chen, J and Langen, R}, title = {TDP43 and huntingtin Exon-1 undergo a conformationally specific interaction that strongly alters the fibril formation of both proteins.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {9}, pages = {107660}, pmid = {39128727}, issn = {1083-351X}, mesh = {*Huntingtin Protein/metabolism/genetics/chemistry ; Humans ; *DNA-Binding Proteins/metabolism/genetics/chemistry ; *Exons ; Amyloid/metabolism/chemistry ; Protein Aggregates ; Protein Aggregation, Pathological/metabolism/genetics ; Protein Binding ; Protein Conformation ; Protein Domains ; }, abstract = {Protein aggregation is a common feature of many neurodegenerative diseases. In Huntington's disease, mutant huntingtin is the primary aggregating protein, but the aggregation of other proteins, such as TDP43, is likely to further contribute to toxicity. Moreover, mutant huntingtin is also a risk factor for TDP pathology in ALS. Despite this co-pathology of huntingtin and TDP43, it remains unknown whether these amyloidogenic proteins directly interact with each other. Using a combination of biophysical methods, we show that the aggregation-prone regions of both proteins, huntingtin exon-1 (Httex1) and the TDP43 low complexity domain (TDP43-LCD), interact in a conformationally specific manner. This interaction significantly slows Httex1 aggregation, while it accelerates TDP43-LCD aggregation. A key intermediate responsible for both effects is a complex formed by liquid TDP43-LCD condensates and Httex1 fibrils. This complex shields seeding competent surfaces of Httex1 fibrils from Httex1 monomers, which are excluded from the condensates. In contrast, TDP43-LCD condensates undergo an accelerated liquid-to-solid transition upon exposure to Httex1 fibrils. Cellular studies show co-aggregation of untagged Httex1 with TDP43. This interaction causes mislocalization of TDP43, which has been linked to TDP43 toxicity. The protection from Httex1 aggregation in lieu of TDP43-LCD aggregation is interesting, as it mirrors what has been found in disease models, namely that TDP43 can protect from huntingtin toxicity, while mutant huntingtin can promote TDP43 pathology. These results suggest that direct protein interaction could, at least in part, be responsible for the linked pathologies of both proteins.}, }
@article {pmid39128005, year = {2024}, author = {Knupp, J and Chen, YJ and Wang, E and Arvan, P and Tsai, B}, title = {Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy.}, journal = {Cell reports}, volume = {43}, number = {8}, pages = {114619}, pmid = {39128005}, issn = {2211-1247}, support = {F31 DK128868/DK/NIDDK NIH HHS/United States ; R01 AI170514/AI/NIAID NIH HHS/United States ; R01 DK111174/DK/NIDDK NIH HHS/United States ; }, mesh = {*Receptors, sigma/metabolism/genetics ; *Sigma-1 Receptor ; *Autophagy ; *Microtubule-Associated Proteins/metabolism/genetics ; *Endoplasmic Reticulum/metabolism ; Humans ; *RNA, Messenger/metabolism/genetics ; *3' Untranslated Regions/genetics ; *Protein Biosynthesis ; Ribosomes/metabolism ; Animals ; Autophagosomes/metabolism ; HeLa Cells ; }, abstract = {Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3' UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3' UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3' UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3' UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.}, }
@article {pmid39127445, year = {2024}, author = {Wang, MY and Zhou, Y and Li, WL and Zhu, LQ and Liu, D}, title = {Friend or foe: Lactate in neurodegenerative diseases.}, journal = {Ageing research reviews}, volume = {101}, number = {}, pages = {102452}, doi = {10.1016/j.arr.2024.102452}, pmid = {39127445}, issn = {1872-9649}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism ; *Lactic Acid/metabolism ; Animals ; }, abstract = {Lactate, a byproduct of glycolysis, was considered as a metabolic waste until identified by studies on the Warburg effect. Increasing evidence elucidates that lactate functions as energy fuel, signaling molecule, and donor for protein lactylation. Altered lactate utilization is a common metabolic feature of the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. This review offers an overview of lactate metabolism from the perspective of production, transportation and clearance, and the role of lactate in neurodegenerative progression, as well as a summary of protein lactylation and the signaling function of lactate in neurodegenerative diseases. Besides, this review delves into the dual roles of changed lactate metabolism during neurodegeneration and explores prospective therapeutic methods targeting lactate. We propose that elucidating the correlation between lactate and neurodegeneration is pivotal for exploring innovative therapeutic interventions for neurodegenerative diseases.}, }
@article {pmid39126873, year = {2024}, author = {Vacchiano, V and Di Stasi, V and Teodorani, L and Faini, C and Morabito, F and Liguori, R}, title = {Comparative assessment of MScanFit MUNE and quantitative EMG in amyotrophic lateral sclerosis diagnosis: A prospective study.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {166}, number = {}, pages = {66-73}, doi = {10.1016/j.clinph.2024.07.017}, pmid = {39126873}, issn = {1872-8952}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; *Electromyography/methods ; Male ; Female ; Middle Aged ; Aged ; Prospective Studies ; *Motor Neurons/physiology ; *Action Potentials/physiology ; *Muscle, Skeletal/physiopathology ; Adult ; }, abstract = {OBJECTIVE: Motor Unit Number Estimation (MUNE) techniques are crucial in assessing lower motor neuron loss. MScanFit MUNE (MScanFit) is a novel tool which estimates MUNE values from compound muscle action potential (CMAP) scans by considering the probabilistic nature of motor unit firing. We conducted a prospective study to evaluate the diagnostic utility of MScanFit compared to quantitative electromyography (qEMG) in ALS patients.<br><br>METHODS: We enrolled 35 patients diagnosed with amyotrophic lateral sclerosis (ALS) and 14 healthy controls, assessing qEMG and MScanFit MUNE in abductor pollicis brevis, abductor digiti minimi and tibialis anterior muscles.<br><br>RESULTS: We found higher sensitivity of qEMG in detecting abnormalities compared to MScanFit, with a high concordance rate between the two techniques. Notably, a few muscles exhibited abnormal MUNE but normal qEMG findings, suggesting a potential complementary role for MScanFit in ALS diagnosis. Neurophysiological parameters from MScanFit showed good correlations with qEMG measures. Subclinical neurophysiological involvement was observed in muscles with normal strength, emphasizing the importance of sensitive diagnostic tools.<br><br>CONCLUSION: MScanFit demonstrated validity in distinguishing ALS patients from healthy subjects and correlated well with qEMG parameters.<br><br>SIGNIFICANCE: Our study confirmed the diagnostic utility of MScanFit MUNE in ALS, highlighting its role as a supplementary diagnostic tool.}, }
@article {pmid39126786, year = {2024}, author = {Neumann, M and Kothare, H and Ramanarayanan, V}, title = {Multimodal speech biomarkers for remote monitoring of ALS disease progression.}, journal = {Computers in biology and medicine}, volume = {180}, number = {}, pages = {108949}, pmid = {39126786}, issn = {1879-0534}, support = {R42 DC019877/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; *Disease Progression ; Female ; Middle Aged ; Aged ; Speech/physiology ; Biomarkers ; Adult ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that severely impacts affected persons' speech and motor functions, yet early detection and tracking of disease progression remain challenging. The current gold standard for monitoring ALS progression, the ALS functional rating scale - revised (ALSFRS-R), is based on subjective ratings of symptom severity, and may not capture subtle but clinically meaningful changes due to a lack of granularity. Multimodal speech measures which can be automatically collected from patients in a remote fashion allow us to bridge this gap because they are continuous-valued and therefore, potentially more granular at capturing disease progression. Here we investigate the responsiveness and sensitivity of multimodal speech measures in persons with ALS (pALS) collected via a remote patient monitoring platform in an effort to quantify how long it takes to detect a clinically-meaningful change associated with disease progression. We recorded audio and video from 278 participants and automatically extracted multimodal speech biomarkers (acoustic, orofacial, linguistic) from the data. We find that the timing alignment of pALS speech relative to a canonical elicitation of the same prompt and the number of words used to describe a picture are the most responsive measures at detecting such change in both pALS with bulbar (n = 36) and non-bulbar onset (n = 107). Interestingly, the responsiveness of these measures is stable even at small sample sizes. We further found that certain speech measures are sensitive enough to track bulbar decline even when there is no patient-reported clinical change, i.e. the ALSFRS-R speech score remains unchanged at 3 out of a total possible score of 4. The findings of this study have the potential to facilitate improved, accelerated and cost-effective clinical trials and care.}, }
@article {pmid39126203, year = {2024}, author = {Tabuchi, R and Momozawa, Y and Hayashi, Y and Noma, H and Ichijo, H and Fujisawa, T}, title = {SoDCoD: a comprehensive database of Cu/Zn superoxide dismutase conformational diversity caused by ALS-linked gene mutations and other perturbations.}, journal = {Database : the journal of biological databases and curation}, volume = {2024}, number = {}, pages = {0}, pmid = {39126203}, issn = {1758-0463}, support = {JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; JP21H04760 JP22H04636 JP22H04804 JP22K06610 JP23K14143//Japan Society for the Promotion of Science/ ; JP21gm5010001//Japan Agency for Medical Research and Development/ ; //SERIKA FUND/ ; 2023-ISMCRP-2033//the ISM Cooperative Research Program/ ; //the researcher exchange promotion program of ROIS (Research Organization of Information and Systems)/ ; JPMJMS2022-18//Japan Science and Technology Agency/ ; }, mesh = {*Amyotrophic Lateral Sclerosis/genetics/enzymology ; Humans ; *Mutation ; *Superoxide Dismutase-1/genetics/chemistry/metabolism ; D